CPD Anaesthesia, 2001; 3(3): 103-108

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Educational Seminars

Neurophysiology of pain
Part I: Mechanisms of pain in the peripheral nervous system
Paul R Wilkinson

Abstract
The traditional view of pain in terms of “hard-wired” conduction of pain signals to the sensory cortex has been modified following extensive research into the physiological, pharmacological and even genetic changes that accompany pain. It is now established that pain whether neuropathic or inflammatory is accompanied by profound and long-lasting changes both at the primary site of injury and at distant sites in the central nervous system for example, in the dorsal horn of the spinal cord. This together with the second article in the next edition explains how pain may be worsened by the phenomena of peripheral sensitisation, wind-up and central sensitisation and changes in the sympathetic nervous system. Additionally pain may be reduced by descending inhibitory and endogenous control mechanisms while anatomical links exist to areas of the brain controlling emotion and autonomic function. The practical value of this knowledge is highlighted with reference to current and potential methods of treating pain.

Keywords
Pain mechanisms, neurophysiology, hyperalgesia. This is the first of two articles introducing the reader to aspects of neurophysiology, neuropharmacology and neuroanatomy involved in the perception of pain. Where possible the modes of action of current therapeutic approaches are highlighted and areas of recent discovery or future interest f lagged to allow the reader to explore further what is a fascinating and rapidly expanding area. In this first article, important definitions are reviewed and mechanisms underlying nociceptive and neuropathic pain in the peripheral nervous system considered. The second article deals with mechanisms in the spinal cord and supraspinal mechanisms.

and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. This definition emphasises that pain is not a predicted physiological response to stimulus nor based on third party observation but is always subjective with each individual learning about pain through experiences relating to tissue injury in early life when pain is reported in terms of its intensity, location and sometimes quality. This is referred to as the sensory-discriminative component of pain. Many people report pain in the absence of tissue injury and this pain may be amplified by psychological, emotional, cognitive and social factors as well as learned behaviours. This pain cannot be distinguished from pain associated with tissue damage and should therefore be accepted as pain. These extra dimensions of pain are sometimes referred to as the affectivemotivational and cognitive-evaluative components of pain. This article is concerned primarily with what we know about the neurophysiology of pain and therefore is focused on the sensory-discriminative aspects of pain.

Paul R Wilkinson FRCA MRCGP B Med Sci Consultant in Anaesthesia and Pain Management Paul Wilkinson graduated from the University of Newcastle upon Tyne. Staring life with general practice, he is now a Consultant with a specialist interest in pain management. His interests include education and he has a research interests in neurophysiology Correspondence: Paul Wilkinson Pain Management Unit Royal Victoria Infirmary Queen Victoria Road Newcastle upon Tyne Tel: 0191 282 4412 E-mail: p.r.wilkinson@ncl.ac.uk

Definitions in pain
Following a mild, painful stimulus such as a pinprick, the pain experience is brief, closely related to the stimulus and often associated with ref lex withdrawal of the affected limb part. However, with increasing stimulus, tissue injury and inf lammation may occur and the pain persists. Nociceptive pain refers to pain associated with potential tissue injury and serves to warn the organism of tissue damage. One associated feature is hyperalgesia, which is defined as an increased response to a normally painful stimulus. Hyperalgesia is often classified as primary or secondary. Primary hyperalgesia occurs immediately around the site of the injury and is interpreted as being due to changes in the peripheral pain receptor. Secondary hyperalgesia occurs over a wider area, is longer lasting and generally involves mechanisms remote from the site

Introduction
The International Association for the Study of Pain has defined pain as “an unpleasant sensory

