Pathophysiology of Pain

Dr. Catherine SmythPain Core ProgramApril 12th, 2007

What is Pain? IASP “An unpleasant

sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”

Descartes (1644) Concept of the Pain Pathway

“If for example fire (A) comes near the foot (B), the minute particles of this fire, which as you know move with great velocity, have the power to set in motion the spot of the skin of the foot which they touch, and by this means pulling upon the delicate thread (cc), which is attached to the spot of the skin, they open at the same instant the pore (de) against which the delicate thread ends, just as by pulling at one end of a rope one makes to strike at the same instant a bell which hangs at the other end.”

Processing of Pain

Normal pain Nociceptive pain

involves the normal activation of the nociceptive system by noxious stimuli.

Nociception consists of four processes: transduction transmission perception modulation

                                                               

                                                                                       

Med School Model of Pain

Multiple afferents Multiple receptors Multiple mediators Multiple

neurotransmitters Ascending,

descending, crossing over

Throw Away (part) of the Old Model! Pain is a dynamic interlocking series of

biological reactive mechanisms that changes with time

The experience of pain alters the pathophysiology

Pain mechanisms may be as varied as the individuals with pain (despite the same complaint!)

There is no such thing as a hard-wired, line-labelled, modality-specific, single pathway which leads from stimulus to sensation (Editorial, BJA 75(2) 1995)

Outline Nociceptors

Inflammation Peripheral Sensitization

Afferent Mechanisms Tracts Neurotransmitters

The Dorsal Horn and Spinal Cord The Gate Theory NMDA Receptors Central “Wind-Up” Secondary Hyperalgesia

Descending Inhibition and Facilitation Opioid Induced Hyperalgesia

Nociceptors Pain sensors/receptors = nociceptors Located in skin, muscle, joints, viscera Closely linked to peripheral sensory and

sympathetic neurons (“free nerve endings”)

Convert sensory information into electrochemical signal (action potentional)

Many and varied types of nociceptors Distinct sensory channels for different

types of pain

A versus C Fibres High threshold Mechanoreceptors and

temperature (painful) Fast, myelinated 5 to 30 m/sec First pain; transient Well localized Sharp, stinging, pricking Uniform from

person:person

Low threshold Polymodal (various

stimuli – mechanical, thermal, metabolic)

Slow, unmyelinated 0.4-1 m/sec Second pain; persistent Diffuse Burning, aching Tolerance varies from

person:person

First Pain

Second Pain

Inflammatory “Soup” Tissue mediators released by cellular injury Neuromediators released by nerves Blood vessels, mast cells, fibroblasts, macrophages,

neutrophils add other compounds to the mix Significant bi-directional interaction of mediators Pool of chemical irritants “excite” the nociceptors The list of tissue mediators includes: K+, lactate, H+,

adenosine, bradykinin, serotonin, histamine, prostaglandins, and leukotrienes

The list of neuromediators includes:Glutamate, Neurokinins, Substance P, CGRP, serotonin, norepinephrine, somatostatin, cholecystokinin, VIP, GRP and Galanin

Tissue-Chemical-Cellular Interactions

Ions and Lactate Physical damage to cells Changes in membrane permeability Failure of sodium-ionic pump Intense irritation and excitation of afferent

nerve endings from high concentrations of K+ H+ ions from celluluar efflux favour the release

of bradykinin from plasma proteins Lactate produced during injury (esp. ischemia)

causes direct excitation of nociceptors

Bradykinin Nonapeptide derived from plasma protein Its release is increased when tissue pH decreases (ie.

Injury) Acts on 2 receptors: B1 (vascular) and B2 (nerves) Vasoneuroactive peptide One of the most potent nociceptor irritants Excites primary sensory neurons provoking the

release of substance P, neurokinin and CGRP (all neuromediators of pain)

Actions of BK are non-specific (affects all nerve endings in the tissue)

Stimulates sympathetic postganglionic nerve fibres to produce PGE2

Prostaglandins and Leukotrienes Result of arachidonic acid (AA) metabolism Again, BK is implicated as it activates

phospholipase A2 which releases AA from phospholipid complexes (cell membranes)

AA metabolized into eicosanoids by cyclooxygenase and lipoxygenase

Prostaglandins and leukotrienes sensitize nociceptors to all stimuli (ie. Chemical, mechanical, heat)

