2- Pain Pathways and Mechanisms

Introduction

Pain Pathways

Peripheral Pathways

Primary Afferent Fibers

Cell Bodies

Nociceptors

Distribution of Nociceptors

Dorsal Root Ganglia and Dorsal Roots

Entry to Spinal Cord—Lissauer’s Tract

Dorsal Horns of the Spinal Cord

Neurons of the Dorsal Horns

Class 1: Low-Threshold (LT) Cells

Class 2: Multireceptive Cells or Wide Dynamic Range (WDR)

Cells

Class 3: Nociceptive Specific (NS) Cells or High-Threshold

(HT) Cells

Class 4: Deep Cells

Neurochemistry of Primary Afferents

Ascending Pathways

Spinothalamic Tract

Spinomesencephalic Tract

Spinoreticular Tract

Spinolimbic Tract

Postsynaptic Dorsal Column Pathway

Supraspinal Systems Contributing to the Processing of Pain

Reticular Activating System

Thalamus

Limbic System

Cerebral Cortex

Modulation of Nociceptive Information

Descending Modulatory Systems

The Periaqueductal Gray

The Rostral Ventromedial Medulla

Locus Ceruleus, Subceruleus, and Parabrachial Area

Intrinsic Interneuron Systems in the Dorsal Horns

Mechanisms of Pain

Referred Pain and Visceral Pain Phenomena

Mechanisms and Hypotheses Explaining the Different

Phases of Pain

Phase 1: Brief, Transient Acute Pain

Phase 2: Chronic Nociceptive Pain

Peripheral Mechanisms of Sensitization

Central Sensitization

Mechanisms of Central Sensitization

The Role of Excitatory Amino Acids and Tachykinins in the

Sensitization of Dorsal Horn Neurons

Phase 3: Neuropathic Pain

Pathophysiologic Mechanisms of Neuropathic Pain

Neuropathic Pain: Peripheral Mechanisms

Neuropathic Pain: Central Mechanisms

Conclusion

Reference

Suggested Reading

INTRODUCTION

The sensation of pain is the final result of a complexand interactive series of mechanisms integrated at all lev-els of the nervous system from the periphery through thespinal cord to the higher cerebral structures. “Pain”describes a conscious, unpleasant sensory and emotionalexperience that can be induced by a wide variety of eventsto which humans can be subjected.It can be defined as theperception of an unpleasant sensation originating from anarea of the body, produced by actual or potential tissuedamage, or described in terms of such damage. However,advances in our knowledge of the physiology of pain overthe last years have lead to other relevant terminology.

The emphasis on the stimulus that activates the painpathway and its immediate consequences has been rec-ognized by the use of the word “nociception,” intro-duced by Sherrington in the early 1900s. Nociception is

1

CHAPTER Pain Pathways and MechanismsCONSTANTINE SARANTOPOULOS1

a specialized form of sensory signaling, describing thegeneration, transmission, and processing of informationassociated with the actual or potential tissue damage. Atits simplest level of organization,nociception can be con-sidered the electrical, chemical, and synaptic activity inthe sensory afferent neuron. At higher levels it includesthe motor reflex responses evoked by that stimulus, andat even higher levels it may describe the response evokedby such stimuli that are organized at the brainstem levelinto cardiovascular,hormonal,or other responses to pain.According to Sherrington, pain is a nociceptive reflexwith a psychical component. “Nociceptors” are theperipheral sensory neurons that respond selectively tonoxious stimuli, thus having the capacity to discriminatebetween painful and nonpainful sensory input.

Pain can be produced by activation of the specific noci-ceptors in the periphery, and in this case is characterizedas “nociceptive” pain. However, it may also result frominjury or alterations to sensory fibers or from disease ordamage to the central nervous system (CNS) itself. This iscalled “neuropathic” pain. A progressive unraveling of theneuroanatomical substrate and cellular mechanismsunderlying pain has been in process, and an increasingunderstanding of these mechanisms facilitates the devel-opment of novel strategies for more effective treatment.

In the 17th century, René Descartes described man asa machine: Man functioned as any other machine, differ-ing only in sensitivity and reasoning capacity. He claimedthat the nerves are connected to the sensory endingsand convey the sensations to the brain. Through a nerve,an effective stimulus makes its way to the brain and pro-duces the sensation of pain. Luigi Galvani was the first tosuggest, in the late 18th century, the electrical nature ofthe nerve conduction, and Du Bois-Reymond measuredinjury currents in nerves using a galvanometer in 1840.

In the following centuries, the foundations of modernanatomy and physiology were laid. With the discovery ofeven more detailed knowledge, we have our presentunderstanding of the science of pain. However, the viewsof Descartes have so thoroughly permeated our conceptsabout physiology and anatomy that it has been difficult toescape them. They have lead to a persistent search ofpain fibers, pathways, and pain centers in the brain. Theresult was the concept of the pain as a specific projectionsystem, which lead to ways to treat severe chronic painwith chemical, electrical, or physical “neural blockade,”utilizing a multitude of different ablative or neurosurgicallesions. We know now that these procedures frequentlyfail and the pain tends to return,even in forms worse thanthose we attempt to abolish. This is explained by thedynamic, plastic properties of the neural tissue itself,something that was not conceived by the early theorists.

Modern pain theories evolved from a number of diver-gent views, which have been argued over the last 100years.In the 1960s,Melzack and Wall1 integrated the strong

data of the specificity and pattern theories with the beliefthat the “straight-through” connection of the Cartesianmodel was contradicted by the more modern theories;they proposed the Gate Control Theory, highlighting thedynamic central nervous system mechanisms as an essen-tial component in pain processes. According to the GateControl Theory, large and small diameter nerve fibers proj-ect to the substantia gelatinosa and the central sensorytransmission neurons. Signals of pain (high-threshold sig-nals) are conveyed by small fibers.Large fibers convey low-threshold,normally nonpainful signals.Input from the largefibers results in activation of central control mechanisms,which subsequently project back and modify the gate con-trol system. This theory forced biomedical sciences toaccept the brain as an active system that filters, selects,andmodulates inputs.The dorsal horns were also accepted asactive sites at which dynamic activities (i.e.,inhibition,exci-tation,and modulation) occurred instead of merely passivetransmission stations. The cutting of nerves and pathwayswas gradually replaced by methods to modulate the input,such as physical therapy, transcutaneous electrical nervestimulation (TENS), or spinal cord stimulation (SCS).

Finally, over the last few years, there has been a sig-nificant contribution to the understanding of pain fromthe advances in the basic sciences, such as molecularbiology, electrophysiology, and basic pharmacology.Particular attention is now focused on cellular and sub-cellular aspects and signaling mediators as well as thedevelopment of more rationalized treatments for bothacute and chronic pain.

PAIN PATHWAYS

The “pathways of pain” as classically understood, con-sist of a three-neuron chain that transmits pain signalsfrom the periphery to the cerebral cortex. Starting fromthe periphery, the first order (or primary afferent) neu-ron has its cell body in the dorsal root ganglion and twoaxons. The peripheral axon projects distally to the tissueit innervates. The proximal axon extends centrally to thedorsal horn of the spinal cord. In the dorsal horn, thisaxon synapses with the second-order neuron, the axonof which crosses the spinal cord through the anteriorwhite commissure and ascends in the spinothalamictracts to the thalamus. At that site, it synapses with thethird order neuron, which projects through the internalcapsule and the corona radiata to the postcentral gyrusof the cerebral cortex, where information is somatotopi-cally organized and perceived (Fig. 1-1).

Peripheral Pathways

The spinal nerves are formed by the junction of theanterior (ventral) and posterior (dorsal) spinal roots

2 PAIN MEDICINE: THE REQUISITES IN ANESTHESIOLOGY

(see Fig. 1-1). Motor and autonomic efferent fibers exitthrough the ventral spinal roots, while input of sensoryafferent fibers is through the dorsal roots. After a lim-ited course, the spinal nerves divide into anterior andposterior primary rami. Thus, sensory and motor fibersare distributed to both primary rami. The posteriorrami innervate the posterior (dorsal) spinal and somaticmuscular and cutaneous structures (such as the mus-cles and skin of the back), while the anterior rami formthe various neural plexuses and peripheral nerves ofthe body.

The peripheral nerves are composed of axons fromsomatic and visceral (autonomic) systems, with sensory(afferent) and motor (efferent) components in each sys-tem. Somatic sensory fibers from several spinal nervesoften fuse to form peripheral nerves. However, eachspinal nerve still conveys cutaneus sensory input froma conceptually discrete area of skin. These discrete areasare called dermatomes and provide a clinically usefulsensory map of the body surface (but there is some over-lap and nonuniformity in their distribution). The cuta-neous somatic input retains a radicular organization, asdo the bone (sclerotomes) and the muscles (myotomes)afferents.

The nerve fibers are characterized by their degree ofmyelination, diameter, and velocity of electrical signalconduction. The A fibers are large, myelinated, and ofrapid conduction. The Αα subtype convey motor signalsto the muscles. The Aβ fibers convey sensory such astouch, pressure, and proprioception, and the Aγ inner-vate muscle spindles. The Aδ fibers convey signals oftouch, heat, and pain faster than the C fibers, which alsoconvey similar modalities that are non-myelinated,smaller, and slower. Aδ and C fibers are referred to assmall fibers,while the Aβ are called large fibers (Fig.1-2).The B fibers are small myelinated fibers, which conveypreganglionic sympathetic signals. Pain signals are con-veyed by a subpopulation of the small fibers.

The visceral afferents convey sensory information(including pain) from the viscera. They are pure sensoryfibers, but follow the nerves of the autonomic nervoussystem and are divided into those that accompany thesympathetic nerves and those that follow the parasympa-thetic nerves. Nociceptive information from the abdomi-nal and thoracic viscera is transmitted by sensory fibers,which follow the sympathetic pathways. The visceralafferents that accompany the sympathetic nerves tra-verse the prevertebral ganglia (e.g., the ganglia in theceliac plexus) without synapsing, reach the paravertebralsympathetic chain via the splanchnic nerves, and thenreach the segmental nerves (T1 to L2) via the white ramicommunicantes (or sometimes the grey), and finally theircell bodies in the dorsal root ganglia (Figs. 1-3 and 1-4).From there,both the somatic and the visceral informationfollow a similar course toward the cerebral cortex.

Most visceral afferents from the sigmoid colon, rectum,neck of the bladder, prostate, and cervix of the uterusaccompany the parasympathetic efferent fibers enteringthe cord in the dorsal roots of S2 to S4.The visceral affer-ents of the vagus nerve have their cell bodies in the nodoseganglion and transmit information such as bloating, disten-tion, and nausea-like sensations, but not pain, except per-haps from those innervating the hypopharynx and theupper respiratory tract. They can, however, modify theresponsiveness of the nociceptive dorsal horn neurons.

PRIMARY AFFERENT FIBERS

Any tissue noxious alterations that involve extrememechanical distortion, thermal stimulation, or changes inthe chemical milieu at the peripheral sensory terminalswill evoke the verbal report of pain in humans andefforts to escape in animals as well as more complexresponses. The circuitry that serves the transduction andencoding of this information, starts with the activation of

Pain Pathways and Mechanisms 3

Figure 1-1 Basic organization of pathways of paintransmission from the periphery to the brain. (Copyright 2004Catherine Twomey/Medical Center Graphics, Milwaukee,Wisconsin.)

Figure 1-2 Types of nerve fibers involved in sensorytransmission. (Copyright 2004 Catherine Twomey/Medical CenterGraphics, Milwaukee, Wisconsin.)

the nociceptors, the subsequent depolarization of theprimary afferent axons, the transmission of the informa-tion to the bodies of the neurons in the dorsal root gan-glia, and finally to the synapses with the dorsal horn cells(see Figs. 1-1, 1-2, and 1-3).

Cell Bodies

The cell bodies of the primary afferent somatic fibersare located in the dorsal root ganglia (DRG). The cell bod-ies of the primary afferent visceral fibers are also locatedin the DRG,but some of these visceral afferents may havecell bodies in the sympathetic ganglia or organs of origin.

Nociceptors

The primary afferent fibers encode and convey differ-ent modalities of sensation. They are classified as noci-ceptors (if they respond to high-threshold noxiousstimuli), mechanoreceptors (if they encode and conveymechanical information), thermoreceptors (responsiblefor thermal information), chemoreceptors (for chemicalinformation), and so forth.