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Pain signals are transmitted from peripheral receptors by A delta and C-fibres which have their cell bodies in the dorsal root ganglion. there is often no active tissue damage and the relationship between pain and injury (“hurt” and “harm”) is less clear. chemical and mechanical stimulation. Pain is commonly divided into acute and chronic.104 CPD Anaesthesia. it is becoming clear that there are broader differences. In chronic pain. Allodynia may also be associated with nociceptive pain for example following sunburn or tissue injury and is not exclusively a feature of neuropathic pain. Fibres enter the spinal cord via the posterior root and synapse in the dorsal horn(DH). 2001. Though this process is known to be more complex. As this article will emphasise. anatomical and even genetic changes ensue. Nociceptors are receptors that detect sensations associated with actual or potential tissue damage and respond to noxious thermal. Anatomy of pain transmission to the spinal cord which is shown in diagrammatic cross-section. Second order neurones then decussate and ascend mainly in the spinothalamic tracts to the thalamus. graded changes Figure 1. serves the biological function of protecting the organism and is largely associated with an undamaged nervous system. the nervous system itself becomes “damaged” after injury and profound neurophysiological. The Cartesian model of pain transmission describes the process of pain perception in terms of discrete pathways linking peripheral stimulus to the sensory cortex. Rila Publications Ltd . allodynia involves a change in the quality of the sensation for example tactile or thermal stimuli becoming painful. Whilst acute and chronic pain could be viewed as differing only on a temporal axis. this simple model will be used to introduce the neurophysiology of pain transmission. acute pain allows the organism to minimise tissue damage and promote healing. They are located in skin as well as deeper structures. hyperalgesia and allodynia. This pain is known as neuropathic pain and can be initiated by a primary lesion or a dysfunction within the nervous system. Nociceptors are fine nerve endings that respond to stimulation usually by small. Therefore. Clinical features may include a “burning”quality”. 3(3): 103-108 Mechanisms of pain in the peripheral nervous system of injury for example in the dorsal horn of the spinal cord. These ganglia from a swelling associated with the posterior root of the spinal nerve. The dorsal horn was divided into various lamina by Rexed (I-V are shown on the diagram). Thus. Acute pain is closely related to stimulus. A second type of pain is distinguished in clinical practice where nerve injury is assumed to have occurred. Allodynia is pain that arises from stimuli that do not normally evoke pain. These changes serve no protective function and the perception of pain is uncoupled from stimulus. Functional anatomy of peripheral sensory nerves Pain transmission begins with transduction of the pain stimulus at receptors in peripheral tissues where painful stimuli are converted into a series of electrical signals.

These are known as silent receptors because they are dormant in unsensitised states. the cell bodies of these afferent (because they conduct signals towards the spinal cord) neurones are situated in the dorsal root ganglion. Action potentials are small all-or-nothing depolarisations in the membrane potential and pain signals are encoded in the pattern of action potential firing. Other receptors are normally activated only at very high stimulation intensities but may be recruited during inf lammation. Specifically. prostaglandins. Aδ fibres are small. the density of sensory receptors is much lower. mechanical and chemical stimuli but some are relatively insensitive to mechanical stimulation. Peripheral sensitisation may explain primary hyperalgesia but not all hyperalgesia can be explained by peripheral mechanisms. may even produce pain directly. only particular types of stimuli such as distension or ischaemia produce pain. These result in changes in local blood flow and vascular permeability.5-2m/s. joints and cornea are similar to skin in that various sensory receptors have been identified with most pain signals being transmitted along myelinated and unmyelinated fibres. bradykinin and substance P. the localisation of pain imprecise and often referred to areas of skin away from the viscera. Cutaneous Aδ fibres are associated with reflex withdrawal and are responsible for an initial pricking pain so-called first or fast pain while conduction along C-fibres is equated with second or slow pain which is burning or dull. Such experiments have shown that many of the chemical mediators of inf lammation increase the responsiveness or decrease the threshold of peripheral sensory nerves. a variety of local inf lammatory substances are released which include histamine. Thus. by the sensory fibres to which they are associated (C or Aδ) or by their responsiveness to different stimuli e. may be more important to noxious stimulation. Anatomically. Nociceptive pain Peripheral sensitisation Nociceptors and inflammation Following peripheral tissue injury. 2001.CPD Anaesthesia.5-1 µm with lower conduction velocities of 0. which are stimulated only at higher intensities (high threshold). It is important to realise that sensory nerves conducting these signals are not modality specific and no individual sensory nerves are identifiable that conduct just pain signals. Thresholds of C and Aδ associated transducers to particular stimuli may vary. which respond to low intensity mechanical or thermal stimulation (low threshold). speed of conduction and degree of myelination. unmyelinated fibres 0. such as bradykinin. Aδ fibres carry information from at least two types of sensory transducers which may respond to heat and mechanical stimuli with differing thresholds. It is now known that there are several species of pain receptor in the skin which can be classified in various ways for example by threshold of activation. Also. Following inf lammation. Rila Publications Ltd . 3(3): 103-108 105 Mechanisms of pain in the peripheral nervous system in membrane electrical potential. The different rates of conduction along these two types of axons may contribute in part to the biphasic perception of pain. while others. Secondary hyperalgesia is also due to changes remote from the peripheral pain receptor including changes in the spinal cord known as central sensitisation. The arrangement of the connections within the spinal cord and the projections to the cerebral cortex is discussed in the section on “central anatomy of pain”. Some receptors. myelinated or unmyelinated afferents (usually autonomic fibres) the understanding of the mechanisms involved and the relationships to specific receptors is not as well understood as in skin. The sensory nerves that conduct noxious impulses to the spinal cord mainly belong to Aδ and C groups. sensitisation occurs where a peripheral receptor (or a central neurone) responds either to stimuli in a more intense fashion than it would under baseline conditions or to a stimulus to which it would normally be insensitive. tendon. Tissues such as muscle. For many years it was unclear whether the sensation of pain was simply an increase in the intensity of normal sensation producing more activity at existing sensory receptors or whether different populations of receptor exist for painful stimuli. mechanical or thermal stimuli. myelinated fibres 2-5 µm in diameter and have conduction velocities of 5-30 m/s while C fibres are smaller. In visceral tissue. in that the cell body sits off the main conducting axon. If threshold is reached action potentials are generated. This classification is based on the size. Though pain is often conducted along small. sensory nerve endings close to the area of injury acquire a state of hyper-responsiveness known as peripheral sensitisation. The characteristic features of tissue inflammation result from the release of these inflammatory mediators and include pain.g. activation of immune cells and some. are responsible for normal nerve conduction. oedema and erythema. Receptors associated with C fibres are usually polymodal in that they respond to heat. Axons from these sensory nerves finally reach the dorsal horn of the spinal cord (Figure 1) and synapse with cell bodies of so-called second order neurones. recordings from single sensory nerves have demonstrated an increased sensitivity of peripheral sensory neurones. This arrangement is unusual.