(action of NSAIDs)

Serotonin/Histamine Serotonin derived from platelets Serotonin is strong nociceptor stimulant Serotonin causes vasoconstriction (At the level of the spinal cord, it antagonizes

substanceP) Histamine is released from mast cells Tissue damage causes BK, H+, PG to activate C

polymodal nociceptors Nociceptors release neuromediators such as substance P

and CGRP triggering mast cells to release histamine Histamine acts on local afferent nerve endings and blood

vessels

Substance P Production is increased in most pain states

in primary afferent neurons Produced in the nucleus and transported

centrally and peripherally Neurotransmitter, edema, vasodilation Release of histamine Capsaicin (neurotoxin, blocks the release of

substance P at free nerve endings, reduces number of neurons containing substance P)

CGRP Calcitonin-Gene Related Peptide Similar action to Substance P Enhances responsiveness of afferent nerve

terminals (sensitizes) Potent vasodilator Causes mast cells to release leukotrienes Contributes to wound healing (fibroblasts and

smooth muscle cells proliferate)

What’s happening at the tissue level??

Tissue injury results in PG, K and BK release

Activated C fibers release Substance P and CGRP locally

This triggers platelets and mast cells to release 5HT, H+ and more BK

Local reactions spread to other nearby axons causing hyperalgesia

Peripheral Sensitization What is it?

Decreased threshold for activation Increased intensity of response to a

stimulus Beginning of spontaneous activity

Why develop it? Reparative role; easier activation of pain

pathway allowing tissue to heal How is it activated?

“inflammatory soup” in damaged tissue

Upregulation in the Periphery

Normal Nociception Peripheral Sensitization

(Inflammatory Soup)

Peripheral Sensitization

Innocuous stimulus

Primary afferent nerve fibersDorsal horn

neurons

Neuropeptide release

NGF

NGF

NGF

NGF

Pain sensation

Woolf and Mannion. Lancet 1999;353:1959-64

Ectopic Activity

Ectopic Discharges

Injured nerve fibers develop increased expression of Na+ channels

Na+ channel expression increased

Primary excitatory afferent nerve fibre

Conduction frequency amplified

England et al. Neurology 1996;47:272-6; Ochoa et al. Brain 1980;103:835-53; Taylor. Curr Pain Headache Rep 2001;5:151-61; Sukhotinsky et al. Eur J Pain 2004;8:135-43.

Na+ = sodium ion

Action Potential in Ectopic Activity

Pathophysiology of PainPeripheral Sensitization Injury to peripheral neural axons can result in abnormal nerve

regeneration in the weeks to months following injury. The damaged axon may grow multiple nerve sprouts, some of which form neuromas. These nerve sprouts, including those forming neuromas, can generate spontaneous activity. These structures are more sensitive to physical distention.

These neuromas become highly sensitive to norepinephrine and thus to sympathetic nerve discharge. The nerves develop active sodium channels that become the sites of tonic impulse generation, known as ectopic foci

After a period of time, atypical connections may develop between nerve sprouts or demyelinated axons in the region of the nerve damage, permitting “cross-talk” between somatic or sympathetic efferent nerves and nociceptors. Dorsal root fibers may also sprout following injury to peripheral nerves

Gate Control Theory Wall & Melzack ’65 Substantia gelatinosa interneurons Balance of:

Afferent nociception Nonnociceptive Afferent neural

traffic (touch) Central inhibition

= Final flow of nociception centrally

Periphery to Spinal Cord

Note the close association between sensory afferents

Note especially the close association of somatic and sympathetic nerves

Neural Circuits Review of 3 order classic

pain pathway 1st order neurons terminate

in the dorsal horn 2nd order neurons cross and

ascend 2nd order neurons may

terminate in brainstem OR 2nd order may ascend to

the thalamus Third order neurons project

to frontal cortex or somatosensory cortex (medial vs. lateral projections)

Pain Pathways

Neural Connections in the Lamina Sensory afferents

enter the dorsal horn Ascend 1-2 segments

in Lissauer’s tract Terminate in the grey

matter of the dorsal horn

Nerve fibers terminate in various laminae

Adelta = lamina I, V C fibers = I through V A beta = lamina III

Changes with Nerve Injury in the Dorsal Horn

Sprouting of nerve terminals in myelinated non-nociceptive A afferents in the dorsal horn