Nociceptors belong either to the Aδ or the C type ofsensory fibers (see Fig.1-2) but not all Aδ and C fibers arenociceptive fibers. Most Aδ and C fibers have free nerveendings without any specialized structures (such as theMeissner’s and Pacinian corpuscles or the propriocep-tive endings). About 75% of the Aδ, and a variable numberof C, respond to low-threshold mechanical, chemical,


Figure 1-3 Transmission of pain signals from visceral organs via the sympathetic chain andspinal nerves. (Copyright 2004 Catherine Twomey/Medical Center Graphics, Milwaukee, Wisconsin.)

Figure 1-4 Transmission of pain signals from upper abdominalviscera. Celiac plexus. (Copyright 2004 CatherineTwomey/Medical Center Graphics, Milwaukee, Wisconsin.)

and thermal stimuli, and the remainder are pure noci-ceptors. Stimulation of the cutaneous Aδ nociceptorsleads to localized, sharp,pricking pain of fast perception,whereas stimulation of the C receptors results in burningor dull, poorly localized pain of a more delayed percep-tion. This has more to do with the signaling of tissueinflammation and the modification of the behaviortoward withdrawal, immobility, and rest. When we toucha hot object, the initial acute, sharp painful sensation(first pain sensation) is conveyed by Aδ fibers, followedby a delayed, more dull, and ongoing painful burningfeeling, transmitted via the C fibers.

With the exception of pathologic conditions, two cri-teria are necessary to define a nociceptor: The first isa response threshold higher than that of low-thresholdmechanoreceptors and thermoreceptors. For example,frankly noxious stimuli capable of causing skin damagecan activate only certain cutaneous nociceptors and beperceived as painful by humans. The second criterion isan ability to encode the intensity of nociceptive stimuliin terms of increasing firing frequency of action poten-tials. When these two criteria are considered, the noci-ceptors have the capacity to distinguish clearly betweennoxious and innocuous events in the signals they send tothe CNS.

It is very difficult to provide an absolute taxonomy ofnociceptors,but functionally they can be classified as fol-lows (although their characterization is complicated byseveral factors such as terminological inconsistencies,species differences, contrasting properties, and methodsof detection):1. High-Threshold Mechanical Nociceptors (HTM).

They are Aδ mostly, which according to otherclassification systems are classified as A-fiberMechano-Heat nociceptors Type I (type I AMH).Theyare high-threshold, rapidly conducting mechano-nociceptors, but they respond weakly to highintensity thermal stimuli. Although they have veryhigh heat thresholds, when a heat stimulus ofsufficient intensity and duration is delivered, theyare sensitized and may respond to heat. They areparticularly prevalent in the glabrous skin (but themajor part for the nociceptive innervation of theskin comes from the C polymodal receptors).

2. Myelinated Mechano-Thermal Nociceptors(MMTN). They are also Aδ fibers, which respond ina graded fashion to progressively intense stimuli.They are also classified as Type II A Mechano-HeatNociceptors (type II AMH) and are distinguished bya substantially lower threshold for activation. Theyhave a lower threshold to noxious heat and respondmore rapidly. These nociceptors are the first tosignal pain sensation.

3. C-fiber Mechano-Heat Nociceptors (CMH). Theyhave a heat threshold between 38°C and 50°C and

encode for the intensity of pain induced by noxiousheat stimuli. They typically show fatigue orhabituation as well as sensitization.

4. Pure Thermal Receptors. They respond to heatalone, showing an all or none response.

5. C Polymodal Receptors (CPN). They make up95% of the human C sensory fibers and respond to avariety of noxious stimuli: intense heat, intensemechanical force, and chemical stimuli. A significantpercentage (probably most) of these receptors aresilent or sleeping nociceptors under normalconditions; they are inactive and unresponsive anddo not participate in any sensory input ofnociception. However, inflammation or tissue injurycan cause the sensitization of these nerves fibers,after which they “awaken.”After sensitization, thesefibers can be stimulated and may easily developevoked or spontaneous discharges. This sensitizationdepends on the activation of second-messengersystems by the action of mediators such asbradykinin, prostaglandins, serotonin, and histamine.The phenomenon of primary hyperalgesia(enhanced pain and reduced threshold at the site ofthe injury) is believed to be a consequence of thesensitization of these nociceptors during theprocess of inflammation.

Distribution of NociceptorsMost of these nociceptors have been described in the

skin of primates and humans. (In the skin there is 70% Cand 10% Aδ fibers as well as 20% Aβ fibers, but the ratiocan vary.) Nociceptive input from noncutaneous tissuesis different and has distinctive characteristics.

Muscle pain seems to be C-fiber mediated. A sepa-rate nomenclature was proposed by Lloyd2 in 1943regarding the nerves supply skeletal muscles; group Iand II are thickly myelinated, fast conducting fibersthat innervate muscle spindles and tendon organs, andRuffini and Pacinian corpuscles, respectively. Group III(thinly myelinated, equivalent to Aδ fibers) and IV(unmyelinated, equivalent to C) fibers are predomi-nantly free nerve endings, which are considered to benociceptors.

Electrophysiologic and psychophysical studies havefocused on three issues relevant to muscle pain:1. The most relevant stimuli for exciting muscle

nociceptors are mechanical and chemical stimuli.2. Regardless of the type of the nociceptor excited,

only one quality of pain sensation arises from theskeletal muscles; that of deep, highly unpleasant,cramping, and poorly localized pain.

3. The duration of the muscle pain and the temporalsummation contributes to diffuse localizationassociated with the rapid expansion of the area ofthe perceived pain shortly after the pain onset.


The joints have both myelinated and nonmyelinatednociceptors, which transmit pain at the extreme rangeof motion, with any motion when sensitized by inflam-mation. Bone and teeth have both Aδ and C innervation,and the teeth have Aβ as well. The periosteum is sup-plied by a dense plexus of Aδ and C fibers and has thelowest pain threshold of all the deep tissues. The can-cellous bone is also well-supplied, but cortex and mar-row have little nociceptive supply.

Cerebral blood vessels are surrounded by a denseplexus of sensory nerves, and this network constitutesa homogeneous population of C polymodal receptors.

Although less well-characterized than nociceptors inthe skin, there is evidence for the existence of polymodalC and Aδ fibers in internal organs, such as the heart andthe gut. As mentioned before, nociceptive informationfrom the viscera of the thorax (heart, lower esophagus)and upper abdomen (stomach, biliary tract, upper gut,pancreas) reaches the dorsal horns of the spinal cord viasensory fibers that travel with the splanchnic nerves andpass through the sympathetic chains (with the excep-tion of the upper respiratory tract). Nociceptive infor-mation from the lower gut and bladder reaches the cordvia sensory fibers that accompany the sacral parasympa-thetic nerves.There is also a small possibility that bothsympathetic and vagal afferents may contribute to car-diac pain, although stimulation of the vagal afferentsdoesn’t result in conscious painful sensation. In the vis-ceral nerves, the ratio of Aδ to C fibers is 1 to 10. Only10% of the dorsal horn fibers are visceral afferents, but75% of the dorsal horn cells receive input of visceral sen-sory information. The density of visceral afferents is gen-erally low compared to the skin, and the visceralnociceptive units have large, weakly defined, and multi-ple receptive fields. These factors contribute to the poorlocalization of the visceral pain, and explain why spatialsummation is needed in order to elicit pain.

Proprioceptive information from the face andoropharynx are conveyed through primary afferents ofthe trigeminal nerve to cell bodies in the trigeminal mes-encephalic nucleus (a unique example of peripheral sen-sory nerves with cell bodies inside the central nervoussystem). Other primary afferents have cell bodies in thegasserian ganglion, like the DRG afferents, with projec-tions through the sensory trigeminal root to the brainstem, terminating in the main sensory nucleus and spinaltrigeminal nucleus. The spinal nucleus, in particular,receives the input of nociceptive information from thetrigeminal system.

Dorsal Root Ganglia and Dorsal Roots

Between 60% and 70% of DRG cell bodies are con-nected to small diameter Aδ or C fibers. The number offibers projecting centrally exceeds the number of gan-

glion cell bodies by 43%. According to the classical views,primary afferents pass into the spinal cord through thedorsal roots. As the dorsal roots approach, the spinal corddivides into many rootlets (12 to 15) and follows a differ-ential distribution pattern (Fig. 1-5). Close to the dorsalroot entry zone, the small nociceptive fibers (Aδ and C)migrate to the lateral side, while the large fibers (Aβ) arepositioned more medially.Because small pain fibers movelaterally before entering the spinal cord, a selective pos-terior rhizotomy has been developed in the past, attempt-ing to ablate the lateral dorsal rootlets while sparing themore medially located large fibers. However, it has a highrate of failure. This is explained by the accumulating evi-dence of the presence of pain fibers in the ventral roots,and the possibility that some primary afferents may passinto the cord from ventral roots as well.

Entry to Spinal Cord—Lissauer’s Tract

Upon entering the spinal cord, the central processesof the primary afferents are distributed in three ways:1. At the entrance to the spinal cord, the afferents may

send a main branch directly to the dorsal horn of thesegment of entry, or may send branching collateralfibers rostrally and caudally up to several segmentsbeyond the segment of entry. Then, upon the finalpenetration of the collaterals into the dorsal hornparenchyma, the terminal fields also ramify rostrallyand caudally for several segments.

2. The route of these ascending and descendingcollaterals, as far as the large fibers are concerned, islocated in the dorsal (posterior) columns of thespinal cord, which are located more medially (seeFig. 1-5). However, the small fibers enter the spinalcord from the most lateral divisions of the dorsalroots, and their branching collaterals ascend ordescend in sites lateral to the dorsal columns. Thus,


Figure 1-5 Structure of dorsal roots at the level of entry tothe dorsal horns of the spinal cord. (Copyright 2004 CatherineTwomey/Medical Center Graphics, Milwaukee, Wisconsin.)

they contribute to the formation of the Lissauer’stract, which also includes small fibers originatingfrom cells of the substantia gelatinosa in the dorsalhorns (which also provide ascending or descendingfibers by one or two segments) (Fig. 1-6).

3. The primary afferent endings are finally distributedand synapse in the dorsal horns of the spinal cord,but this distribution is determined from the fiber size(small or large) and type (visceral or somatic). Thesmall fibers end in the more superficial laminae of thedorsal horns (marginal layer and substantiagelatinosa), while the large fibers end deeper in thenucleus proprius (Fig.1-7). However,this organizationcan change dynamically under conditions of injury ofthe peripheral nerve.

DORSAL HORNS OF THE SPINAL CORD

The central pathways that further process nocicep-tive information begin at the level of the spinal cord dor-sal horns. Interneuronal networks in the dorsal horn areresponsible not only for transmission of the nociceptiveinformation to neurons that project to the brain, but alsomodulate that information and pass it on to other spinalcord neurons, including flexor motoneurons and noci-ceptive projection neurons. Certain processes lead toenhanced reflex actions, sensitization of projection neu-rons, and increased nociceptive transmission. Otherinputs result in inhibition of the synaptic transmissionand projection neurons.

The spinal grey matter can be best viewed as a systemof layers or zones that are continuous in all segments. In1952, Rexed3 described that at any level the spinal cordis organized into several laminae, which are continuousand homologous from the sacral up to the cervical lev-

els. He divided the spinal cord into 10 laminae, based ontype, density, and myelinization of the cells.

Lamina I or the marginal layer is a thin band “cap-ping” the grey matter (see Fig. 1-7). In lamina I, differenttypes of cells can be found. Populations of these neu-rons respond to intense cutaneous and visceral stimula-tion. Most of these cells project to the brain viacontralateral ascending tracts. Lamina II is also calledsubstantia gelatinosa (SG), and is subdivided into anouter (IIo) and an inner part (IIi). It contains a large,densely packed concentration of small neurons and hasan absence of myelinated axons. Substantia gelatinosa isa key station for integration and modulation of the noci-ceptive information. A significant proportion of the SGneurons receive input from Aδ and C fibers and areexcited by thermal or mechanical stimulation, but manyof the SG cells are interneurons, projecting to other SGneurons (see Fig. 1-7). In many ways, Lamina III is con-sidered a transition between II and IV, but sometimes isincluded, together with the laminae IV and V, into thenucleus proprius. Cells in the nucleus proprius may beclassified as those that respond almost uniquely toinnocuous, low-threshold (Aβ) input, and those thatrespond to Aβ, Αδ, and C input. Lamina X surrounds thecentral canal, and some of its cells can convey nocicep-tive information (see Fig. 1-7).