These changes which are controlled through the “engine-room” of the neurone .g. prostaglandins are produced from arachidonic acid under the action of cyclooxygenase. 3(3): 103-108 Mechanisms of pain in the peripheral nervous system Diverse mechanisms and effects of peripheral sensitisation Though the mechanisms by which inf lammatory substances cause peripheral sensitisation are far from understood. COX enzymes are familiar targets for non-steroidal analgesics drugs such as ibuprofen and diclofenac. Prostaglandins do not usually produce pain on injection but sensitise sensory neurones to other chemicals such as bradykinin. The important example of prostaglandins is considered in more detail as an illustration. ?P2X3 member of ATP receptor sub Adenosine triphosphate -family named P2X (ATP) Kinins Bradykinin type 2 receptors e. Cell Injury Phospholipase Arachidonic acid Phospholipase Intermediates (PGG2.g. Likely mediators of peripheral sensitisation and possible main targets of action. Also. two major types containing nerve growth factor 1) Trk A receptors regulated by NGF. peripheral sensitisation may be associated with diverse neurophysiological changes. PGE2. In contrast. it was realised that at least two forms of the enzyme existed. CGRP Serotonin = 5-HT1 and 5-HT2 receptors 5-hydroxytryptamine (5HT) Histamine Histamine type 1 receptor Other:Various Reactive oxygen species e. Activation of intracellular messenger systems may result in increased synthesis of neurotransmitters or affect gene expression by the alteration of the phenotype of some neurones leading to the production of new neurotransmitters. which may be remote from the site of injury. Neuropeptides e. They can also stimulate the release of other inf lammatory mediators such as substance P.g Neurokinin receptors Neurokinins – (Neurokinin A and B. enzyme may produce analgesic effects with a lower incidence of gastrointestinal and other side effects.g Nitric oxide and cytokines Table 1. Following injury. kalliden Growth factors Nociceptors neurones are divided into Neurotrophins e. Prostaglandins are synthesised from arachidonic acid under the action of the cyclo-oxygenase (COX) enzyme system (Figure 2) and are important mediators of peripheral sensitisation. alter sensitivity of heat and temperature activated capsaicin/ vanilloid receptors VR-1 and vanilloidlike receptor VLR-1. there is an increased production of COX-2 enzyme following tissue injury and selectively blocking this Prostaglandin E receptors. Thromboxane and leukotrienes are also important in inf lammation and depend on the COX enzyme system for their synthesis. This latter finding is particularly interesting since intracellular links may then be established to protein synthesis.g. Production of the COX-1 type enzyme is relatively stable and not produced in altered quantity during pain and inf lammation.* (NGF) and Non2) c-ret receptors regulated by GDNF. Despite being effective analgesics these drugs have a number of sideeffects including gastrointestinal bleeding.106 CPD Anaesthesia. Substance-P). Arachidonic acid is an essential fatty acid that is produced following the breakdown of cell wall phopholipids under the action of phospholipase A when tissue injury occurs. neurotrophins e. glialcell-derived neurotrophic factor (GDNF).g. bradykinin. Rila Publications Ltd .g. PGF2α Figure 2. Receptors that bind neurotrophins with high affinity are known as Trk receptors. it is clear that some inf lammatory mediators act by opening ion channels and altering membrane electrical properties. The name net refers to the signal–transducing domain of the GDNF receptor. Others may act via intracellular messengers. in a recent advance. Neurosubstance Prostaglandins Protons Possible main targets of action Prostaglandins are important mediators of peripheral sensitisation A variety of inf lammatory mediators have been identified which may be potentially responsible for nociceptive pain and hyperalgesia. Thus. *Neurotrophins act through receptors that produce effects via specific receptor tyrosine kinases. Adenosine e. These substances and their likely sites of action are summarised in Table 1.the cell body in the dorsal root ganglion – can also modify pain transmission in the dorsal horn since many neurotransmitters located in the peripheral nerve terminals and synthesised in the dorsal root ganglia are also transported to proximal nerve terminals of afferent nerves in the dorsal horn.1 The clinical introduction of COX-2 inhibitors is an example of how a fundamental understanding of pain neurophysiology has led to potential advances in treatment.PGH2) Leukotrienes Thromboxane A & B Prostaglandins e. Acid sensitive ion channels (ASIC). However. 2001.

