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Pathophysiology of Pain

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

2 PAIN is something that definitely grabs one’s attention
PAIN is something that definitely grabs one’s attention. It is a four letter word that causes significant suffering and distress for many of our patients. As we all know, pain is not an easy entity to treat. Fortunately, there is an ever growing and fascinating scientific literature dealing with the molecular biology and neurophysiology of pain. I believe that the comprehension of pain mechanisms is important in tailoring effective treatment. Unfortunately, there is still a huge gap between what we know from a mechanistic point of view of pain and the availability of specific drugs or modalities to treat pain. The technical and pharmaceutical advances in pain lag significantly behind comprehension but it is still a worthy topic to study and discuss – if only to comprehend the reasons for such suffering in our patients.

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” “Pain is a hurt we feel” Richard A. Sternbach (Mastering Pain – 12 step approach). How many of you have tried to ask patients what their pain feels like and have been told “IT JUST REALLY HURTS A LOT”?? Pain is a unique personal experience that cannot be fully shard by anyone else. Pain is personal, subjective and difficult to quantify (if quantity is really what’s important). The understanding of pain is complicated further by the fact that the same painful stimulus may be perceived differently by different people, and differently by the same people at different times. In 1992, the International association for the study of pain (IASP) defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. Actually, pain is an extremely complex network of neurotransmitters, receptors, and pathways. From the tissue level with nociceptors via nerve fibers to the dorsal horn of the spinal cord and then rostral to the medulla, brainstem, thalamus and cerebral cortex – pain is complex! (Go over diagram in more detail drawing attention to pathways and chemical mediators at the various levels.)

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.” We have to begin somewhere in our discussion of the pathophysiology of pain. This is an illustration of Descartes concept of the pain pathway which was proposed in 1644. This is a very simplified diagram but Descartes was aware of the rapid connection between the periphery and the brain in the conduction of pain.

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 This is representative of one of the current models of pain. Note that it includes pain transmission pathways as well as pain modulation (central inhibition) pathways. The classic pain pathway consists of a three-neuron chain that transmits pain from the periphery to the thalamus and cerebral cortex. The first order neuron has its cell body in the dorsal root ganglion and two axons, one that projects distally to the tissue it innervates and the other that extends centrally to the dorsal horn of the spinal cord. In the dorsal horn, this axon synapses with the second-order neuron, the axon which crosses the spinal cord through the anterior white commissure and ascends in the spinothalamic tract to the thalamus. In the thalamus, the nerve synapses with the third-order neuron which projects through the internal capsule and corona radiata to the postcentral gyrus of the cerebral cortex. The information is then somatopically organized in the cerbral cortex. It is relatively complex compared to Descartes concept of the pain pathway. However, one of the interesting and challenging facts about the neural pathways of pain is that the system is PLASTIC. Neural plasticity dominates the physiology of pain and is especially relevant in patients with chronic malignant and non-malignant change. New connections are formed, cells prematurely die from apoptosis, phenotypes of cells are changed, production of new nerve transmitters are triggered. Suddenly there is an entirely new system. I am certain that in years, our model of pain will be viewed similarly to that of Descartes.

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) Throw away all the old models.

8 Outline Nociceptors Afferent Mechanisms
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 As I stated before, we need to go over some of the bread and butter type of information regarding the pathophysiology of pain. We are also going to look at some of the concepts that come up frequently in conversation but are we really sure what they mean in pain terms. Lastly, I am going to introduce some new exciting topics about pain physiology that might make your brain hurt and may ultimately change the way we practice both in the OR and in the pain clinic setting.

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 As you all likely know already, pain receptors are known as “nociceptors” and are located in various structures throughout the body. It is believe that nociceptors are not directly localized on nerve terminals but are spatially very closely related to peripheral sensory and sympathetic nerve fibres - they play a role as transducers of pain. The purpose of nociceptors is to convert the sensory information (whether it is mechanical, caustic or temperature related) into an electrochemical signal. There are different sensory channels on the nociceptor which allow it to respond to different types of pain stimuli. For instance, mechanical stimuli generates a different frequency of signal than a chemical irritant.

10 Ad 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 In this slide, we compare and contrast the two types of afferent pain fibers, the A delta and C fibers.

11 First Pain First pain is a sensation carried by small myelinated A-delta fibers. Noxious stimuli such as extreme cold, mechanical stimuli, heat and acid (protons) are able to stimulate individual nociceptors or ion channels in tissue. For instance, TRPV are heat transducer nociceptors. The nociceptors are located at the peripheral terminals of unmyelinated C-fibers and thinly myelinated Adelta fibers. Activation leads to the generation of electrical activity which propogates the message to the dorsal root ganglion, spinal cord and via central pathways to the cortex.

12 Second Pain Unmyelinated C-fibers carry “second pain”
In the situation of second pain, there is damaged tissue or tumour cells which release chemical mediators of pain. The ten mediators in this “inflammatory soup” are the biggest offenders and I will discuss some of them in a few minutes. In this process of inflammation, mast cells, macrophages and neutrophils also release chemicals which activate or modify a response in the nociceptor afferents.

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 Several chemicals and inflammatory mediators are released by cellular injury and stimulate tissue nociceptors directly and indirectly. There are both tissue and neuromediators that are involved but there is a significant amount of cross-talk or bi-directional interaction between the mediators. In addition, blood vessels, fibroblasts, macrophages and neutrophils add other compounds to a pool of chemical irritants that excite then sensitize nociceptors. GRP == gastrin-related peptide.

14 Tissue-Chemical-Cellular Interactions
Note that the various “players” i.e. mast cells, neutrophils, macrophages, blood vessels and fibroblasts can have direct effects on the primary afferent neurons but they are also releasing mediators which are stimulating/regulating their counterparts. This is what is meant by bi-directional interaction by the mediators

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 Bradykinin is one of the most notorious chemicals in the inflammatory soup. It is a protein made up of 9 amino acids. It is released from blood vessels when the pH of tissue decreases (this represents virtually every sort of injury). Bradykinin causes the direct excitation of sensory neurons causing them to release substance P, neurokinin and calcitonin-gene related peptide. They are all neuromediators of pain.

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 Tissue injury results in prostaglandin, potassium and bradykinin release Activated C fibers release substance P and CGRP locally (antidromic) Platelets and mast cells release serotonin, hydrogen ions and more bradykinin Affects adjacent axons spreading the inflammation and 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 One of the phrases that we talk about fairly often as physicians is the concept of sensitization to pain. It is something we see fairly often in the short and long-term with tissue injury (this includes tumours). Patients appear much more sensitive to slightly painful or even touch in the area of injury. There is a physiological explanation for this phenomenon.

23 Upregulation in the Periphery
The diagram on the left represents the normal transmission of external noxious stimuli into electrical activity in either Adelta and C somatosensory afferent terminals. In this situation there is a heat stimulus which must reach a certain threshold before activating TRPV1 (heat transducer receptor). The action potentials are conducted to the dorsal horn of the spinal cord and the input is conveyed after synaptic processing, via the spinothalamic and spinoparabrachial pathways to higher centers. Therefore, The diagram on the left demonstrates normal nociception under physiological conditions. The diagram on the right shows the changes that occur to the Adelta and C somatosensory afferent terminals under the conditions of inflammation following injury. Some of these processes occur very quickly causing peripheral sensitization. Components of the inflammatory soup which we recently discussed (bradykinin, prostoglandins), bind to G-protein coupled receptors and activate protein kinase C. The heat transducing proteins are phosphorylated in the process of inflammation which reduces their threshold for activation, thereby increasing the excitability of the nerve terminal. There may also be general alterations in the membrane properties in inflammation. Also, a more delayed response is the retrograde transmission of signals to the cell body which begins to increase transcription and translation of proteins that are then transported in an orthograde manner to the periphery. (point out increase in sodium channels). All of this contributes to a heightened sensitvity in the terminal membrane. This is the definition of peripheral sensitization Normal Nociception Peripheral Sensitization (Inflammatory Soup)