As mentioned above, the distribution of the primaryafferents into the dorsal horns of the spinal corddepends on their size and function. The large myeli-nated fibers enter into the dorsal columns. After havingsent branches to the dorsal horn at the segment ofentry or collaterals to nearby segments, they terminateat synapses in the nuclei gracilis and cuneatus (in thehigher spinal segments). Collateral branches from thelarge fibers synapse mainly to the nucleus proprius(laminae III, IV, and V). Some fibers synapse into the


Figure 1-6 The tract of Lissauer and dorsal columns.(Copyright 2004 Catherine Twomey/Medical Center Graphics,Milwaukee, Wisconsin.)

Figure 1-7 Differential distribution of large and small afferentfibers into the laminae of the dorsal horns. (Copyright 2004Catherine Twomey/Medical Center Graphics, Milwaukee,Wisconsin.)

motor neurons of the ventral horns, where they feedmonosynaptic reflexes (see Figs. 1-6 and 1-7). TheC fibers end in the lamina I, and mainly in the SG (par-ticularly in the IIo) (see Figs. 1-6 and 1-7).They also endin laminae V and X (central canal).The Aδ fibers sharecommon features of both the large Aβ and the C fibers,regarding their pattern of termination. Some (especiallythe non-nociceptive fibers) pass medially and enter intolaminae III and IV, while others pass directly to I, IIo, V,and X. Visceral afferents synapse with cells in laminae Iand V, where somatic afferents also terminate; thesecells are called viscerosomatic dorsal horn neurons.This dual innervation is known as convergence, andmay be a mechanism of the phenomenon of thereferred pain.

Neurons of the Dorsal Horns

Primary afferents relay sensory information to differ-ent populations of neurons upon entering the spinalcord. These neurons can be classified by different sys-tems. In the simplest formulation, there are three cate-gories of dorsal horn neurons:1. Projection neurons, which send axons out of the

spinal cord, to terminate in supraspinal centers. Theyare responsible for the rostral transmission of sensoryinformation.

2. Propriospinal neurons, which send axons thatextend over several spinal segments. They participatein hetero-segmental reflexes and interactions amongstimuli administered to separate loci.

3. Interneurons, with axons terminating in the vicinityof the parent cell body. They are small cells, whichserve as relays,and participate in local processing andintegration of information. They can be eitherexcitatory or inhibitory. These interneurons are moreprevalent in the substantia gelatinosa (SG), which isa very important station of processing and control ofthe nociceptive information. These interneuronsproject to other neurons, form a network, and thencan modify the activity of other neurons, not only inthe II lamina, but in the marginal layer and thenucleus proprius as well. The outer IIo SG cellsreceive mostly high-threshold mechanical andthermal input of nociceptive nature from the smallfibers, while the inner IIi SG cells receive low-threshold mechanical information. Descendinginhibitory axons from higher centers in the brain alsoend up in IIo. The cells that receive the nociceptiveinput from the small fibers are inhibited by the low-threshold input from the large fibers, and vice versa.Thus, many lamina II cells can increase or decreasethe firing threshold of other cells.

In many cases the response of these cells depends onthe function of the afferent input (low-threshold versus

high-threshold afferent input). In other situations, thenet response of the cell is determined by the complexexcitatory/inhibitory milieu in which the cell is sub-jected in the dorsal horn, and complex activity patternsmay arise.

The following functional classification can be pro-posed according to an activity-dependent categorization:

Class 1: Low-Threshold (LT) Cells These are neurons that respond selectively to non-

nociceptive signaling. They are most prevalent in laminaIV, and the majority of their input is conveyed by largemyelinated Aβ fibers. They respond maximally to lighttouch, pressure, hair movement, and/or vibration.Stimulation of their receptive fields within the noxiousrange produces no increase in firing frequency.

Class 2: Multireceptive Cells or Wide DynamicRange (WDR) Cells Their name implies the fact that their dynamic

response is determined by the intensity of the incom-ing stimulus. The intensity of the stimulation from theperiphery is thus encoded by this response. The WDRcells receive both low-threshold (non-nociceptive)and high-threshold (nociceptive) input via the conver-gence of afferent input from both large diametermyelinated Aβ, and small diameter lightly myelinatedAδ and unmyelinated C fibers. Their output differen-tially encodes for the intensity of the stimulus. Theyrespond to both non-nociceptive and nociceptiveinformation by changing their firing frequency (theyfire at a higher frequency as afferent stimulus intensityincreases, over a range from the innocuous to noxiouslevels). The highest concentrations of WDR cells arecentered around lamina V, with smaller populations inlaminae I and X. Other properties of these cellsinclude:● Large receptive fields. These fields have centers

responding to a range of both noxious and innocuousstimulation, and a less sensitive surrounding area acti-vated only by noxious stimulation. There is an evenlarger surrounding inhibitory peripheral field. Theexcitatory fields enlarge, and the inhibitory disappearin the spinalized state.

● Low frequency (>0.33 Hz). Repetitive stimulationincoming from C fibers only (but not from A) pro-duces a gradual increase in their firing frequency,until the WDR neuron reaches a state of virtually con-tinuous discharge. This is known as the wind-up phe-nomenon.

● Convergence. The same WDR cell can be excited bycutaneous or deep (muscle, joint,viscera) input,provid-ing a substrate of musculo-somatic or viscero-somaticconvergence, which explains the phenomenon of thereferred pain.


Class 3: Nociceptive Specific (NS) Cells or High-Threshold (HT) Cells They respond exclusively to stimuli within the nox-

ious range. Class 3A cells are principally excited by Aδnociceptors and respond almost exclusively to noxiousmechanical stimulation. Class 3B cells that receive inputfrom both Aδ and C fibers respond to both noxious heatand noxious mechanical input. Both are more concen-trated in lamina I, with lower numbers in laminae V andX. They have small receptive fields (but larger than thoseof the primary afferents) and many have convergentfields from muscle and skin. NS cells produce activitygraded in proportion to the stimulus intensity, and theyalso code for both stimulus location and magnitude.

Class 4: Deep CellsDeep cells respond maximally to stimulation of sub-

cutaneous structure, such as muscles or joints, and oftenthey have convergent cutaneous or visceral input.

Neurochemistry of Primary Afferents

Nociceptive primary afferents synthesize a diversityof substances potentially involved in the synaptic trans-mission and modulation of the nociceptive information.These include the glutamate and other excitatory aminoacids (EAA), neuropeptides, such as the tachykininsubstance P (sP) and calcitonin gene related peptide(CGRP), adenosine triphosphate (ATP), nitric oxide(NO), prostaglandins (PG), and neurotrophins (growthfactors). These potential transmitters, a variety of otherneuropeptides, various enzymes, and several other mole-cules display a complex pattern of colocalization,comodulation, and corelease in primary afferent fibers.Actually, each specific, functional type of primary affer-ents possesses a characteristic complement of markers,but this has yet to be fully demonstrated by research. Inany case, the neurochemical composition of the primaryafferents varies qualitatively and quantitatively as a func-tion of several factors, and differences are apparentamongst various tissues, between normal state versusperipheral tissue inflammation or nerve injury, andamongst various fiber classes.The neurochemical charac-terization of specific classes of primary afferents is far fromcomplete and remains the topic of intensive research.

A substantial population of the small fibers is sensitiveto capsaicin, which is an ingredient of the hot peppers.A subpopulation of the capsaicin-sensitive neurons con-tains neurotransmitter such as the sP and CGRP, whilea second contains the lectin IB-4. Substance P (sP) ismore prominent in C fibers originating from the musclesand deep tissues, than in C fibers innervating the skin.Cutaneous Aδ fibers contain little or no sP, while theirmajor transmitters are excitatory amino acids (e.g., glu-tamate, aspartate). Excitatory amino acids, tachykinins

(sP), and CGRP are colocalized in a subset of capsaicin-sensitive, small nociceptive C fibers. The tachykinins(e.g., sP and neurokinin A) act at the neurokinin NK1 andNK2 receptors, respectively, while CGRP at (at least) tworeceptors in the dorsal horn cells.

Excitatory amino acids,such as glutamate,also act at spe-cific membrane receptors. These include the metabotropicreceptors (coupled via G proteins to second messengers),and inotropic receptors (coupled directly to cation chan-nels that allow the influx of calcium and sodium). Themajor types of inotropic receptors are the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainateand N-methyl-D-glutamine (NMDA) receptors. The abovereceptors show a complex pattern of localization on vari-ous postsynaptic neurons in the dorsal horns as well aspresynaptically on the primary afferents.Activation by EAAsof AMPA receptors is the principal mechanism involved inthe input from Aβ fibers to the dorsal horn cells.

EAA acting at the AMPA receptors also mediate thedirect monosynaptic response from the acute simplenociceptive input, while EAAs, tachykinins (sP), and pos-sibly CGRP all cooperatively and synergistically elicitpostsynaptic responses from repetitive or persistentnoxious stimulation, leading to temporal summation andamplification of responses in the dorsal horn cells.Release of the transmitters is reduced by the presynapticaction of agents known to be analgesics, such as opioidsand α2-agonists (clonidine). The same agents acting post-synaptically may reduce the excitability of the dorsalhorn neurons. The inhibitory amino acid γ-aminobutyricacid (GABA) also may have a similar action by inhibitingthe primary afferent depolarization. Glycine hasinhibitory, mainly postsynaptic hyperpolarizing actions.

ASCENDING PATHWAYS

Second-order neurons, or projection neurons in thespinal cord transmit information of pain via axons thatcross the midline and ascend to a number of regions ofthe brainstem and diencephalon, including the thalamus,periaqueductal gray (PAG), parabrachial region, and bul-bar reticular formation as well as to the limbic structuresin the hypothalamus, amygdaloid nucleus, and othersites. Depending on the site of projection, they are beingclassified as spinothalamic, spinomesencephalic, spin-oreticular, and so forth. These are shown schematicallyin Figure 1-8. The existence of a visceral nociceptivepathway in the dorsal columns involving the postsynap-tic dorsal column pathway has also been demonstrated.

Spinothalamic Tract

The anterolateral quadrant of the spinal cord containsthe most important pathway for ascending nociceptive


fibers. These range from the spinal cord to the thalamus,thus forming the spinothalamic tract (Fig. 1-8). Most ofthe cells project to the contralateral thalamus, althougha small fraction ascends and projects ipsilaterally. Theaxons most often decussate through the ventral whitecommissure at a very short distance from the cell body,enter the ventral funiculus, and then shift into the lateralfuniculus as they ascend. Spinothalamic axons arearranged somatotopically; at cervical levels, those repre-senting the lower extremity and caudal body are placedmore laterally, and those representing the upper extrem-ity and rostral body more anteromedially. The spinothal-

amic tract in humans mediates the sensations of pain,cold, warmth, and touch.

Two parts of the spinothalamic tract are discerned.One part, phylogenetically newer, projects from laminae Iand V to the contralateral lateral thalamus and is known asneospinothalamic tract. Neospinothalamic tract cellsthat project to the lateral thalamus have receptive fieldson a restricted area of the skin, thus are well-suited tofunction in signaling the sensory-discriminative aspects ofpain. These aspects include the detailed perception anddetection of noxious stimuli, and their characteristics interms of quality, intensity, location, duration, and temporalpattern. The other part, phylogenetically older, projectsfrom deeper laminae to the contralateral medial thalamus,and is known as the paleospinothalamic tract. The cellsof origin of the paleospinothalamic tract have very largereceptive fields, often encompassing the entire surface ofthe body and face. Some cells receive input from both theskin and the viscera. The large receptive fields suggesta role in the motivational-affective aspects of pain. Theseaspects include the relationship between pain and moodor emotions rather than sensory discrimination, the atten-tion to pain and memory of pain, the capacity to modifythe behavior as a result of the pain, and the capacity tocope with and tolerate pain and its rationalization.

The neospinothalamic tract is part of the neospinothal-amic (or lateral) system, which rapidly conveys informa-tion of more detailed and discriminative nature. Thepaleospinothalamic tract is part of the paleospinothalamic(or medial) system, which slowly conveys tonic informa-tion.The paleospinothalamic system sends connections tothe reticular activating system, the limbic system, the PAG,and the hypothalamus. Through these connections,evoked responses alter the motivational drive, theendocrine function, the respiratory, and the cardiovascu-lar function.

Different response patterns in the dorsal horn cellsmay reflect the differing roles in the processing and expe-rience of pain. WDR cells and/or cells with smaller recep-tive fields may encode the intensity and location ofcutaneous, noxious stimuli, providing significant input toneospinothalamic tract. In contrast, nociceptive specificcells of superficial laminae project via the paleospinothal-amic tract to medial thalamus nuclei, concerned with theemotional–behavioral aspects of pain.

Nevertheless, the spinothalamic tract cells have notonly excitatory but also inhibitory receptive fields.Inhibition can occur when stimuli are applied contralat-erally, or to dermatomes remote from those of the excita-tory receptive field, but spinothalamic tract cells can alsobe inhibited effectively by repetitive electrical stimula-tion of the peripheral nerves. The best inhibition is pro-duced by stimulation of a peripheral nerve in the samelimb as the excitatory receptive field,but some inhibitionoccurs when nerves in other limbs are stimulated.


Figure 1-8 Second-order sensory neurons projecting fromdorsal horns to higher CNS structures. Spinothalamic tractsproject to the thalamic nuclei, while spinomesencephalic ones tomesencephalon, mediating different functions. (Copyright 2004Catherine Twomey/Medical Center Graphics, Milwaukee,Wisconsin.)

Several other pathways accompany the spinothalamictract in the white matter of the anterolateral quadrant ofthe spinal cord.

Spinomesencephalic Tract

The spinomesencephalic tract includes several pro-jection systems that terminate in different areas of themidbrain (see Fig. 1-8). The cells of origin are located inlaminae I and IV-VI (mostly V), and project to midbrainnuclei, such as the PAG and the cuneiform nucleus.Spinomesencephalic neurons have complex receptivefields on widely separated areas of the body,and respondbest to noxious stimuli, but also to innocuous stimuli.There is a rough somatotopic organization. Differentcomponents of this tract have different functions:1. Projections to the PAG contribute to aversive

behavior and activate the descending analgesiasystem that arises from the PAG.

2. The projections to the cuneiform nucleus access themidbrain locomotor center and the ascendingreticular activating system.

3. Projections to other nuclei may also be related withproduction of analgesia.

Spinoreticular Tract

Many of the cells of origin of the spinoreticular tractare located in the deep layers of the dorsal horn and inlaminae VII and VIII of the ventral horns. The spinoretic-ular tract projects, without somatotopic organization, toseveral nuclei in the caudal medulla. More rostral projec-tions go to the lateral reticular nucleus, the nucleusgigantocellularis, and the paragigantocellularis dorsalisand lateralis. Another major termination in the brainstemis in the parabrachial region. Functions of the spinoretic-ular tract are to signal homeostatic changes to autonomiccenters in the brainstem, activate endogenous analgesiasystems, and relay information that triggers motivational-affective responses.

Spinolimbic Tract

This is a multisynaptic pathway that carries informa-tion to the medial thalamus, from which it is relayed tothe limbic system. A possible anatomic substrate for thispathway is the spinoreticular tract, but direct spinohy-pothalamic and spino-amygdalar pathways have beendescribed. This tract is a major bilateral projection, rele-vant to the motivational and emotional aspects of pain.

Postsynaptic Dorsal Column Pathway

Classical view holds that the dorsal column pathwaysconvey graphesthesia, two-point discrimination, and

position sense. However, evidence has implied an addi-tional functional role of the dorsal columns in the relayof visceral pain from the pelvis in humans. Visceral noci-ceptive signals from pelvic organs (including the uterusand vagina), as well as from the sacrum and perineum, isrelayed via this tract to the thalamus.This pathway canbe ablated via a limited midline myelotomy, in order torelieve intractable pelvic pain in patients with cancer.

SUPRASPINAL SYSTEMSCONTRIBUTING TO THE PROCESSINGOF PAIN

Reticular Activating System

The reticular activating system has connections withthe thalamus, hypothalamus, cortex, and PAG, and noci-ception is among its most effective inputs. The extensiveinterconnections of the reticular activating system withother supraspinal sites may also explain the multipleinfluences on suffering from pain.

Thalamus

The thalamus relays signals from the ascending affer-ents to the cortex (see Fig. 1-8), contributing to theawareness of the pain. Two parts can be identified:1. The neothalamus (lateral thalamus) is located

laterally and ventrobasally, is highly organized ona somatotopic basis, receives input from theneospinothalamic tract, and sends projections tothe sensory SI cortex for localization and dis-crimination of pain. The neothalamus includes theventroposterolateral nucleus (VPL) and theventroposteromedial nucleus (VPM). In both nuclei,a small number of cells are nociceptive specific, anda slightly larger number are WDR cells. Theproportion of thalamic neurons relevant to noci-ception compared with neurons activated only byinnocuous stimuli is low (about 10%). Thenociceptive neurons of the VPL have restrictedreceptive fields on the contralateral side, and most(85%) respond to both cutaneous and visceralstimuli; although the cutaneous input is soma-totopic, the visceral input is not viscerotropic.

2. The paleothalamus (medial thalamus) includes themedial and intralaminar nuclei, is not somatotopicallyorganized, and projects diffusely to a wide area of thecortex. Several of its neurons are nociceptive,responding as nociceptive specific (NS) or WDR, withlarge, usually bilateral receptive fields. This suggeststhat they do not contribute to sensory discrimination,but play a role in motivational-affective behavior, andpossibly in memory processing.


Limbic System

Pain is quite often accompanied by affective-motiva-tional responses,which are important to behavior. Theseare mediated via the limbic system. A variety of lesionsto parts of the limbic system have been shown to psy-chophysically dissociate the reported stimulus intensityfrom its affective component.

The hypothalamus (part of the limbic system) incor-porates nociceptive information, which may influencethe integration of homeostasis via the autonomic nervoussystem and neuroendocrine response.

CEREBRAL CORTEX

Evidence favors the participation of both the cortexand the thalamus, not only in the sensory-discriminativeaspects of pain, but also in the motivational-affectiveaspects. Although old views attributed little impor-tance to the cortex in the appreciation of pain,responses have now recorded from nociceptive corti-cal neurons, and evidence from imaging studies revealsthat the human cerebral cortex participates in noci-ception. Cortical areas most prominently involvedinclude the somatosensory SI and SII cortex, the ante-rior insula, and the anterior cingulate gyrus. The pri-mary somatosensory cortex (SI) has been viewed asthe first level of conscious pain perception, treatingthe incoming information about pain as any othernovel stimulus. Processes in SI are very dynamic acrossall somatosensory modalities and provide input formotor control and performance. However, it seemslikely that the SI is not “the pain center” because it isthe interaction of SI with the other pain-related areas(cortical and subcortical), rather than the activity ofthe SI itself, that results in the experience of the pain.So, destruction of the SI leads to altered pain percep-tion but not to abolition of pain. Also, because of theneuroplasticity dynamics, properties of the SI nocicep-tive neurons are altered in subjects with chronic painwhen compared to pain responses of SI neurons insubjects without chronic pain.

MODULATION OF NOCICEPTIVEINFORMATION

The anatomic tracts through which afferent informa-tion evoked by high-threshold (noxious) informationtravels, are traditionally known as the “pain pathways.”In fact this schematic definition vastly oversimplifiesand distorts the true organization.At every synapse, thetransmission through the dorsal horn and brain stem is

not “straight-through,” but is subjected to significantmodulation. In some instances, the modulation dimin-ishes the pain message, but in others actively facilitatesthe transmission and amplifies the message of pain. Inregards to the attenuation of the incoming nociceptivemessages, it is well-known that the activation of opioidreceptor, α2 adrenoreceptors, serotonin receptors, adeno-sine receptors, muscarinic, GABA, and other receptors,is implicated.

The activation of afferent nociceptive input results inthe subsequent activation of a number of circuits in thespinal cord and supraspinal levels. These include someinteractive systems of neurons that serve to alter theafferent message, thus changing the sensory perceptionof the stimulus. Inhibitory modulation exists at severallevels, including the level of the dorsal horns (Fig. 1-9),but there are two primary endogenous sources of thesemodulatory systems that can attenuate pain: (1) thedescending bulbospinal pathways (serotoninergic ornoradrenergic), and (2) the intrinsic interneurons in thedorsal horns (enkephalinergic and GABA-ergic or glycin-ergic). Both monoamines and endorphins are released inthe dorsal horns by high-intensity nociceptive input.Spinal transection inhibits this effect indicating that therelease is dependent on a spino-bulbo-spinal negativefeedback loop.

Descending Modulatory Systems

Melzack and Wall first clearly proposed in 1962that descending systems from supraspinal sourcescould modulate nociception (see Fig. 1-9).According tothe Gate Control Theory, large and small diameternerve fibers project to the substantia gelatinosa andthe central sensory transmission neurons and can


Figure 1-9 Mechanisms predicted by the Gate Control Theory.(Copyright 2004 Catherine Twomey/Medical Center Graphics,Milwaukee, Wisconsin.)

differentially modulate the further transmission ofpain. Signals of pain are conveyed by small fibers. Largefibers convey low-threshold, normally nonpainful sig-nals, which can inhibit the input from small fibers.Input from the large fibers results in activation of cen-tral control mechanisms, which subsequently projectback and modify the gate control system. In 1969,Reynolds4 performed abdominal surgery on rats, with-out chemical anesthesia, during stimulation of theregion of the midbrain PAG. Since then, numerousinvestigations have been made of what became knownas the descending analgesia systems (Fig. 1-10).Thesepathways utilize several neurotransmitters, includingendogenous opioids, serotonin, and/or catecholamines.The anatomic structures of the brainstem that give riseto them include the PAG, the locus ceruleus, sub-ceruleus, and Kölliker-Fuse nuclei, the nucleus raphemagnus (NRM), and several nuclei of the reticular for-mation. In addition, higher structures including thecerebral cortex, and various limbic structures includ-ing the hypothalamus, contribute to the analgesia path-ways. Conditions of “stress” can produce opioid andnon-opioid mediated analgesia; this can be a learnedresponse, triggered also in the absence of nociception.The descending analgesia systems descend in the dor-solateral funiculus, with fibers that project to neuronsin laminae I, IIo, IV, and V and have the following gen-eral properties:1. They act presynaptically and reduce the release of

neurotransmitters from the primary afferentnociceptive terminals (Aδ and C, but not from Aβfibers).

2. They inhibit the response of the dorsal horn cellsboth directly, and indirectly (via the inhibition ofexcitatory interneurons and the activation ofinhibitory interneurons), and these postsynapticactions are probably of greater importance.

3. They preferentially inhibit the excitation of WDRcells by noxious, as compared to innocuous stimuli.

4. Monoamines are considered to be the majorneurotransmitters released from these descendingpathways, although several other transmitters maybe colocalized and coreleased (e.g., acetylcholine,GABA, enkephalin).

5. Both endogenous opioid and nonopioid local spinalcord systems may mediate the inhibition of theresponse of the dorsal horn cells.

Descending pathways, however, do not exclusivelyexert inhibitory actions in the dorsal horns, butdescending facilitatory pathways do exist. Many cere-bral regions, including the cortex, may be the origin ofexcitatory projections to the dorsal horns. In addition,individual transmitters may exert multiple actions in thedorsal horns, depending on the type of neuron they tar-get (inhibitory versus excitatory). There is now evi-dence that descending facilitatory systems can exciteboth the terminals of nociceptive primary afferents aswell as intrinsic dorsal horn neurons. Experiments inprimates showed that dorsal horn WDR cells, projectingto the thalamus, can be excited without any primaryafferent input, just as a response to a conditioned stim-ulus previously connected with pain.