sodium channels are found concentrated at the injured end of axons. Similar findings were confirmed in painful human neuroma of amputees which gave a potential explanation for pain and paraesthesia following nerve injury.g. 2) Baskets of fine new sympathetic nerve sprouts grow and spread round sensory cell bodies in the dorsal ganglia. Second. to their clinical effects. 3) There is a demonstrable increase in hyperexcitability of injured neurones following sympathetic stimulation and application of catecholamines. Local anaesthetic drugs also target sodium channels in peripheral nerves and lignocaine infusions and local anaesthetic blocks used in the treatment of neuropathic pain may give an analgesic effect considerably longer than the anticipated duration of effect of the infusion or local anaesthetic injection. The following findings in injured sensory neurones may be relevant to any explanation:1) Injured nerve axons develop an increased population of adrenergic receptors on their surfaces. Thus. neuronal degeneration and nerve regrowth in the form of tiny sprouts which may become entangled and form a swelling known as a neuroma. it seems that certain types of neuropathic pain may be driven by impulses from new anatomical connections with the sympathetic nervous system or by circulating catecholamines acting on new receptors on Rila Publications Ltd . inf lammatory changes. Volleys of spontaneous electrical impulses arise from areas of nerve damage and are sent to the spinal cord and thereafter perceived as pain. Significantly. by cutting completely (neuroma model) or by placing a tight suture round the nerve (nerve constriction model). gentle probing of nerve. Neuropathic pain and animal models Understanding of the mechanisms of neuropathic pain is based largely on studies using animal models where nerves may be experimentally injured. Sodium channels and neuropathic pain A number of drugs used in the management of neuropathic pain are known to block sodium channels. in some experiments it was possible to use a local anaesthetic intravenous infusion to stop the spontaneous electrical activity in a nerve without stopping normal conduction. altered sweating and trophic changes. ectopic electrical activity is abolished most reliably by sodium channel blockers. adrenaline and noradrenaline. First. A completely transected nerve exhibits a variety of pathological changes which include demyelination. the most interesting discovery relates to changes in sodium channels in injured nerves. membrane stabilising agents and antidepressants. arguably. Sympathetic mechanisms and neuropathic pain It is well known that immobilisation or nerve injury can result in a clinical syndrome where ongoing pain. for example. 2001. a property which may be important. Such patients with “Complex Regional Pain Syndromes” have been treated successfully with antisympathetic interventions such as phentolamine blocks or regional sympathetic blockade with local anaesthetic3 but it is not clear why these treatments are effective. It considers also treatments which may be useful in the treatment of such pain. 3) Chemical substances e. but not exclusive. The tantalising question for the future is whether specific drugs can be designed to target specific sodium channel sub-types2 without preventing normal conduction or causing other side effects. injured sensory axons could behave like pain receptors producing pain signals in response to external stimuli which could be as small as the pulsation of small blood vessels. 2) Physiological stimuli e. These agents that can block sodium channels include drugs used normally as anticonvulsants. A crucial finding of early studies was that the proximal ends of sensory nerve fibres that form neuroma may begin to produce electrical activity without any apparent stimulus. Thus. The additional finding of increased excitability in nerve cell bodies in the dorsal root ganglion might amplify these effects further.CPD Anaesthesia. There is emerging evidence for this view. changes in local blood f low. The reasons for this hyperexcitability were not clear but one contributing factor relates to the finding that axons which were normally electrically isolated could cross-excite each other after injury (“Ephaptic” transmission). stimulation of sympathetic ganglia. It is logical to ask whether sodium channels are important in the observed hyperexcitability in injured peripheral nerves. The nerve end may become painful to touch. It is now apparent that there are a number of different sub-types of sodium channels. Subsequently it was shown that the excitability of such “injured fibres” could be increased by: 1) Mechanical stimuli e.g. The generation of action potentials is normally restricted to areas close to the nerve cell body but this novel “ electrical activity” was remote from these sites. allodynia and hyperalgesia are associated with oedema. There are other potential factors contributing to the hyperexcitability but. 3(3): 103-108 107 Mechanisms of pain in the peripheral nervous system Neuropathic pain –Peripheral mechanisms This section considers the pathological processes in the peripheral nervous system that underlie neuropathic pain.g.

