Pain Physiology

Dr. Christopher A. JennerConsultant in Pain Medicine and Anaesthesia, SMH

2nd March 2007

What can u say?

Its very complicated !!!

Agenda

• FRCA requirements

• Basic definitions

• Overview of pain pathways

• Tissue Injury

Agenda

• Nociceptors

• Pain transmission

• Spinal cord

Agenda

• Second order neurones

• Ascending spinal pathways

• Pain modulation

• Descending inhibitory pathways

Agenda

• Gate control

• Neurotransmitters

• Neuropathic pain

FRCA requirements

FRCA requirements

• Syllabus- Physiology and Biochemistry

• ‘Pain: afferent nociceptive pathways, dorsal horn, peripheral and central mechanisms, visceral pain, neuropathic pain…influence of therapy on nociceptive mechanisms…’

FRCA requirements

• Syllabus- Regional Anaesthesia

• ‘Indications, technique and management of complications of spinal and epidural (including caudal approach) analgesia…

FRCA requirements

• Multiple Choice Questions

FRCA requirements

• Primary FRCA Viva question

• Give a detailed description of the pain pathways that become activated if you prick your finger with a pin. What happens in the thalamus and cerebral cortex? Describe the neurotransmitters involved.

FRCA requirements

• Primary FRCA Viva question

• Describe the principles of management of neuropathic pain

Techniques for answering MCQ’s

A. Knowledge

1. Learning from MCQ’s

• Learning rather than just T/ F

• E.g: when measuring jugular venous saturations

• Good opportunity to learn

2. Method

• Decide on style eg: 10 MCQ’s at a time

• Mark them

• Break

• Go thru questions with suitable textbooks

• Sounds very labor intensive BUT can cover entire syllabus including minutiae

• Learn subjects relatively painlessly

• Small bite-sized topics!

3. References

• A-Z Anaesthesia/ Sasada n Smith/ Parbrook/ others

• Library!

4. Answers

• Answers in MCQ’s- both loose and books not necessarily correct

• Many answers maybe subject to interpretation

5. Beware!

• In exam hall- even if u see a question u recognise- it may be worded differently or otherwise altered

B. Techniques

Techniques

• Numerous!

• Research papers (including info on probability and guessing, etc)

• Simple method:

Techniques

• Read the question fully!

• Answers to the stem question can be roughly divided into 4 categories

• Each category has its own hit rate for answering it correctly

• However- u will have to find out your own hit-rate for answering these

Category Hit rate for answering correctly

Certain 80-100%

Fairly certain 60-80%

Probably 50-60%

No clue 50%!

• Remember- to get 55-60% and pass (mark varies with cohort) u must answer sufficient questions

• Overall need to answer at least 80%

• Answer 50-60%- start saving up!

• BEWARE

• Negative marking can seriously damage your health

• More MCQ u practice, more knowledge u will acquire, more questions u can answer, more ‘lucky’ u get

• Will become better at attempting difficult questions and getting them right

• Combination of knowledge, confidence and improving technique

• Other strategies- immediately identify 3 answers u are happy with

• DON’T PANIC

• If u see a very difficult/ complex question- everyone else facing the same

• Some new MCQ’s are tried out- if crap at differentiating candidates, are removed

Definitions

Definitions

• Pain• An unpleasant sensory or emotional experience

associated with actual or potential tissue damage. It is a subjective phenomenon.

• Nociception • The process by which the painful stimulus is conveyed

by the nervous system to the brain.

• Chronic Pain• Pain which persists even when the noxious stimulus is

removed. >3/12

• Acute pain

Overview to Pain Pathways

Cue the CD-ROM !

Nociceptors

Nociceptors

• Receptors respond to different noxious stimuli

• Mechanical

• Thermal – temps above 45-50 oC

• Chemical – exogenous eg capsaicin

- endogenous eg bradykinin, H+, substance P, histamine,

K+.

Receptors

• Unimodal or polymodal

Unimodal

Unimodal- Mechanical

Mechanoreceptors

High Threshold Mechanoreceptors

• Activated by intense mechanical stimulation

• Innervated by A fibres

• Sharp, prickling, localised pain

Unimodal- Thermal

Thermal- Noxious heat/ cold

Noxious cold CMR1

TRPM8

Noxious heat VR1

TRPV1

Unimodal- Chemical

Chemical

Receptor Ligand

PTX3 ATP

B2 Bradykinin

EP2 PGE2

ASIC H+

TTX-R (predominate) Na+

Chemical-other ligands

• GABA A/B

• Somatostatin

• Adrenaline

• Glutamate

• Capsaicin

Chemical-other ligands

• Angiotensin II

• ATP

• CCK

• Adenosine

Polymodal nociceptors

Polymodal nociceptors

– Activated by mechanical stimulation/ high temps/ irritant chemicals

– Innervated by unmyelinated C fibres

– Slow, burning, poorly localised pain

Tissue Injury

Tissue injury causes the release of various inflammatory and pain mediators resulting in peripheral

sensitisation

Pain Response Mediators

Pain Response Mediators

Released from Mediator

Damaged endothelial cells and platelets

ATP, ACh, serotonin, PG E2

Damaged vessels Bradykinin

Inflammatory Response Mediators

Inflammatory Response Mediators

Released from Mediator

Mast cells Histamine

Sub P, CGRP trigger mast cell degranulation

Blood cells Cytokines, Complement factors C3a, C5a, serotonin, PAF, NCF, LK, fibrinopeptides

Actions of Inflammatory Mediators

Inflammatory Mediators

• Peripheral vasodilatation

• Increased vascular permeability

• Plasma extravasation

• Leucocyte migration

• Clotting response

Outcome on pain pathways?

Outcome on pain pathways?

• Sensitisation primary afferent sensory fibres

• By mediators of the pain response- greater, more frequent transmission of APs to the nociceptive

Outcome?

• Synapse level, sensitised primary afferent sensory fibres decrease thresholds for activation of nociceptors

• These become hyperexcitable and transmit frequent APs.

Pain Transmission

Pain Transmission

• Cutaneous sensation- Low and high threshold primary afferents

• Low threshold

• Ab light touch, vibration, pressure

• Aa proprioception

Pain Transmission

• High threshold

• Stimulation of nociceptive afferents leads to propagation of impulses to the spine (via Ad and C fibres)

Properties of Ad and C fibres(rote learning!)

C Ad Ab

Myelination No Yes Yes

Diameter 0.4-1.2 mcm 2-5 mcm

Conduction velocity

0.5-2 m/s 12-30 m/s

Normal sensation

Slow pain

Diffuse, dull

Fast pain

Sharp, localised, reflex withdrawal

Pathological sensation

Hyperalgesia Allodynia

C Ad Ab

Threshold high high low

Main Transmitters

peptides EAA EAA

Main receptors activated

NK1,2

(neurokinin)

NMDA

AMPA

mGlu

AMPA

Lamina 1,2,5 1,2,5 3,4

Target sc neurones

NS

(nociceptor specific)

WDR LT

WDR

Note about Ad and C fibres

• NB: not all are nociceptor specific

• Some to low threshold eg: touching/ brushing

• Many thermoreceptors

Synapses

Activity of Synapses

Synapses

• Action potentials- voltage-gated Ca channels to open in terminals

Synapses

• Opening channels enables influx of Ca, causing neurotransmitter molecules to fuse with the pre-synaptic membrane and release their contents into the synaptic cleft

Synapses

• Neurotransmitters eg: glutamate, substance P diffuse across synaptic cleft

• Neurotransmitters bind to receptors on ion channels in post synaptic membrane

Synapses

• Activation via:

• G protein coupled effector enzymes

• direct on ion channels

• enabling efflux of K and influx Ca

• Na into post synaptic cell

• Influx Na enables continuation of AP

Spinal Cord

Spinal Cord

• Grey and White matter

• White matter- ascending/ descending fibres

• Grey matter- cells and central terminals of primary afferents from periphery

Dorsal Horn

Dorsal Horn

• Dorsal horn divided into 6 layers (laminae)

• Primary afferents terminate in the dorsal horn.