The Periaqueductal Gray

The PAG has been implicated in complex behavioralresponses to stressful or to life-threatening situations.These responses tend to promote recuperative behaviorafter a defense reaction. These behaviors are mediated byactivation of complex ascending and descending projec-tions.PAG produces mixed aversive and analgesic effects.However, the effectiveness of the PAG to suppress bothspinally and supraspinally organized responses to nox-ious stimuli is thought to result in large part from the inhi-bition of nociceptive transmission at the level of thespinal cord dorsal horns. The PAG receives direct soma-totopic spinomesencephalic input deriving from laminaeI and IV-VI contralaterally. Although some PAG neuronsproject directly to the spinal cord, most of the connec-tions between the PAG and the spinal cord are indirect.PAG neurons project to: (1) the nucleus raphe magnus(NRM) and the adjacent reticular formation, located inthe rostral ventromedial medulla, and (2) to locusceruleus, and other nuclei in the parabrachial area (dor-solateral pons). Stimulation of the PAG causes inhibitionof nociceptive dorsal horn neurons, including spinothala-mic tract cells (see Fig. 1-10).This inhibition is produced


Figure 1-10 Descending systems that modulate thetransmission of pain. (Copyright 2004 Catherine Twomey/MedicalCenter Graphics, Milwaukee, Wisconsin.)

via 5-HT3 and 5-HT1A receptors, α2 adrenoreceptors (nor-epinephrine and α2-agonists applied directly to the spinalcord produce analgesia), GABAA, and glycine receptors.The actions on the serotonin receptors are mediated byrelease of serotonin (5-HT) from axons projecting fromthe nucleus raphe magnus,and those on adrenoreceptorsare mediated by norepinephrine, released from noradren-ergic axons projecting from the locus ceruleus. GABAand glycine perhaps are released by inhibitory interneu-rons in the dorsal horns, or by other long descendingaxons from the medulla.

The PAG is also an important substrate for opioid anal-gesia, with a dense concentration of opioid peptides andreceptors. Microinjection of opioids into the PAG pro-duces a dose dependent, μ-mediated, naloxone reversibleantinociception. (This is thought to be mediated by anindirect mechanism, by directly inhibiting the activity ofGABA-ergic inhibitory interneurons.)

The Rostral Ventromedial Medulla

The descending inhibition resulting from activation ofthe PAG neurons is largely mediated through a relay inthe rostral ventromedial medulla (RVM). RVM plays a sig-nificant role in the nociceptive modulation, in whichserotoninergic mechanisms are clearly important, yetinsufficiently understood. RVM is also an important sub-strate for opioid antinociception, and it is believed tocontribute to the antinociceptive action of systemicallyadministered opioids. These seem to act via a complexmechanism including both direct and indirect, excita-tory and inhibitory actions on neurons that project andmodulate the spinal nociceptive transmission (“on” and“off” cells).

The exact action of the analgesia from systemicallyadministered opioids most likely reflects their ability tosimultaneously activate elements of an interconnectedopioidergic network whose elements span the whole neu-raxis, from the forebrain to the spinal cord (see Fig. 1-10).The PAG-RVM axis appears to be linked with opioid-sensi-tive sites in the forebrain, including the amygdala and thenucleus accumbens, which form a part of an opioiddependent mesolimbic loop. In addition, the interactionof the axis with the spinal sites seems to be of synergisticnature (concurrent spinal and supraspinal administrationleads to prominent synergy).

Locus Ceruleus, Subceruleus, andParabrachial Area

Noradrenergic projections to all regions of the spinalcord arise from these areas, which are known as the dor-solateral pontine catecholamine cell groups A5, A6, andA7. Their stimulation produces inhibition of nociceptiveneurons in the deep dorsal horns. Noradrenergic termi-

nals have been shown to make direct contact with dor-sal horn neurons, including spinothalamic cells. The anal-gesic effect is mediated by α2-adrenoceptors.

Intrinsic Interneuron Systems in theDorsal Horns

These intrinsic interneurons play an integrative rolewithin the cord in facilitating communication betweenvarious segments and various cells. In addition, they playa critical role in processing nociceptive afferent input,participate in excitatory circuits implicated in dorsalhorn processes of neuronal sensitization and referredpain, and also in mediating the actions of the descendinganalgesia systems.

Spinothalamic neurons may be directly activated byprimary afferents, but also indirectly via excitatoryinterneurons (particularly cells in deeper laminae, whichare activated by C fibers via intervening interneurons inIIo). Excitatory amino acids may be the primary trans-mitters.

Inhibitory interneurons, by contrast, limit the flowof nociceptive input. Most inhibitory interneuronsreduce nociception by directly targeting nociceptivespecific or WDR cells and/or presynaptic primary affer-ent terminals.

The descending axons of the serotoninergic and nora-drenergic neurons may contact the dendrites of thespinothalamic tract neurons (this is the case particularlyregarding the noradrenergic axons), but they may alsocontact local inhibitory (enkephalinergic, glycinergic, orGABA-ergic) interneurons in the superficial dorsal horn.They may also exert presynaptic influences to the pri-mary afferent endings. Thus, the descending inhibitionof the nociceptive input is likely to be mediated in partby the activation of these interneurons in the dorsalhorns. A population of these interneurons releaseendogenous opioids (i.e., enkephalin, dynorphin). Theopioids (endogenous or exogenous) reduce the nocicep-tive transmission in the dorsal horns by a combination ofpresynaptic (on the primary afferents) and postsynaptic(on the dorsal horn cells) actions. They reduce the pri-mary afferent action potential duration and transmitterrelease via decreasing the calcium channel conductance,and hyperpolarize the dorsal horn neurons by enhancingthe potassium channel conductance. Other interneuronsrelease GABA or glycine, likewise altering the release oftransmitters or the postsynaptic excitability. GABAAreceptor mediated inhibition occurs through largelypostsynaptic mechanisms, while GABAB mechanismspreferentially suppress presynaptic transmitter release.Although baclofen, a GABAB agonist, has antinociceptiveaction in vitro, it is of limited use in chronic pain becauseof the increased excitability of the postsynaptic dorsalhorn neuron disproportionately to the amount of the


transmitter released. GABA-ergic and glycinergicinterneurons have a high level of tonic or evoked activ-ity, and loss of their function results into a spinal pro-cessing system in which low-threshold afferent input ishandled as if noxious. Cholinergic inhibitory interneu-rons have been described, which act via multiple mus-carinic and probably nicotinic receptors localized onprimary afferent terminals and dorsal horn neurons.Intrathecal administration of muscarinergic substances,such as neostigmine, produces analgesia.

Nociceptive neurons can be inhibited also by activa-tion of the large, primary afferent fibers, or their collat-erals in the dorsal columns. Such activation initiates localspinal circuits of interneurons in the substantia gelati-nosa, which subsequently produce presynaptic inhibi-tion of the C fibers in the same segments. Release ofinhibitory transmitters, such as the GABA, from theinterneurons is implicated. Natural activation of largemyelinated fibers by vibratory stimuli and electrical stim-ulation of the dorsal columns are known to reducechronic pain. This is relevant to the Gate Theory, whichpredicates that sensory input from the large fibersinhibits the nociceptive input from the small fibers.Stimulation of nociceptive afferents can also lead to inhi-bition of dorsal horn neurons, through both spinal andsupraspinal components. A large population (92%) of theWDR cells (versus 10% of the NS cells) has distant, largeinhibitory receptive fields (even in the contralateralbody); high-threshold stimulation of their fields caninhibit their nociceptive evoked activity. Viscerosomaticneurons are also inhibited from stimulation of distantsites.

MECHANISMS OF PAIN

The transmission of pain from peripheral tissuesthrough the spinal cord to the higher centers of thebrain is not a passive, simple process using exclusivestraight-through pathways. The spinal and supraspinalcircuits have the potential to alter dynamically the rela-tionship between the stimulus and the perception andresponse to pain. Altered perception regarding thelocalization of the painful input underlies the phenom-enon of “referred pain.” Plasticity is the induciblecapacity of the nociceptive transmission systems thatmediate pain for change. In other words, plasticity isthe ability of the nervous system to modify the out-put/input relationship. The interplay between excita-tory and inhibitory systems will determine the intensityof the messages delivered to the higher levels of theCNS and sensed. The incoming messages may be atten-uated or enhanced, depending on particular circum-stances. The latter state can result from the conditionof central sensitization.

Referred Pain and Visceral PainPhenomena

Referred pain is the pain that is localized in a differ-ent site than the site of its origin. In general, pain origi-nating from visceral organs, like the heart or theabdominal viscera, is primary referred and perceived toan overlying or adjacent somatic area. It can be accom-panied by other phenomena, such as cutaneous(secondary) hyperalgesia, reflex muscle spasm, deep ten-derness, and intense autonomic hyperactivity. Visceral ordeep nociception, in particular, can produce secondaryhyperalgesia and muscular spasm proportional to theintensity of the original stimulus. Persistent and intensenociception can lead to prolonged excitability in the dor-sal horn neurons, with expansion of their receptivefields and reduction of their depolarization thresholds.These phenomena can also spread beyond the initiallyinvolved segments, with further extension of the spasm.Autonomic reflexes can also produce many different vis-cero-visceral, vascular, and neuroendocrine responses,which together with the muscular spasm lead to a newnociceptive source that may outlast the original.

The mechanistic substrate of the referred pain isrelated to the convergence of cutaneous, deep somatic,and visceral input on to certain populations of dorsalhorn neurons, so that spinothalamic tract neuronsreceive convergent input from visceral and overlyingsomatic structures. Convergence can occur also insupraspinal levels. The ratio of Aδ to C fibers in the vis-cera is 1/10 versus 1/2 in the skin, and the visceral affer-ents innervate larger areas with extensively overlappingreceptive fields.The above factors explain why visceralpain is poorly localized, dull and aching versus the local-ized sharp ectodermal pain.

MECHANISMS AND HYPOTHESESEXPLAINING THE DIFFERENT PHASESOF PAIN

Different states or types of pain, reflecting a largerange of sensory experiences exist, can be viewed as theexpression of different neurophysiological mechanisms,not necessarily of absolute teleological significance.Under normal conditions, a physiologic state exists inwhich there is a close correlation between the noxiousstimulus and the perception of a painful response.However, changes induced by the nociceptive input orby the coexisting conditions can result in variations inthe quality and intensity of the perception of the painproduced by a certain noxious stimulus. These changestend to be temporary, as homeostatic mechanisms tendto restore the system to the normal interrelationships


between stimulus and pain. Nonetheless, very intense orprolonged nociceptive input, or disruption or loss of thenormal input, distort the nociceptive system to such anextent that the correlation between stimulation and painis lost. A contribution to the understanding of thesemechanisms, made by Cervero and Laird,5 proposed thatpain can be viewed in three states, or phases rangingfrom a more normal, adaptive, to an abnormal, nonpro-ductive end of a spectrum. These phases are not exclu-sive; at any given time, several of the underlyingmechanisms may coexist in the same individual. Thethree phases of pain are:1. The input, processing, and perception of a brief or

transient noxious stimulus, corresponding to whatwe perceive as a brief, transient, acute painfulsensation.

2. The consequences of a prolonged noxious stim-ulation and nociceptive input resulting from tissuedamage and peripheral inflammation. These com-prise the substrate of the chronic, nociceptive painstates.

3. The consequences of damage or injury to the neuraltissue itself, including the peripheral neuropathiesand central neuropathic states.This correlates withthe various neuropathic pain states.

Phase 1: Brief, Transient Acute Pain

Under normal conditions, the nociceptive primaryafferent fibers do not display any spontaneous activity.Nonetheless, the brief application of a mechanical orthermal noxious stimulus will cause discharges of thesesmall fibers.This is proportional to the intensity of thestimulus, and results into subsequent reports of sensa-tion of pain in humans and escape behavior in animals.There is a close correlation between the intensity of thestimulus, the discharges in the primary afferents, and thesubjective expression of pain. Information is propagatedpredominantly by the Aδ fibers. The underlying synapticevents from this acute response to a noxious stimulusare mediated predominantly by glutamate acting at theAMPA/kainate receptors (Fig. 1-11), but only to a mini-mal degree by neurokinins (substance P) acting at NK1receptors. The consequence is a phasic response ofa discrete population of the dorsal horn neurons, lead-ing to a brief discharge of action potentials and activa-tion of discriminative-sensory pathways. This phasecorresponds to the adaptive, warning role of acute,localized, and transient exposure to (particularly cuta-neous) noxious stimulation.