1999. Ions in the fire: recent ion-channel research and approaches to pain therapy. Sept/Oct 1998. Sundrel R: Cox-2 Inhibitors: A status report. Trends in Pharmacological Sciences 1999. A) Tissue injury 1. Table 2. Elgen RM. IASP Press. S121-126. Functional anatomy of supraspinal pain processing with reference to the central pain syndrome. This is discussed in the next article. • • Melzack R. 2. Max M. Trends in Pharmacological Sciences 1999. Supplement 6. 1999. Hunter JC. This may be worsened by an increased sympathetic drive. Seattle. 2001. Max M. both result in extensive changes in the peripheral nervous system (Table 3). Nociceptive pain occurs as a consequence of inf lammatory changes resulting from tissue injury and the peripheral sensitisation which results. editor: Pain 1999 – An updated review. Cummins et al. Dib-Hajj. Seattle 1998. Seattle. Blocking this sympathetic drive might be expected to improve pain but there is still considerable debate whether the results of such clinical practice meet the theoretical expectation. Further Reading • Craig AD. Spinal systems and pain processing:development of novel analgesic drugs with mechanistically defined models. 3(3): 103-108 Mechanisms of pain in the peripheral nervous system injured nerves. editor: Pain 1999 – An updated review. • • Borsook D. IASP Newsletter. Nociceptive Pain Nature of Injury Peripheral nerve terminal changes Ectopic neuronal activity Neurone structure Sympathetic hyperexcitability Central sensitisation Tissue +++ Intact +/Yes Neuropathic Nerve +/Often Neuronal degeneration +++ Yes Summary Tissue and nerve injury produce pain with different pathological features (Table 2). However. 3. Rila Publications Ltd . IASP Press. References Berde C. Proc Natl Acad Sci USA 1999. notably nociceptive and neuropathic pain. Summary of changes in the peripheral nervous system in A) Tissue injury and B) Nerve injury. Local Inflammatory Inflammatory mediator activation and release Changes in local blood flow Altered vascular permeability Migration and activation of white blood cells Trophic changes Peripheral sensory neurones Sensitisation of afferent nerves endings Activation of silent nociceptors B) Nerve injury Anatomical Proximal axonal degeneration Neuronal death Myelin sheath disruption Neuroma formation Formation of axonal sprouts which may form “microneuromas” or reinervate target tissue Invasion of nerve sprouts into new areas of dorsal root ganglia Electrophysiological Spontaneous neuronal firing Abnormal sensitivity of neurones Abnormal sympathetic coupling Ephaptic transmission Increased activity of dorsal root ganglia cells Table 3. 20: 337-342. 20: 329-337. Pain.108 CPD Anaesthesia. Waxman SG. Neuropathic pain implies nerve injury and injured nerves become hyperexcitable. Scientific basis for the evaluation and treatment of RSD/CRPS syndromes: Laboratory studies in animals and man. Seattle. 96: 7635-7639. 1999 IASP Press. Dray A. From the gate to the neuromatrix. Summary of some of the important differences between nociceptive and neuropathic pain. editor: Molecular Neurobiology of Pain. Yaksh TL. