The Neurobiology of Pain

What is Pain?

• Pain is part of the body's defense system.

• The reflex reaction to escape painful stimulus is meant to adjust behavior to avoid the harmful situation in the future.

Sensation & Perception of Pain

• The sensation of pain consists of four distinct processes:

»Transduction»Transmission» Interpretation »Modulation

Transduction

• Nociceptors are stimulated in skin and muscle.• Noxious stimulus affects a periphery sensory

nerve ending.• Neuron is depolarized.• Electrical impulse is generated

Transmission

• Impulse is transmitted or carried throughout the nervous system.

• Spinothalamic tract is the most important pathway for transmission.

»We will come back to this

Interpretation • Subjective interpretation of pain.• How does it feel?– Sharp, Dull, Ache, Burn, etc.

• Behavioral, psychological, and emotional factors involved.

Modulation

• Modulation can either suppress or aggravate pain.

• Neural response.• Peptides, amino acids, neurotransmitters and

other mediators are released.• Chemical messages are released.

Transduction

Nociception

• Sensory neurons, called nociceptors, are found in every part of the body that can sense pain.– Skin, muscle, joints, and the digestive tract.

• When exposed to noxious stimuli, an action potential is generated and driven from the periphery toward the CNS

• There are four main categories of nociceptors: Thermal, Chemical, Mechanical and Sleeping.

Types of Nociceptors

• Thermal Nociceptors:– Detect hot or cold noxious stimuli.

• Mechanical Nociceptors:– Detect noxious pressure or deformation, such an an

incision.• Chemical Nociceptors:– Respond to many different types of chemicals, including

capsaicin.• Sleeping / Silent Nociceptors:– Only respond to post-injury inflammation.

Types of Nociceptive Pain

• Superficial Somatic pain is caused by injury to the skin or superficial tissues– produces a sharp, localized pain of short duration.

• Deep Somatic pain originates from ligaments, tendons, bones, and muscles.– Produces a dull, aching, non-localized pain of longer

duration. • Visceral pain originates from the body’s organs.– Produces more of an aching or cramping pain that is of a

longer duration than somatic pain

Pain Pathway

Transmission

• Activation nociceptors by noxious stimuli generates signals that travel to the dorsal horn of the spinal cord.– How?

Peripheral Nerves

• Nerves can either be slow or fast.– The slower type neural fibers are

deeper in the skin and transmit signals at a rate of 1-2 meters per second on un-myelinated C neurons.

– The fast type pain sensors require an intense stimulus to activate and transfer signals that are perceived as acute sharp stinging pain at a rate of 5 to 30 meters per second along myelinated A Delta neurons

The Spinal Cord• The signal reaches the Dorsal Horn of the spinal cord.• Action potentials induce neurotransmitter release.

– Voltage gated sodium ion channels – Glutamate (fast) binds to ionotropic AMPA and NMDA receptors.

The Brain

• From the dorsal horn, the signals are carried along the Spinothalamic Tract to the Thalamus, Cortex, PAG and other regions of the brain.

The Descending Pain Pathway

• The descending pathway of the spinal processing of nociceptive input is relayed through the:

»Periaqueductal gray»Frontal Cortex» Insula»Amygdala»Hypothalamus»Brainstem

Other Types of Pain

• Inflammatory pain– This type of pain results from the cascade of

biochemical events that are initiated with tissue damage.

• Neuropathic pain– Pain generated independently by the nervous system

resulting directly from action on nerves, such as severing. May also result from the culmination of physiological processes that are set in motion by persistent nociceptive or inflammatory processes.

Inflammatory / Neuropathic Pain

Treatment

NSAID’s

• Non Steroid Anti Inflammatory Drugs– The most prominent members of this group of drugs are

aspirin, ibuprofen, and naproxen.• They act as non-selective inhibitors of the enzyme

cyclooxygenase.– Inhibition of COX-1 and COX-2

• Cyclooxygenase catalyzes the formation of prostaglandins.– Prostaglandins act as messenger molecules in the

process of inflammation

Cox-2 Inhibitors

• A form of NSAID that directly targets COX-2.– i.e., Celebrex and Vioxx

• Similar in effectiveness to NSAID’s, but do not cause the gastrointestinal problems common to non-specific COX inhibitors.

• May increase the risk for heart attack and stroke

Opioids

• Opioids are commonly prescribed for moderate to severe pain.– Morphine, Vicodin, OxyContin, etc.

• They work by blocking the transmission of pain signals to the brain.

• Many side effects – Addiction, tolerance, risk for overdose, respiratory

depression.• We will explore this class of drugs in depth next

lecture.

Off – Label Perscriptions

• Some medications typically prescribed for other non-pain conditions can be used for pain relief of certain conditions.– Axiolytics (Benzodiazepines)– Antidepressants (SSRI / Tricyclic)– Anticonvulsants – Muscle Relaxers

Nociceptor

Peripheral Nerve

Interneuron

AscendingPathway

Descending Pathway

Sympathetic Efferent's

Spinal Cord

NSAID’sOpioids

Opioids

Opioids

Tricyclics

Antidepressants

AnxiolyticsAnticonvulsants

Alpha-1 BlockersAlpha-2 Agonists

NMDA Receptor Blockers