Phase 2: Chronic Nociceptive Pain

Conditions of tissue damage and persisting inflamma-tion lead to very intense and prolonged noxious stimula-

tion. There is a significantly increased afferent traffic tothe nociceptive pathways, such that the response prop-erties of their components and mechanisms may change.Not only is there an increased afferent input to the CNSfrom the injured area, but in addition, nociceptive spinalcord neurons modify their responses, moving to moreexcitable state. In this phase of pain, the subject experi-ences spontaneous pain, painful sensations evoked fromstimulation of the injured area as well as pain from stim-ulation of the undamaged surrounding area. The curvewhich describes the relationship between the intensity ofthe pain and that of the stimulus shows a leftward shift(Fig.1-12).The relevant clinical phenomena are: (a) hyper-algesia, which is an increased response (increased pain)to a stimulus which is normally painful, but much less;and (b) allodynia,which is pain evoked by a stimulus thatdoes not normally produce pain.This enhancement of theresponse of the nociceptive pathways after prolongedinput of stimuli of certain intensity is called sensitization,and constitutes an elementary form of neural “memory”


Figure 1-11 Synaptic transmission of brief, acute pain.

Figure 1-12 Increased responsiveness with allodynia andhyperalgesia in chronic pain states.

and “learning.” Both peripheral and central mechanismscontribute so that sensitization can occur at any pointfrom nociceptors in the peripheral tissues to the spinalcord and to the brain.A similar phenomenon, known aslong-term potentiation, is seen in the hippocampus andis associated with memory and learning. Ultimately, apathologic state of chronic pain may develop thatinvolves more or less permanent changes in the CNS,per-sisting long after the original injury has healed.

Peripheral Mechanisms of SensitizationSurgical or traumatic mechanical insults, chemical irrita-

tion,heat injury, or disease leading to cutaneous tissue dam-age or inflammation is associated with two zones of pain:1. The first is called the area of primary hyperalgesia

and is located over the area of the original tissuedamage itself. It is characterized by spontaneouspain and increased sensitivity to mechanical,thermal, and chemical stimuli.

2. The second zone, secondary hyperalgesia, displaysan increased sensitivity to mechanical stimuli, butnot to thermal stimuli in an undamaged areasurrounding the first zone.

Increased sensitivity implies: (a) a decrease in thestimulus threshold required to elicit painful responseand (b) an exaggerated response to a suprathresholdstimulus. Primary hyperalgesia is produced mainly byevents and mechanisms occurring in the periphery, atthe level of the primary afferent nociceptive fibers. Incontrast, secondary hyperalgesia is mediated by predom-inantly central mechanisms.

The primary hyperalgesia can be explained bychanges in the transduction sensitivity, responsiveness,and activity of peripheral nociceptors as well as by therecruitment of silent nociceptors. Specific mechanismsare very complex and include:1. Direct stimulation of nociceptive primary afferents.

This can be mediated by a large variety ofsubstances, which can act independently orsynergistically to activate the nociceptor. Algogenicsubstances include:● Kinins, such as bradykinin and kallidin, produced

from activation of plasma and tissue kallikreins.Action is mediated via two types of receptors(B1 and B2), which can excite polymodal andmechanosensitive C as well as high-threshold Aδfibers, producing pain.

● Prostaglandins and leukotrienes. Prostaglandinsmay be derived from virtually all tissues, but,under conditions of tissue inflammation and tis-sue injury, immunocompetent cells and terminalsof sympathetic efferent fibers become predomi-nant sources. Mediators, such as the nitric oxideand certain cytokines (e.g., IL-1,TNF), induce theinducible enzyme cyclooxygenase (COX)-2 syn-

thase, which is the main source.The constitutiveCOX-1 enzyme may also play a certain role. TheCOX-2 form is essentially absent from healthy tis-sues,but gets rapidly induced under conditions ofinflammation, and parallels the production ofprostaglandins. Inflammation results in de novosynthesis of COX-2 enzyme. The COX-1 enzymeis constitutively expressed in most tissues, pro-ducing prostaglandins as part of normal healthytissue function.

● ATP, which can elicit pain by stimulating rapidlydesensitizing, cation permeable, inotropic recep-tors of the P2X family. Particular sources includetumor cells, endothelial cells, and/or platelets andsympathetic nerve endings.

● Protons and vanilloids (capsaicin). Hydrogen (H+)protons are algogenic agents. Protons depolarizenociceptors by triggering a transient Na+ ionchannel, or by opening poorly selective channelspermeable to Na+, K+, and Ca++. Capsaicin, a sub-stance of pepper, provokes pain by openingcation-permeable ion channels with several simi-larities to the protons. By this activation capsaicincauses the release of sP,but prolonged applicationeventually leads to ultimate sP depletion from theafferent terminals, thereby inactivating the noci-ceptive function. Some nociceptors respond toeither protons or capsaicin, but a significant over-lap suggests a common site of action.

● Serotonin (5-HT).This can be derived from manysources, and excites nociceptors via 5-HT3 recep-tors by directly gating ion channels, or sensitizesthem via endocellular messenger systems.

● Norepinephrine, derived from sympathetic effer-ent terminals. This does not directly excite, butenhances the sensitivity of the nociceptors via α2and α1 adrenoreceptors present on the neuronalmembrane. The hyperalgesia produced by nor-epinephrine has been shown only in the pres-ence of tissue injury or inflammation. Anexcitatory effect of norepinephrine on bothintact and damaged sensory neurons developsafter nerve injury. Sensory neurons express α2receptors, and this expression is upregulatedafter nerve injury. It is likely that these adrenore-ceptors may mediate an effect by modulating ionchannel activity via G protein interactions.

● Histamine, excitatory amino acids, tachykinins(sP), and CGRP all have sensitizing effects in theperiphery.

2. Antidromic activation of nociceptive primaryafferents and neurogenic inflammation. Classically,algogenic substances depolarize the nociceptorleading to an orthodromic transmission of impulses,from the periphery to the dorsal horns. However,


concurrently, antidromic impulses may be triggeredin collateral fibers, propagating from the moreproximal parts to the periphery, where they provokethe peripheral release of excitatory amino acids, sP,and other mediators. These further enhance theactivity of the nociceptors by a positive feedbackmechanism and elicit vascular effects, such asincreased permeability and other processes.Peripherally released sP evokes the release ofalgogenic substances, sensitizes nociceptors, andaugments the stimulation of nearby axons, thusspreading the response. CGRP leads to vasodilationand increased permeability, and the excitatoryamino acids produce various feedback actions.

3. Synergistic actions and sensitization of nociceptorsby the engagement of intracellular transductionsystems. These events include the activation ofadenyl-cyclase and phospholipase C as well as anincrease in neuronal Ca++. Thus, the likelihood,intensity, and duration of further discharges areenhanced. Of significance is the effect ofprostaglandins and bradykinin. Previously “silent”nociceptors are recruited by this mechanism.

4. Modulatory events involving a complex pattern ofreciprocal interactions amongst primary afferents,glial cells, immunocompetent cells, sympatheticterminals, etc.

5. Altered phenotype of primary afferents. Changes inthe activity and properties of nociceptors ininflamed tissues may reflect modification of geneexpression and altered phenotype. This may accountfor the increase in primary afferent levels of sP,CGRP,nitric oxide and glutamate, and other changes.

Central SensitizationThe concept of increased responsiveness of the cen-

tral pathways as a consequence of intense afferent trafficwas first introduced by Woolf 6 in 1983, where hedescribed the “enhancement of the withdrawal reflex inrats after high frequency stimulation of the C fibers.”Central sensitization refers to the increased responsive-ness of the spinal cord, an important cause of enhancedresponses of pain after prolonged, intense nociceptiveinput. This increased responsiveness includes the dorsalhorn neurons, interneurons, and ventral horn neurons.The thalamus, cortex, and other brain areas also developrelevant changes. As a consequence of the central sensi-tization, low intensity or normal input of stimuli can pro-duce an inappropriately greater response. Thissensitization is mainly produced from massive and pro-longed nociceptive afferent barrage mainly through theC-fibers and is associated with extensive changes in thedorsal horn cells, resulting in expansion of their recep-tive fields and encoding of the innocuous stimuli aspainful.

Effective neural blockade with local anesthetics priorto initiation of the noxious stimulation, or appropriatepreemptive suppression of the impending nociceptivesignaling, may, theoretically, have the capacity to preventthese changes. This is the background of the preemp-tive analgesia, which,clinically,consists of an attempt toreduce postoperative pain or analgesic requirements bypreemptively administering analgesic agents (local orgeneral anesthetics, opioids) prior to the surgical stimu-lus. Nevertheless, a considerable discrepancy existsbetween laboratory evidence and clinical practice, andmost available clinical studies have failed to show anysignificant benefits or are equivocal.

Mechanisms of Central SensitizationThe increased neuronal excitability and responsive-

ness, as a consequence of prolonged, intense nociceptivetraffic, displays three general electrophysiological char-acteristics at the cellular level:● A stimulus provokes a response of greater duration

and intensity, involving a greater number ofgenerated action potentials (hyperalgesia).

● Receptive fields expand so that responses can beevoked from a larger area, previously ineffective ineliciting firing (area of secondary hyperalgesia).

● The threshold for firing is reduced so that neuronscan be now activated by normally subnoxiousstimulus intensities. There is also appearance ofnovel responses to Aβ fibers (allodynia).

Two relevant events are recognized:1. The knowledge that the prolonged nociceptive

input can sensitize the neurons in the CNS is notnew. In 1966, Mendell7 showed that repetitivestimulation of primary afferent C fibers at rates≥0.33 Hz, at constant intensity, can elicit aprogressive increase in the number of the actionpotentials generated by dorsal horn cells andmotoneurons. This phenomenon is called wind-upand constitutes a simple, cellular model of painsensitization at the CNS level.

2. Heterosynaptic facilitation refers to the processwhereby a progressive increase in neuronalexcitability leads to an increased responsiveness toother inputs, specifically Aβ fibers.

Nevertheless, the processes of central sensitizationare not only suggested by the above electrophysiologicalphenomena, but by psychophysical or behavioral studiesas well.One model of spinal sensitization is the formalintest. Subcutaneous injection of an inflammatory sub-stance, formalin, in the hindfoot of a rodent, results in anacute period (3 to 5 min.) of high C fibers afferent bar-rage activity, followed by low or minimal afferent activity.However, the recording of the parallel electrical dis-charge activity of the dorsal horn WDR cells in anes-thetized animals as well as of the number of flinches orlicking of the foot in awake animals (an indication of


pain behavior), displays two distinct phases: An acuteinitial phase of high activity, lasting 3 to 5 minutes, fol-lowed—after a period of inactivity—by a second phaseof an inappropriately intense activity,with regard to bothrecordings. This second phase of the resumed WDR dis-charge activity and the pain behavior, in spite of the min-imal afferent nociceptive input, is indicative of the spinalsensitization. Pretreatment of the animals with intrathe-cal administration of MK801, a selective NMDA antago-nist,has little effect on the initial phase, but can markedlyattenuate the second phase phenomena. If the drug isgiven after the injection, it has no effect.

This observation underlies the significance of theexcitatory amino acids acting on the NMDA receptorsfor the development of the spinal sensitization, but theunderlying processes are of considerable complexity.

The Role of Excitatory Amino Acids andTachykinins in the Sensitization of Dorsal HornNeuronsThe influence of transmitters, released by the primary

afferent, on the activity of the dorsal horn neurons ismediated via:1. A direct alteration in ion flux at cation-permeable

channels.2. Interactions with intracellular transduction mech-

anisms leading to subsequent ionic current modi-fications (e.g., via receptor phosphorylation).

3. Long-term effects involving processes like receptorregulation or recycling and changes in genetranscription of receptors, transmitters, and othermolecules.

Brief noxious mechanical or heat stimuli producerapid depolarization and action potential discharges innociceptive specific and WDR dorsal horn cells. Theacute response to noxious stimulation or injury isencoded peripherally as electrical discharge predomi-nantly in Aδ, and to a much lesser degree in C fibers, sub-sequently the electrical discharge propagates toward thecentral presynaptic endings, where it evokes the releaseof neurotransmitters.The major transmitters in Aδ fibersare excitatory amino acids (glutamate).The acute pain isfurther mediated mainly by the glutamate acting at theAMPA/kainate receptors, and to a smaller extent, by sub-stance P (from C fibers) acting at NK1 receptors.Activation of the AMPA/kainate receptor elicits briefexcitatory postsynaptic potentials with no cumulativeresponse from low-frequency stimulation. The conse-quences are brief depolarizations of the dorsal horn neu-rons and activation of the central pathways.

However, under conditions of persisting inflamma-tion, more and more C fibers become sensitized andmight fire either sporadically, at a lower threshold, or asa response to previously innocuous stimuli, conse-quently providing a more sustained input to the dorsal

horns. In addition, silent C fibers become active duringinflammation, which further increases the alreadyenhanced afferent input. In addition to the release ofexcitatory amino acids, activation of C fibers results inthe release of tachykinins (sP and neurokinin A). In thesame dorsal horn cells previously briefly activated by theAδ fibers, now C fiber activation can produce longer last-ing excitatory postsynaptic potentials that give rise tocumulative depolarization and firing of action potentialsupon repetitive stimulation. What makes the differencebetween the Aδ and the C fiber elicited postsynapticresponse is the neuropeptide (sP and neurokinin A) con-tent of the latter. While Aδ fiber stimulation activatesmostly the non-NMDA (AMPA/kainate) receptor, inputfrom the C fibers leads to a synergistic activation of boththe AMPA/kainate and the neurokinin receptor, whichwith sufficient magnitude and duration can subsequentlyexcite the NMDA receptor (Fig. 1-13).Therefore, it is sug-gested that NMDA receptors are modulated by activationof the neurokinin receptors.

NMDA receptors are linked to special inotropic chan-nels, permeable to Ca++ (see Fig. 1-13). The sensitizingnociceptive mechanisms converge to reinforce transmis-sion via the NMDA receptors, resulting in a pronounced,sustained elevation in Ca++ influx and intracellular Ca++

levels. However, under normal conditions NMDA recep-tors are quiescent, secondary to an intra-channel blockby a Mg++ plug.

Activation of the neurokinin receptors, leads toincreased activity of second messenger cascade leadingto activation of protein kinase C, which phosphorylatesthe NMDA receptor, counteracts the Mg++ block, andallows NMDA receptor to operate at more negative,hyperpolarized potentials. The activation of the NMDAreceptors results in increased intracellular Ca++ levels


Figure 1-13 Complexity of synaptic transmission in chronicpain states.

and can elicit burst-like patterns of firing in the dorsalhorn neurons. Furthermore, it may set up reverbatory,hyperexcitable circuits and reinforce the rostral trans-mission of the nociceptive information.

Activation of NMDA receptors and increases in intra-cellular Ca++ level play a particularly important role intriggering and maintaining neuronal sensitization in thedorsal horns, a process underlying the development ofhyperalgesic and allodynic states. Key factors in an inter-related cascade of events at the cellular level include:1. Activation of the phospholipase A2 and production

of prostaglandins, which augment the hyperalgesicstate.

2. Activation of second messenger systems andproduction of mediators, such as inositol triphosphateand diacylglycerol, which further enhances thecascade via intracellular Ca++ release and activation ofthe protein kinase C, respectively (Fig. 1-14).

3. Increases in intracellular calcium and protein kinaseC, which further enhance NMDA receptor excitation.They also increase the expression of proto-oncogenes, such as c-fos and c-jun, which act as thirdmessengers that control transcription of “target”genes that encode various peptides or proteins,receptors, or enzymes capable of modulatingresponses to nociception.

4. Another mechanism involves the production ofintracellular NO, which rapidly diffuses inside andoutside the cell, further enhancing the nociception-

driven spinal sensitization. However, it may exert amultiplicity of even contradictory actions in differentcells.

5. NMDA-mediated central events, and activation of theprotein kinase C, have been also associated withreduced sensitivity to opioids, so that doseescalation is required to overcome it, but clinically,this is complicated by side effects. In contrast,NMDA receptor antagonists (ketamine) potentiatethe analgesic effect of opioids and may play a role inpreventing central hypersensitive states.

6. A negative feedback mechanism is related to therelease of adenosine after activation of the NMDAreceptor. Adenosine acts on A1 receptors on themembrane of dorsal horn neurons and has anantinociceptive effect. Adenosine, administeredsystemically or intrathecally, can produce analgesia.

Another way by which information of noxious stimu-lation can propagate centrally is associated with the rel-atively slower transport of chemical substances. Theseare called neurotrophins and can modify the metabo-lism of the dorsal root ganglion cells as well as the prop-erties of the cytoplasm and the membrane of the cellbody and presynaptic endings.

Finally, it is recognized that a (at least) transient, func-tional reduction of the tonic GABA-ergic and glycinergicinhibitory interneuronal activity can mimic and accentu-ate processes of dorsal horn sensitization, contributingto the allodynia and hyperalgesia. The exact mechanisms


Figure 1-14 Central role of activation of NMDA receptor, calcium influx, and intracellularsignaling in chronic pain states.

remain unclear, but a destruction of a subpopulation ofinhibitory interneurons might be attributed to NMDA-receptor excitotoxic mechanisms.Additionally, in accor-dance with the Gate Theory, stimulation of Aβ fibersprovides an analgesic effect, mediated via inhibitoryinterneurons, to the dorsal horns (this explains the painrelieving effect of manipulations, such as rubbing thepainful site). Consequently, any reduction of Aβ fibermediated stimulation of the inhibitory interneuronsmight disinhibit and further sensitize nociceptive neu-rons in the dorsal horns.

Phase 3: Neuropathic Pain

Phase 3 pains are abnormal (pathological) pain states,which develop as the consequence of disease or damageto peripheral nerves or to the CNS itself. They comprisethe neuropathic pain states, which are characterized bya lack of correlation between injury and pain. In clinicalterms, the Phase 1 and 2 pains are symptoms of periph-eral tissue injury, but the neuropathic (Phase 3) pain isa symptom of neurological diseases that include lesionsof peripheral nerves or damage to any portion of thesomatosensory system within the CNS.

Neuropathic pain can be spontaneous or evoked,triggered by innocuous stimuli or associated withexaggerated responses to minor noxious stimuli.Pathophysiologically, neuropathic pain originates as anexpression of substantial alterations in the normal noci-ceptive system induced by peripheral or centraldamage. However, the particular combination of mecha-nisms responsible for each one of the various neuro-pathic pain states is unique to the individual disease, orto particular patient subpopulation (patients with seem-ingly identical damage to their central nervous systemmay or may not complain of pain). Thus, it is believedthat the development of neuropathic pain may involvegenetic, cognitive, or emotional factors.

Damage to the sensory pathways of the nervous sys-tem may result in loss of sensory function as well as inpain and abnormal sensory symptoms (e.g., allodynia,hyperalgesia, dysesthesia). Two groups of mechanismsprobably account for the latter symptoms:1. Pathological changes in the damaged neurons; and2. Reactive changes in response to nociceptive input,

and to the loss of portions of the normal afferentinput.

Characteristic sensory experiences of the neuro-pathic pain include:1. Spontaneous pain with burning quality or

intermittent, sharp stabbing, or lancinating pain.2. Thermal hyperalgesia, to both cold and hot stimuli.3. Mechanical allodynia, elicited by touch or brushing.

This is a very common neuropathic manifestation,considered a hallmark of the neuropathic pain.

While the pathological changes in damaged neuronsare unique to neuropathic pain states, some of the reac-tive changes to the nociceptive input are the expressionof the pathophysiological mechanisms also seen in thechronic pain states of non-neuropathic nature. Theseinclude the mechanisms of central sensitization, asdescribed in the previous section. In neuropathic painstates, the activation of these mechanisms may be abnor-mally prolonged or intense, due to ongoing abnormalinput from damaged neurons. Sometimes healing neveroccurs, but even if successful regeneration develops, theproperties of the regenerated afferents may not be com-pletely normal. The role of supraspinal or descendingmechanisms may also be significant, although not ade-quately clarified.

Other painful conditions, described as ComplexRegional Pain Syndrome (or Reflex SympatheticDystrophy) can be also considered types of neuropathicpain because of the predominant role of the changes inthe nervous system. The syndrome is the likely result ofboth peripheral and central sensitization mechanisms, inaddition to dysregulation of the autonomic function.Another type of neuropathic pain, the phantom pain inamputees, may also be explained by central mechanisms,involving the dorsal horns or probably higher centers.

Pathophysiologic Mechanisms of NeuropathicPainBoth peripheral and central changes have been iden-

tified and may play a role, of different significanceamongst the different types of the neuropathic pain.However, it is not clear which of the described changesare causative mechanisms determining the pathogenesisof neuropathic pain and which are bystander events oract as correlates with indirect significance.

The peripheral mechanisms illustrate the complexityof the peripheral events involved in the generation andmaintenance of pain provoked by primary afferentnerve injury. Injury to the primary afferents results in aninitial, intense electrical discharge, followed by the gen-eration of abnormal ectopic impulses, which is involvedin the initiation and maintenance of the neuropathicstate. Peripheral events contribute mostly to sponta-neous pain and hyperalgesic responses, while allodynia-like phenomena are best explained by centralmechanisms.

Neuropathic Pain: Peripheral MechanismsPeripheral mechanisms implicated in neuropathic

pain include:1. Alterations in afferent function after nerve injury.

Acute injury to the nerve leads to an “afferentbarrage.” This includes the rapid, intense centraldischarge of both Aβ and C fibers for a period ofminutes, and even several days for some fibers.Suppressing this initial barrage by applying local


anesthetics to the nerve before the injury canprevent the development of subsequent hyperalgesicmanifestations.

2. The injured axons begin to sprout,and the sproutedterminals display a characteristic “confused” growthcone (neuroma) characterized by transductionproperties not possessed by the original, normalaxon. These include hyperexcitability to a range ofvarious applied stimuli, and increased sensitivity tohumoral (e.g., cytokines, prostaglandins, cate-cholamines) and mechanical factors (i.e., pressure,touch). Those stimuli and factors may enhanceongoing firing, or elicit firing in previously silentafferents. Spontaneous ectopic firing and ectopicmechanosensitivity have been shown to originate atthe same sites, and many injured axons show bothchanges, although mechanosensitivity can occurwithout spontaneous firing, and spontaneous firingwithout mechanosensitivity. It has been shown thatmechanosensitive “hotspots” develop in the neu-romas, on the surface of the injured nerves, or onregenerating nerves. Clinically, their presence isresponsible for the Tinel sign in carpal tunnelsyndrome.

3. After the acute injury,persistent spontaneous firingalso originates after an interval of days to weeksfrom small afferent fibers at the site of the lesion(neuroma) to the DRG and neurons in theipsilateral dorsal horn. Again, suppression withlocal anesthetics appears to reduce facilitatedresponses. It should be noted that the DRGscontribute significantly to the ectopic neuropathicbarrage and the mechanosensitivity in traumatizednerves, and when neuropathic symptoms and painpersist despite peripheral nerve blocks, ectopicsources in the DRG should be considered. Duringeveryday movements and after manipulations, suchas straight-leg lifting, the nerve roots and DRG aresubjected to significant mechanical stress, with noeffect normally. However, if there is mechanosen-sitivity due to radiculopathy, these stresses elicitectopic impulse discharge and pain. The increasesin the spontaneous excitability and responsivenessof the injured axons are mediated by changes in theexpression and function of multiple ion channelsubtypes localized in the DRG and neuroma:various classes of Ca++, K+, and particularly Na+

channels are involved. Regenerating nerves showincreased production, transport and concentrationof aberrant sodium channels at the lesionedterminals. These regenerated channels differsignificantly from those of the normal axon. This isa target for sodium-channel blocking drugs, such asmexiletine or lidocaine, which can suppressectopic firing at concentrations not adequate to

suppress normal neural conduction. Expressionand increased concentration of novel adrenore-ceptors has also been demonstrated.

4. Activation of damaged and adjacent intact fibers byinflammatory mediators. These include pro-inflammatory mediators (sP, CGRP), 5-HT, ATP, NO,leukotrienes, prostaglandins, nerve growth factor,cytokines, etc. They may exert direct and indirectactions on damaged and intact fibers contributingto an increase in afferent traffic.

5. Abnormal patterns of inter-neuronal communicationin the DRG and/or neuroma. The apposition of themembranes of adjacent axons can lead to the directcurrent transfer from one to another, causing“ephaptic” excitatory cross-talk between the fibers(Fig.1-15). Thus,sympathetic fibers or low-thresholdAβ fibers can activate high-threshold C fibers,contributing to mechanical allodynia. “Crossed-after-discharge” communication involves the depolar-ization of neurons as a result of the repetitive firingof their neighbors, probably mediated by diffusiblemediators (ATP or K+).

6. Increased sympathetic innervation and excitation ofthe DRG and/or the neuromas of the primary afferents.Following injury, primary afferent responsiveness tosympathetic stimulation is markedly augmented.Afternerve damage, sympathetic terminals extend into theneuroma of the sprouting afferent axon (Fig.1-16),witha time course parallel to the appearance of mechanicalallodynia. Postganglionic sympathetic terminals alsosprout and form basket-like projections around DRGcell bodies,particularly the large somata correspondingto Aβ fibers (see Fig. 1-16). Smaller fibers may also beaffected.This novel sympathetic innervation has beenshown to exert an excitatory drive on both theneuroma,and, independently,on DRG neurons. This isconsistent with the observations that chemicalsympathetic blockade, bretylium, guanethidine, and


Figure 1-15 Excitatory “cross-talk” between injured peripheralfibers. (Copyright 2004 Catherine Twomey/Medical CenterGraphics, Milwaukee, Wisconsin.)

adrenergic antagonists can alleviate mechanicalallodynia and other manifestations of sympatheticallymaintained painful states. The predominant mech-anism of excitation is direct action of releasednorepinephrine at upregulated and/or oversensitive αadrenoreceptors on the damaged primary afferents.Data favor a principal role of α2,rather than the α1 type(but this is confounded by the antinociceptive actionsof the α2 agonists at the central α2 receptors). It isknown that many intact DRG neurons express αadrenoreceptors,and an upregulation following axonalinjury seems likely, or the receptors normallyexpressed may produce exaggerated responses. Thesympathetic terminals themselves also express α2receptors,which can mediate release of prostaglandinsfrom these terminals. Other sympathetic mechanismsinclude changes in vascular permeability and bloodflow, edema and pressure on pressure-sensitive noci-ceptors,vasoconstriction,and ischemia.

Finally,it should be noted that neuropathic,painfulstates are not invariably sympathetic dependent.Clinically, “sympathetically maintained” and “non-sympathetic dependent” states of pain can be differ-entiated, based on the fact that in some patientsneuropathic pain can be relieved by sympatheticblocks. Furthermore, surgical sympathectomy canitself trigger a painful syndrome in some patients.

7. With regards to the edema and trophic changes inskin, nails, and bone that characterize thelongstanding cases of reflex sympathetic dystrophy,it seems that these changes are mediated by therelease of various vasoactive peptides (such as sP),triggered by the antidromic impulses in C fibers.Sustained ectopic firing can travel both toward theCNS as well as antidromically to the periphery.

8. Altered phenotype of damaged fibers.The levels ofmany neuropeptides and receptors change in smalland large afferent fibers following their injury.

Despite a decrease of sP and CGRP levels, at least atsome time periods, in damaged C fibers, nociceptivetransmission is maintained as a result of the residualstores of transmitters at upregulated NK1 andCGRP receptors on sensitized dorsal horn cells.Other transmitters, such as vasoactive intestinalpolypeptide (VIP) and neuropeptide Y (NPY),assume excitatory and antinociceptive roles,respectively. A reduction in the DRG cells access tonerve growth factor seems to mediate the decreaseof the sP. Simultaneously to the loss of sP in the Cfibers, sP actually appear in axotomized, large Aβfibers upon their injury. The consequences of thisinduction of sP synthesis in the Aβ fibers arecompounded by their release of glutamate, theirconcurrent sprouting into more superficial dorsalhorn laminae (where they make inappropriatecontacts with nociceptive neurons), and theupregulation of the NK1 receptors.The Aβ fibers alsoincrease their levels of VIP and NO, furthercontributing to a pronociceptive role.

9. Aberrant patterns of peripheral regeneration ofdamaged peripheral afferents, and alterations intheir functional properties. Sprouting of intact,collateral primary afferents occurs into areas ofdenervated peripheral tissue while regeneratinginjured primary afferent fibers do not regaintheir original distribution in the peripheral tissues.These alterations are associated withreorganization of receptive fields of the dorsal hornneurons, with subsequent reconstruction ofcortical somatosensory maps. Intact peripheral Cfibers sprout to reinnervate denervated cutaneousareas after nerve injury, and these collaterals mayplay a role in the “extraterritorial” allodynia andhyperalgesia.

10. Surgical or traumatic interruption of primaryafferent input to dorsal horns via lesions proximalto DRG produces spontaneous pain andincreased responsiveness of dorsal horn neurons.Mechanisms involved are the sensitization ofthe dorsal horn cells by the intense transientprimary afferent discharge upon the injury,a reduction of inhibitory tone, enhanced orattenuated supraspinal mechanisms of facilitationor inhibition, respectively, and a novel afferentinput to denervated dorsal horns from collateralsprouting.

Neuropathic Pain: Central Mechanisms1. There is evidence that stimulation of Aβ fibers

mediates the mechanical allodynia in neuropathicpain, and that central mechanisms are required forits expression. However, the role of C fibers in theinduction or maintenance of central sensitization inthe neuropathic pain should not be underestimated.


Figure 1-16 Sympathetic efferent fiber sprouting afterperipheral nerve injury. (Copyright 2004 CatherineTwomey/Medical Center Graphics, Milwaukee, Wisconsin.)

It is the afferent barrage from the C fibers thattriggers the WDR sensitization in the dorsal horns,and a persistent, low level of C afferent input may benecessary for maintaining central mechanismsunderlying certain neuropathic states. Thus, C fiberinput to dorsal horns may facilitate Aβ fibermediated allodynia by inducing and accentuatingcentral sensitization. Excitatory C and Aβ fibers mayeven synergize upon the WDR neurons.

2. Afferent sprouting of the large afferents to moresuperficial dorsal horn laminae involved innociception. After primary afferent injury, there isincreased sprouting and reorientation of the Aβ fiberterminals into more superficial laminae (Fig.1-17). Inparticular, migration from the deeper, non-nociceptive laminae III, IV, and V into lamina IIo,a region involved in the reception, processing, andtransmission of nociceptive information. In laminaIIo, Aβ fiber sprouts may interact synaptically (orotherwise) with nociceptive-specific or WDRneurons, which they would not normally access.Thus, their stimulation will be misinterpreted asnoxious. This is compounded by their phenotypicswitch to produce sP and VIP as well as by theupregulation of the NK1 receptors. C fibers anddescending pathways may also invade inappropriateregions of dorsal horns: regenerating damagedC fibers expand into deeper laminae contacting NSor WDR cells, producing abnormal signaling.

3. Reduction of Aβ fiber input to inhibitoryinterneurons. Following primary afferent injury,there is evidence of reduction of the action of theinhibitory interneurons at the small fibers andprojection neurons. This is attributed to thereduction of the Aβ fiber-mediated stimulation of theinhibitory interneurons.

4. Functional reduction in the activity or physicaldegeneration of inhibitory interneurons. Inhibitory

interneurons normally suppress the propagation ofnociceptive information via inhibitory actions at theprojection neurons, excitatory interneurons, andprimary afferent terminals. After peripheral nerveinjury, dark-staining neurons appear in the ipsilateraldorsal horn (particularly in I and II laminae).These aredying or degenerating inhibitory interneurons, andloss of their tone can induce a hyperexcitableallodynic state. As a result of peripheral nerve injury,activation of NMDA receptor by C fibers triggers thesensitization of WDR cells in dorsal horns. On thisbasis, it seems possible that primary afferent injurycan elicit a transient massive release of glutamate.This, subsequently, via activation of NMDA receptorson to small, vulnerable interneurons, may lead to anexcessive intracellular accumulation of Ca++, and theinduction of mechanisms provoking their excitotoxicdegeneration.

5. Other central mechanisms, including the mechanismsof sensitization and increased excitability of dorsalhorn neurons and possible changes in descendingmechanisms of inhibition and facilitation.

6. Adaptive changes in the thalamus, cortex, andother higher centers responsible for thediscriminative-sensory and affective-cognitivedimension of pain. These include alterations in theneuronal responsiveness together with areorganization of patterns of synaptic connectivity.Higher centers (e.g., cortex, thalamus) do notbehave as passive recipients or relayers ofinformation, but are also themselves activelyinvolved in further integration processes.Additionally, pain can be provoked by damage toCNS itself (central pain), as a result of a stroke,multiple sclerosis, malignancy, etc. However, morework is needed at the cerebral level for animproved understanding of supraspinal mecha-nisms of both chronic and neuropathic pain, butinitial analyses at the cellular level of thesemechanisms have suggested striking many simi-larities to events occurring at the dorsal horns.

The predominant pathophysiological abnormalitythat particularly characterizes neuropathic pain is thatthe injured sensory neurons become electrically hyper-excitable and generate ectopic firing discharge.Sympathetic stimulation activates a high proportion ofectopic discharge sites, but in each case of neuropathythe ectopic firing is sustained by a different kind of “idio-syncrasy” of precipitating factors. Only if sensitivity tosympathetic stimulation is the major factor, for example,sympathetic blockade will produce improvement.Nevertheless, suppression of the sodium channel-dependent electrical activity seems to provide more con-sistency since it constitutes the basis of the generatorcurrent. Finally,heredity may play a significant role in the


Figure 1-17 Altered large fiber distribution in dorsal hornsafter peripheral nerve injury. (Copyright 2004 CatherineTwomey/Medical Center Graphics, Milwaukee, Wisconsin.)

genesis and maintenance of the neuropathic painthrough details that remain unknown.

CONCLUSION

To summarize, it is reasonable to distinguish severalpathways and mechanisms fulfilling contrasting andcomplementary roles in the detection, processing, andappreciation of pain. Different systems or “phases” ofpain may play different teleologic roles. The brief, tran-sient acute pain immediately after a noxious stimulus orinjury is processed mainly by systems fitted for gaugingthe intensity and determining the location. This sensory-discriminative component is of adaptive value in trigger-ing evasive action to a threat, in the comparative absenceof modulation by emotional or cognitive factors. On theother hand, other circuits are more involved in the affec-tive dimension of pain and influence or are influencedby emotional-cognitive factors (Fig. 1-18). Rather thandetecting stimuli, they serve the ability to rationalize andcope with pain, in particular long-term clinical pain ofdiverse origins. These systems are associated with moodchanges reflecting and modifying pain.

Both of these systems should be regarded as comple-mentary and operating reciprocally and interactively.Regarding the higher levels, it seems that specific “paincenters” do not exist. Rather, a “neuromatrix” of cerebralstructures and multiple, interactive thalamo-cortico-lim-bic networks synergistically contribute to the globalexperience of pain.The lack of discrete, circumscribedCNS regions underlying pain sensation, is related to, andcomplicated by, the extensive redundancy of circuitsand mechanisms transmitting nociceptive information,and the extensive pattern of reciprocal interactionsamongst them. There exists a multiplicity of anatomicalstructures and ascending and descending pathways,neurotransmitters, inflammatory mediators, mecha-

nisms triggering abnormal patterns of firing and cas-cades of intracellular signals. A fundamental processunderlying prolonged painful states is the sensitizationof peripheral and central neurons involved in the pro-cessing of pain, and this is elicited by sustained andrepetitive stimulation. Isolated selective inactivation ofdelineated regions of the CNS, or blockade of theactions of specific pronociceptive mechanisms, isunlikely to offer a generalized solution for counteractingthe experience of pain. Many discrete therapeuticmanipulations in clinical practice, including surgicalprocedures, sympathectomies, blocks or pharmacologicantagonisms may have limited efficacy. Nevertheless,rational strategies appropriate to the effective control ofspecific and defined painful conditions remain as theonly realistic approaches,and advances in basic sciencesprovide an improved understanding of mechanismsunderlying pain for the discovery of novel analgesicagents and interventions. Relevant to this, is a growingrealization that a characterization of the molecular basesof the mechanisms generating rather than inhibitingnociception may provide more fertile ground for thispurpose.

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Figure 1-18 Interacting physiologic, emotional, andenvironmental factors in the behavioral expression of pain.

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2- Pain Pathways and Mechanisms

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