Dorsal Horn

• Majority at same segmental level

• Proportion travel up or down a few segments (tracts of Lissauer)

Dorsal Horn

• Cell bodies lie in DRG (dorsal root ganglia).

• Synapse with projection or interneurones

Dorsal Horn

• Dorsal horn is divided up into various laminae – Rexed’s laminae

– A synapse in I and V

– C synapse in substantia gelatinosa (II and III)

Anatomy of the spinal cord

Anatomy of the spinal cord

Rexed’s laminae

Rexed’s laminae

I,II Most nociceptors terminate in superficial layers via Ad and C

III, IV Tactile afferents synapse

V Some A project into deeper layers.

V Nociceptive and tactile afferents converge (directly or via inter-neurones)

V,VI Inter-neurones mainly regulate flow of nocicpetive info

Summary of the Spinal Cord

• SC not just a relay station

• Modulation of pain via spinal and supraspinal mechanisms

• Regulatory circuits involve primary afferents, spinal interneurones and descending fibres

Anyone been to …

…healthy eating…

…leads to…

Second Order Neurones

Second- order neurones• Primary afferents synapse with various

classes of second-order neurone

Second- order neurones

– Nociceptive specific – exclusively respond to noxious stimuli, small receptor fields, mainly found in superficial laminae

– Wide Dynamic Ranging (WDR) neurones – non-specific, large receptor fields, located in deeper laminae.

– Low-threshold neurones – for innocuous stimuli, predominatly in III and IV

Second- order neurones

• Inter-neurones can be inhibitory or excitatory

NMDA Receptors

NMDA Receptors

Ascending Spinal Pathways

Tract Information

STT Spinothalamic tract

Temp, Pain, Touch, Visceral

Mediates and separates discriminative (fast) and affective (slow) aspects into different regions of the tract

Anterior STT- simple touch

Lateral STT- pain and temperature

VPL, VPM, PO nuclei- conscious perception of pain

SRT Spinoreticular tract

To reticular formation- arousal-emotional pain. Slow pain

SMT

SPT

Others

• Paleospinothalamic tract

• Spinomesencephalic tract

• Neotrigeminothalamic tract

Details of the tracts

Direct (fast) Indirect (slow)

Tract Lateral STT Lateral STT

SRT

Origin I, IV, V I, IV, V (+VII,VIII)

Somatotopic organisation

Yes No

Direct (fast) Indirect (slow)

Body representation Contralateral Bilateral

Synapse in RF No Yes

Sub-cortical targets None Hypothalamus

Limbic system

Autonomic centres

Direct (fast) Indirect (slow)

Thalamic nucleus VPL Intra-laminar nuclei

Other midline nuclei

Cortical location Parietal lobe Cingulate gyrus

Role Discriminative pain (quality, intensity, location)

Affective-arousal component of pain

Other functions Temperature

Touch

Ascending Spinal Pathways

• Most secondary afferents decussate to ascend in the lateral spinothalamic tract. (Some pass up posterolateral part of cord)

Ascending Spinal Pathways

• Fibres pass through the medulla, mid-brain and pons giving off projection neurones.

Ascending Spinal Pathways

• Terminate in the ventral posterior and medial nuclei of the thalamus.

• Other pathways– Spinorecticular pathway – terminates in RF

then thalamus

– Spinomesencepthalic pathway – terminates in mid-brain and PAG

Ascending Spinal Pathways

• From the thalamus, there is a specific sensory relay to areas of the contralateral cortex

– To somatic sensory area I (SSI) in the post-central gyrus

– To somatic sensory area II (SSII) in the wall of the Sylvian fissue

– Cingulate gyrus – mediates the affective component of pain

Pain Modulation

Pain Modulation

• At numerous levels

• Dorsal horn, complex interaction between afferent input fibres, local intrinsic spinal neurones and descending central afferents.