24 Peripheral Sensitization
This diagram shows how nociceptor stimulation can lead to the sensitization of peripheral nerve terminals. Key Talking Points: The perception of pain in response to innocuous stimuli may be, in part, attributed to peripheral sensitization. Peripheral sensitization lowers the activation threshold of both damaged nerve fibres and undamaged neighbouring nerve fibres. When certain types of nociceptors are stimulated, the action potentials travel orthodromically towards the central nervous system, but also antidromically, to invade all the peripheral terminal branches of the neuron (a phenomenon called “axon reflex”). This antidromic invasion of the terminal branches will induce the release of inflammatory mediators, causing neurogenic inflammation that will, in turn, sensitize nearby nociceptors. Antidromic activity can trigger the release of excitatory neuropeptides, such as substance P and calcitonin-gene-related peptide. These neuropeptides may lead to the sensitization of the peripheral sensory terminals of injured and neighbouring uninjured fibres. Therefore, spontaneous activity (neuropeptide release) in primary afferents can produce peripheral sensitization in injured and uninjured adjacent neurons. Partial denervation also increases relative concentrations of nerve growth factor (NGF) for intact cells. Nerve growth factor is found in a variety of peripheral tissues. It attracts neurites to the tissues by chemotropism, where they form synapses. The successful neurons are then protected from neuronal death by continuing supplies of nerve growth factor. References:Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353: Orstavik K, et al. Pathological C-fibres in patients with a chronic painful condition. Brain 2003;126:

25 Ectopic Activity The other thing that can happen followng tissue injury is the production of spontaneous or ectopic activity from the nociceptor afferents. In other words, a stimulus (heat, chemical mechanical) is not required in order for the nerve to discharge, sending a message of pain to the spinal cord and thalamus. In the situation where there is damage or injury (even if its microscopic) either to the axon or the terminal end of a afferent nerve terminal. One of the adaptations that the nerve undergoes in injury is to upregulate the sodium channels (both through post-translational changes) such as phosphorylation and by increases in the transcription of sodium channels. At the same time there is a general trend to a reduction in potassium channels in injured nerves.

26 Ectopic Discharges This slide illustrates the concept that after nerve injury, membrane hyperexcitability may develop at different sites. Key Talking Points: The ability of nerve fibres to conduct impulses is mainly related to the normal interplay between sodium (Na+) and potassium (K+) channels in the axonal membrane of the neuron. After nerve injury, this normal equilibrium is altered, which leads to conduction failure (the cause of negative symptoms, e.g., numbness), and frequently to hyperexcitability (a cause of positive symptoms, e.g. tingling). Regenerating fibres from parent axons in damaged nerves are highly excitable and develop with an abnormally high number of Na+ channels, which may result in ectopic discharges (i.e., repetitive firing capability in the region of the nerve injury), these ectopic discharges may be spontaneous or evoked by mechanical or chemical stimuli. The sensory modality of the ectopically active fibre cause different sensations; ectopic activity in A-beta touch fibres leads to the experience of tactile paresthesias or dysesthesias and ectopic activity in A-delta or C nociceptors induces pain of different qualities (sharp-pricking or burning-aching pain). Ectopic discharges may also occur in other parts of injured axons; including damaged or demyelinated segments of injured fibres. The body of the damaged neuron, located in the dorsal root ganglion, may also engage in spontaneous ectopic discharges, even if the original injury took part in a distal segment of the axon. References:England JD, et al. Sodium channel accumulation in humans with painful neuromas. Neurology 1996;47: Ochoa JL, Torebjork HE. Paraesthesiae from ectopic impulse generation in human sensory nerves. Brain 1980;103: Taylor BK. Pathophysiologic mechanisms of neuropathic pain. Curr Pain Headache Rep 2001;5: Sukhotinsky I, et al. Key role of the dorsal root ganglion in neuropathic tactile hypersensibility. Eur J Pain 2004;8:

27 Action Potential in Ectopic Activity
If you recall your first physiology course – you may remember the Nernst equation and the derivation of the resting membrane potential. Generally, the resting membrane potential in a nerve may be -65 mV to -90 mV. The resting membrane potential depends on the ratio of Na and K ions in the intracellular and extracellular fluid. In a simplistic view, the resting membrane potential is regulated by sodium and potassium pumps. The membrane potential needs to reach a more positive value (such as -65 or -45 depending on the sensitivity of the system) in order to reach a threshold which then leads to an action potential. When sodium moves into a cell, it causes the resting membrane potential to rise, bringing it closer to threshold. This is equilibrated by the movement of another positive ion potassium out of the cell. However, in the situation of a damaged nerve that has upregulated its sodium channels and downregulated its potassium channels. The nerve is much more likely to be at a higher resting membrane potential than normal following injury. Indeed, the threshold may be reached and there could be ectopic firing of an action potential in the damaged nerves without a stimulus.

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 According to the theory of Wall and Melzack, incoming small-diameter fibers (such as pain fibers Adelta and C) decreased the activity of inhibitory interneurons in the substantia gelatinosa (therefore causing increased excitation). This is balanced by the fact that large-diameter afferent fibers (i.e. touch) increase the activity of inhibitory neurons. The balance of decreased inhibition by the pain fibres and increased inhibition by the touch fibers leads to a a final tally between the two afferents and a final flow of nociception centrally. One way that anesthetists use the gate control theory on a daily basis is to gently touch or scratch the skin immediately adjacent to the insertion site of an IV. According to the theory, the touch which is transmitted by large fibers should increase the inhibition of the interneurons in the spinal cord and inhibit pain transmission to the CNS.

30 Periphery to Spinal Cord
Note the close association between sensory afferents Note especially the close association of somatic and sympathetic nerves The neurotransmitter, substance P plays an important role in the dorsal horn. It is released synaptically and extra-synaptically. It can act on its own nerve endings (autotransmitter) or on other post-synaptic nerve fibers (neurotransmitter). It is definitely involved in the regulation of hyperalgesia, as injection of substance P into the spinal fluid leads to increased sensitivity to painful stimuli. This is an appropriate slide to take an aside and briefly look at the anatomy in order to understand a dorsal rhizotomy versus a dorsal root entry zone lesion. Dorsal rhizotomies (point out location on diagram) occur at this level. They have shown to be not overly successful as they actually lead to an upregulation of substance P in the spinal cord and a type of denervation hypersensitivity. Alternatively, the dorsal root entry zone lesion may be more effective. In this situation, a radio-frequency lesion is made in the cord itself. This affects the entering axons, their terminations and various surrounding interneurons.

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 The posterior columns include the Fasciculus gracilis and fasciculus cuneatus. They are involved in the transmission of touch, pressure, vibration sense and proprioception. The anterior spinothalamic tract transmits light touch. The lateral spinothalamic tract transmits pain and temperature. This is one of the reasons that when an anesthetist tests for adequacy of nerve block (presumably for a surgical incision), they use sensation of temperature to see if these tracts are adequately blocked. These tracts will ascend to the thalamus. The spinoreticular tract transmits pain. As the name dictates, these tracts ascend to the reticular system in the brainstem.

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) The top diagram shows the normal situation and arrangement between nociceptive and non-nociceptive afferent nerve terminals. Indeed, the interneuron which connects or feedsback onto the nociceptive afferent is a diagramatic representation of the Gate Theory and inhibition of nociception by stimulation of non-nociceptive nerve fibers. In contrast, when there is nerve injury, the central terminals of myelinated non-nociceptive A-beta afferents sprout in the dorsal horn and form new connections with nociceptive neurons in laminae I and II. This re-wiring of the circuitry of the spinal cord may contribute to persistent pain hypersensitivity.

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 This diagram is a summary of the functional organization of elements in the dorsal horn which impact upon the processing of afferent input. The primary afferent C fibres contain and release both peptides (substance P and CGRP) and excitatory amino acids (glutamate). These neurons have been shown to contain and release nitric oxide with stimulation. When peptides and excitatory amino acids are released they excite 2nd order neurons. Interneurons can also be excited by an afferent barrage of information and causes excitation of a second order neuron through glutamate and the NMDA receptor. Intervening products such as prostaglandins may arise from non-neuronal structures such as glia by the action of substance P. Second order neurons also receive excitatory input from large afferents. It appears as though GABA and glycine released by large afferents inhibits the second order neurons. Interneurons containing enkephalins may be activated by afferent input and reflexly exert a modulatory influence upon the release of C-fibre peptides and to hyperpolarize the projection neuron. The bulbospinal pathways containing monoamines such as serotonin and norepineprine may also play a modulatory role on the release of C-fibre peptides and the hyperpolarization of the projection neuron.

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 An example of wind-up in a dorsal horn nociceptive neurone from a rat under halothane anesthesia. A number of repeated identical C-fibre stimuli are given and the response of the neurone is measured. In the control (open circles) the response starts to increase after the first few stimuli and ends up at a much higher level. Note how block of the NMDA.R (ketamine, MK-801) in the dark circles prevents the neuron from exhibiting wind-up and so the response to the stimulus remains constant.

40 Central Mechanisms: Wind-up
This slide demonstrates “wind up” in which repetitive afferent barrages in C-fibres induce discharges of dorsal horn neurons at progressively greater frequencies. Key Talking Points: Central mechanisms may play a role in the development of neuropathic pain. Repetitive stimulation of peripheral nociceptors may cause repetitive impulse propagation along C fibres. This repetitive volley of impulses leads to the depolarization of the membrane of the dorsal horn neuron and propagation of the pain impulse to the brain. The response elicited in the dorsal horn neuron may increase with continued C-fibre input. This progressive increase in the response of the dorsal horn neuron is perceived as an increasing pain sensation and is referred to as wind up. After the incoming impulses have ceased, the dorsal horn neurons continue to fire and transmit pain impulses to the brain. References: Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain. In: Wall PD, Melzack R, eds. Textbook of Pain, 4th ed. Edinburgh, UK: Harcourt Publishers Limited; Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain 2000;16:S Siddall PJ, Cousins MJ. Spine update: spinal pain mechanisms. Spine 1997;22:

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.

42 Central Mechanisms: Stimulus-dependent Sensitization
This slide shows how central sensitization can result from increased nociceptor drive or disinhibition after nerve injury. Key Learning Points: The top visual, which represents normal sensory function, demonstrates that activation of the Aβ mechanoreceptors by low threshold mechanical stimuli is unable to activate dorsal horn pain pathways. In the bottom visual, increased nociceptor drive leads to central sensitization of dorsal horn neurons wide dynamic range neurons and Aβ fibre input is now sufficient to activate these neurons that will transmit to the sensing brain. These changes manifest as hypersensitivity to pain that spreads from the site of injury and includes tactile Aβ-fibre-mediated allodynia. When nerves are damaged and their function is increased, innocuous mechanical stimuli result in dysfunction of A-beta fibres with resultant dynamic mechanical allodynia (a sensation of pain when it is not appropriate). Reference:Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353:

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 In addition to sensitization of the periphery, there is also sensitization of the central neural circuits in the face of continued, prolonged excitation of the nerves and/or damage to the nervous tissue. Even in the short-term, very early on in the transmission of pain, there is an automatic increase in the performance of the dorsal horn neuron. This is a result of immediate phosphorylation of ion channels and receptors on the post-synaptic membrane of the dorsal horn neuron. This is secondary to glutamate, substance P and other neurotransmitters that are released into the neural cleft and activate their respective receptors. Once the receptors are activated and the associated ion channels are opened, there is the increase in 2nd messengers in the cell, such as IP3 and PKC and Ca2+. These 2nd messengers cause post-translational changes to the receptors (i.e. phosphorylation) which makes them more responsive or sensitive. Therefore, even previous subthreshold stimuli may now be able to excite the postsynaptic neuron (dorsal horn neuron)