Form connections with nociceptive neurons in laminae I and II

Rewiring = persistent pain and hypersensitivity (?allodynia)

Central Pharmacology and Nociceptive Transmission

Afferent transmitters (receptor-mediated) Neurokinins, bradykinins, CGRP,

bombesin, somatostatin, VIP, glutamate (NMDA and non-NMDA), nitric oxide

Non-afferent receptor systems Opioids, adrenergic, dopamine, serotonin,

adenosine, GABA, cholinergic, Neuropeptide Y, Neurotensin, glutamate (NMDA and non-NMDA)

Organization of the Dorsal Horn Afferents release

peptides and “excite” 2nd order neurons

Afferents excite interneurons through NMDA.R

Substance P causes glia to release PG

Lg. afferent fibres release GABA, glycine and inhibit 2nd order neurons

Some activated interneurons release enkephalins

Bulbospinal pathways (5-HT, NE) hyperpolarizes membrane

Second Order Neurons In general, there are two types of

second-order nociceptive neurons in the dorsal horn

Those that respond to range of gentle - intense stimuli and progressively increase their response (Wide Dynamic Range Neurons; WDR)

Those that respond only to noxious stimuli (Nociceptive-specific; NS)

WDR Neurons Predominate in lamina V (also in IV, VI) Respond to afferents of both Adelta and C

fibres Deafferentation injury leads to classic response

of WDR neurons (work harder) With a fixed rate of stimulation from C fibers,

the WDR neurons progressively increase their response

This is termed the “wind-up” phenomenon Pre-emptive analgesia

Wind Up and the NMDA.R Action of opioids

mainly presynaptic (reduced release neurotransmitters)

NMDA.R implicated in Wind Up phenomenon

Dorsal horn nociceptive neuron and effects of repeated stimuli in two groups

Central Mechanisms: Wind-up

Primary afferent nerve fibres Dorsal horn neurons

Repetitive afferent barrages in C-fibers induce discharges of dorsal horn neurons at progressively greater frequencies

Stimulus

Stimulus

“Wind Up”

Repetitive noxious stimulation of unmyelinated C–fibers can result in prolonged discharge of dorsal horn cells. This phenomenon which is termed "wind–up", is a progressive increase in the number of action potentials elicited per stimulus.

Repetitive episodes of "wind–up" may precipitate long–term potentiation (LTP), which involves a long lasting increase in pain transmission. This is part of the central sensitization process involved in many chronic pain states.

AAßß mechanoreceptormechanoreceptor

innocuousinnocuousstimulusstimulus

innocuousinnocuousstimulusstimulus

Nerve injury: Increased nociceptor drive leads to central sensitization

nonnon--painfulpainful

painful

Normal: Aß activation will not stimulate pain-mediating dorsal horn neurones

Woolf and Mannion. Lancet 1999;353:1959-64

AAßß mechanoreceptormechanoreceptor

Central Mechanisms:Stimulus-dependent Sensitization

Central Sensitization (Early) Neurotransmitte

rs activate their respective receptors

Activated receptors cause an increase in 2nd messengers (IP3, PKC, Ca2+)

Phosphorylation of their own receptors

Increased responsiveness and sensitivity

Central Sensitization (Late) Stimulation of

DRG neurons cause gene induction (Cox-2)

Production of prostaglandins (PGE2)

Directly alter excitability neuronal membrane

PGE2 reduces inhibitory transmission

++nociception decreases transcription of inhibitory genes (DREAM)

Central Sensitization

Following a peripheral nerve injury, anatomical and neuro–chemical changes can occur within the central nervous system (CNS) that can persist long after the injury has healed.

As is the case in the periphery, sensitization of neurons can occur within the dorsal horn following peripheral tissue damage and this is characterized by an increased spontaneous activity of the dorsal horn neurons, a decreased threshold and an increased responsivity to afferent input,

A beta fibers (large myelinated afferents) penetrate the dorsal horn, travel ventrally, and terminate in lamina III and deeper. C fibers (small unmyelinated afferents) penetrate directly and generally terminate no deeper than lamina II. However, after peripheral nerve injury there is a prominent sprouting of large afferents dorsally from lamina III into laminae I and II. After peripheral nerve injury, these large afferents gain access to spinal regions involved in transmitting high intensity, noxious signals, instead of merely encoding low threshold information.

Explaining Allodynia

The allodynia and hyperalgesia associated with neuropathic pain may be best explained by: 1) the development of spontaneous activity of afferent

input 2) the sprouting of large primary afferents (eg. A–beta

fibers from lamina 3 into lamina 1 and 2), 3) sprouting of sympathetic efferents into neuromas and

dorsal root and ganglion cells, 4) elimination or reduction of intrinsic modulatory

(inhibitory) systems 5) up regulation of receptors in the dorsal horn which

mediate the excitatory process

Descending Modulation Brain stem descending pathways play a

major role in control of pain transmission Well established neural circuit linking

Periaqueductal Gray (PAG), Rostral Ventromedial Medulla (RVM) and the spinal cord

Parallel mechanisms of Descending Inhibition and Facilitation arise from the brainstem

The Rostral Ventromedial Medulla On-Cells

Fires before and facilitates a nocifensive response Facilitates nociceptive transmission Firing of on-cells increases in inflammation

Off-Cells Pause in activity before nocifensive response Decrease firing in the face of noxious stimulation

(antinociceptive neurons) Pauses reduced in inflammation (i.e.less

antinociception) There is a balance between synaptic excitation and

inhibition in various pain conditions Severe persistent pain may represent the central

facilitatory network overriding the central inhibition

The Usual Response to Pain and Inflammation Early (within 48-72 hrs)

Increase in descending facilitation Primary hyperalgesia and allodynia Enhances nocifensive escape behaviour and

protects the organism Secondary hyperalgesia occurs when the

balance favours facilitation of pain (protective)

Late (> 3 days) Increase in descending inhibition Movement of the injured site is suppressed or

reduced to aid in healing/recuperation

Upsetting the Balance of Descending Pathways Nerve injury and Neuropathic Pain Disrupts the balance between facilitation

and inhibition of pain Maintenance of hyperalgesia for prolonged

periods of time is indicative of enhanced descending facilitation

The nervous system is inherently plastic; therefore nerve injury may activate a descending nociceptive system that is meant to protect the organism early in inflammation but actually leads to persistent pain states.

Disinhibition of Pain Reduced synthesis of

GABA and glycine Destruction of

inhibitory interneurons due to the excitotoxic effects of massive releases of glutamate following nerve injury

Less GABA and glycine Leads to increased

excitability of pain transmission neurons

Pain response with innocuous inputs

Normal

Injured

Innocuous ornoxious stimulus

Exaggeratedpain

response

To brain

Descending

Local

Dorsal horn neuronDorsal horn neuron

Descending

Local

To brain

Woolf and Mannion. Lancet 1999;353:1959-64

Spontaneous Spontaneous firingfiring

Central Mechanisms: Loss of Inhibitory Controls

Opioid-induced abnormal pain sensitivity Opioids as pro-nociceptors Not due to “mini-withdrawals” Likely due to tonic activation of descending

pain facilitory pathways from the RVM NMDA.R implicated in opioid-induced pain

sensitivity (experimental inhibition) Spinal dynorphin increases with opiate

infusions and modulates opioid-induced pain

How to distinguish opiate pharmacological tolerance vs. opioid-induced pain sensitivity

Summary Nociceptors

Inflammation Peripheral Sensitization

Afferent Mechanisms Tracts Neurotransmitters

The Dorsal Horn and Spinal Cord The Gate Theory NMDA Receptors Central “Wind-Up” Secondary Hyperalgesia

Descending Inhibition and Facilitation Opioid Induced Hyperalgesia

Summary (We have not discussed central modulation of pain (role of

the cerebral cortex)) Pain is critical for survival but with chronic pain, may

become the disease itself Targeted approach to analgesia --- We need new drugs and

technologies (however …) The pain pathways are not static – they are plastic with new

connections forming constantly (just to keep you on your toes)!

Chemicals that transmit pain can be neurotoxic and lead to loss of inhibitory controls

Translational then transcriptional changes in neurons predominate with pain and inflammation and nerve injury causing hypersensitivity

Any Questions????