Pain Modulation

• Afferent impulses arriving at the dorsal horn, themselves initiate inhibitory mechanisms.

Pain Modulation

• As fibre ascends collateral projections to higher centres (eg PAG and locus ceruleus of mid-brain).

• Descending fibres from PAG project to the nucleus raphe magnus (medulla) and RF to activate descending inhibitory neurones.

Pain Modulation

• Endogenous opioids- enorphins, enkephalins, dynorphins

• Action- bind opioid receptors, inhibit presynaptic release glutamate, increased K conductance across post synaptic membrane

Pain and Cannabinoids

Pain and Cannabinoids

• Endogenous cannabinoid system widespread n responsible for number modulatory functions, including analgesia

Pain and Cannabinoids

• Akin to endogenous opioid system, analgesic action mediated via:

• CB1- neuronal receptor

• CB2- immune cell-expressed receptor

Pain and Cannabinoids

• Animal data shown cannabinoids effective in many models of inflammatory and neuropathic pain

Pain and Cannabinoids

• Less evidence in human studies

• An effective cannabinoid analgesic should be therapeutic but without the ‘high’ of unwanted central side effects

Descending Inhibitory Pathways

Descending Inhibitory Pathways

• Travel in dorsolateral funiculus to terminate on interneurones in the dorsal horn.

• Fibres from PAG thought to be main source of inhibitory control.

Descending Inhibitory Pathways

• Descending inhibition also from LC (locus ceruleus) and NRM (nucleus raphe magnus).

• Inhibitory activity from PAG also stimulated by endorphins released from the pituitary- act directly at that site.

• 70% of endorphin/ enkephalin receptors in presynaptic membrane of nociceptors

Gate Control Theory

‘Gate’ control

• One aspect of modulation

• Synaptic transmission between 1o and 2o nociceptive afferents can be ‘gated’ by interneurones.

‘Gate’ control

• Neurones in SG exert pre-synaptic inhibition on 1o afferents and post-synaptic inhibition on 2o neurones

the pain response to a nociceptive stimulus.

• Inhibitory interneurones may be activated by afferents- subserve different sensory modalities eg: pressue (Aß fibres)

Gate theory

Gate theory

• Phenomenon underlies use of counter-irritation, dorsal column stimulation, TENS and mechanical stimulation (‘rubbing it better’)

• Descending central efferents from the PAG and locus

ceruleus can also activate these inhibitory interneurones.

Neurotransmitters

Neurotransmitters

• Numerous

• No single ‘pain neuro-transmitter’

Neurotransmitters

• Major excitatory transmitters at dorsal horn involved in nociceptive transmission:

– Glutamate

– Aspartate

Neurotransmitters

• Multiple receptors present at dorsal horn

– NMDA, non-NMDA, glutamate, AMPA, neurokinin, adenosine, 5-HT, GABA, -adrenergic and opioid receptors.

Neurotransmitters

• Primary afferents release various peptides, incl Substance P, neurokinin A and calcitonin gene-related peptide (CGRP).

Neurotransmitters

• Different neurotransmitters in various descending inhibitory pathways:

– Encephalins and endorphins in the PAG

– Metencephalin and 5-HT in the NRM pathway

– Noradrenaline in the locus ceruleus pathway

The Brain

The Brain

• Substantia Gelatinosa

• Periaqueductal Grey

• Reticular Formation

• Parabrachial Nucleus

The Brain

• Hypothalamus

• Cingulate Cortex

• Cortex

Neuropathic Pain

Neuropathic Pain

• Definitions?

• Causes?