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) Late central sensitization depends on transcription changes in the dorsal horn neurons. There is the induction of such genes as COX-2 which generates prostaglandins such as PGE2. This prostaglandin directly alters the excitability of neuronal cell membranes. In fact prostaglandins do this both by facilitating excitation and by reducing inhibitory transmission. Again, this is one of the reason that drugs such as anti-inflammatories and specifically the COX-2 inhibitors have been used as pre-emptive analgesics. My concern, however, is whether systemic (oral or parental) administration of these medications crosses the blood brain barrier. Eventually, transcriptional changes also start to decrease the transcription of so-called inhibitory genes such as “DREAM”. These genetic changes in the dorsal horn neurons lead to longlasting changes in the function and sensitivity.

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 We have already spent some time discussing the very vital role of central disinhibition of pain. Indeed, the brain stem plays an enormous role in controlling the transmission of pain impulses. There is a well established and studies circuit that links the periaqueductal gray, the rostral ventrolmedial medulla and the spinal cord. It is interesting however, that not only does the brainstem play a role in descending inhibition, but it also has an equivalent pathway directed at the facilitation of pain transmission. Therefore, there are dual pathways that descend from the brainstem that either inhibit or facilitate the transmission of pain.

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 The key coordinator of this descending control seems to be localized to the rostral ventromedial medulla. There are three classes of cells in the RVM: On-cells, Off-cells and Neutral cells. In the case of On-cells …

49 The Usual Response to Pain and Inflammation
Early (within 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.

51 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 Disinhibition Normal sensory inflow is actively controlled by inhibitory interneurons. Reduced synthesis of the inhibitory neurotransmitters GABA and glycine or loss of these inhibitory interneurons after excessive release of the excitotoxic amino acid glutamate following peripheral nerve injury increases the excitability of pain transmission neurons such that they begin to respond to normally innocuous inputs.

52 Central Mechanisms: Loss of Inhibitory Controls
This slide illustrates how nervous system injury can reduce inhibition in the dorsal horn through various mechanisms. Key Talking Points: Stimulation of inhibitory interneurons located in the dorsal horn of the spinal cord releases neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine, which have the effect of reducing synaptic transmission of sensory impulses. Inhibitory mechanisms that arise from descending pathways from the brain are mediated by endogenous opioids or neurotransmitters, such as serotonin and noradrenaline. This inhibitory system prevents overstimulation.  Experimental peripheral nerve injuries in animals have been associated with decreased GABA and glycine levels. In addition, GABA receptors and opioid receptors are downregulated following nerve injury. It has been hypothesized that if inhibitory controls are lost or impaired, then excitatory mechanisms may dominate, allowing dorsal horn neurons to fire in an exaggerated way in response to noxious input which may eventually result in an increased pain perception. References: Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand Suppl 1999;173: Doubell TP, Mannion RJ, Woolf CJ. In: Wall PD, Melzack R, eds. Textbook of Pain, 4th ed. Edinburgh, UK: Harcourt Publishers Limited; Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353:

53 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 One of the phenomenon that we may be seeing as physicians is inadvertent activation of pro-nociception or descending facilitation via the use of opioids. There is definitely the clinical picture that opiates can cause increased sensitivity to noxious stimuli (hyperesthesia) and pain elicited by normally innocuous stimulation (allodynia). This unexpected result has been demonstrated numerous times in laboratory experiments in animals and has also been reported in humans. For me, this is a very interesting and challenging paradigm that the opiates we are using as analgesics may actually be causing pain in certain individuals.

54 Summary Nociceptors Afferent Mechanisms
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

55 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????

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