Pathophysiology of Pain

1. Pathophysiology of Pain Dr. Catherine Smyth Pain Core Program April 12th, 2007

3. What is Pain? • IASP • “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”

4. 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.”

5. 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

6. Med School Model of Pain • Multiple afferents • Multiple receptors • Multiple mediators • Multiple neurotransmitters • Ascending, descending, crossing over

7. 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)

8. 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

9. 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

10. 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 Ad versus C Fibres

11. First Pain

12. Second Pain

13. 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

14. Tissue-Chemical-Cellular Interactions

15. 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

16. 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

17. 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)

18. 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

19. 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)

20. 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)

21. 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

22. 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

23. Upregulation in the Periphery Normal Nociception Peripheral Sensitization (Inflammatory Soup)

25. Ectopic Activity

27. Action Potential in Ectopic Activity

28. Pathophysiology of Pain Peripheral 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

29. 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

30. Periphery to Spinal Cord • Note the close association between sensory afferents • Note especially the close association of somatic and sympathetic nerves

31. 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)

32. Pain Pathways

33. 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

34. Changes with Nerve Injury in the Dorsal Horn • Sprouting of nerve terminals in myelinated non-nociceptive Ab afferents in the dorsal horn • Form connections with nociceptive neurons in laminae I and II • Rewiring = persistent pain and hypersensitivity (?allodynia)

35. 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)

36. 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

37. 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)

38. 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

39. 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

41. “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.

43. Central Sensitization (Early) • Neurotransmitters activate their respective receptors • Activated receptors cause an increase in 2nd messengers (IP3, PKC, Ca2+) • Phosphorylation of their own receptors • Increased responsiveness and sensitivity

44. 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)

45. 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.

46. 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

47. 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

48. 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

49. 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

50. 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.