More definitions

Term Definition

Allodynia Pain due to a stimulus which does not normally provoke pain

Analgesia Absence of pain in response to stimulation which would normally be painful

Central Pain Pain initiated or caused by a primary lesion or dysfunction in the CNS

Dysaesthesia An unpleasant abnormal sensation, whether spontaneous or provoked

Hyperalgesia An increased response to a stimulus which is normally painful

Hyperaesthesia Increased sensitivity to stimulation, excluding the special senses

Hyperpathia A painful syndrome characterised by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold

Hypoalgesia Diminished pain in response to a normally painful stimulus

Neuralgia Pain in the distribution of a nerve or nerves

Neuritis Inflammation of a nerve or nerves

Neuropathic Pain

Pain initiated or caused by a primary lesion or dysfunction in the nervous system

Neuropathy A disturbance of function or pathological change in a nerve: in one nerve, momoneuropathy; in several nerves, momoneuritis multiplex; if diffuse and bilateral, polyneuropathy

Pain threshold The least experience of pain which a subject can recognise

Pain tolerance level

The greatest level of pain which a subject is prepared to tolerate

Paraesthesia An abnormal sensation, whether spontaneous or eveoked

Causes of Neuropathic Pain?

INVITE

DAMP C

Pathophysiology of Neuropathic Pain

Mechanisms

• Ectopic activity

• Changes in membrane thresholds

• Wind up

• Ephamptic cross talk

• Neuromas

• Ab sprouting

Mechanisms

• CNS plasticity- following nerve injury, anatomical and neurochemical changes can occur in CNS

• Increased spontaneous activity in dh

Mechanisms

• Decreased threshold

• Increased responsivity to afferent input

• Cell death in sc

Mechanisms

• Ab sprouting- from laminae III to I,II

Mechanisms

• Barrage of afferent inputs:

•

• ↑ mRNA for specific neurotransmitters

• differential expression of mRNA and receptors

Mechanisms

• ↓ opioid binding sites

• ↑ immediate early gene products eg: c-fos, alterations in relative levels of neuropeptides/ neuromodulators

Wind-up

Wind-up

• Repetitive noxious stimulation of C fibres- prolonged discharge of dh cells

• Wind-up- progressive increase in no. of APs elicited per stimulus in dh

Wind-up

• Repetitive episodes of wind-up can lead to LTP (long-term potentiation)

• Long lasting increase in efficacy of synaptic transmission

Wind-up

• Wind-up n LTP both part of sensitisation process in many chronic pain states

• Expansion of receptive fields with tissue injury

Wind-up

• Therefore peripheral stimulation will activate more dh cells due to overlap of receptive fields

Allodynia and Hyperalgesia

Allodynia and Hyperalgesia

• Ectopic activity- spontaneous

• Ab sprouting fron III to I,II

• Sympathetic efferents sprouting into dh

• ↓ intrinsic modulatory systems

• ↑ excitatory activity

NMDA Receptor

NMDA Receptor

• C fibres to dh interneurones which release EAA (glutamate, glycine) via NMDA receptor which excites WDR neurones

NMDA Receptor

• NMDA receptor activation triggers a cascade of events leading to sensitisation of dh WDR

• ↑ Ca, ↑ PK, ↑ phosphorylating enzyme

NMDA Antagonists

• AP5 (2-amino-5-phosphonopentanoate)

• Ketamine

• MK-801 (dizocilipine)

• Phencyclidine

• Dextromethorphan

• Memantine

RCT evidence of effect of drugs on evoked pain

Drug Effect on

Tramadol Mechanical allodynia

TCA Mechanical allodynia

Gabapentin Cold allodynia

Opioids Skin hypersensitivity

IV lidocaine Mechanical allodynia

Topical lidocaine Mechanical and thermal hyperalgesia

Clinical Confusion

Clinical confusion

• Current classification little use!

• Same symptom- several mechanisms

• Same mechanism- different symptoms

• Same lesion- different symptoms

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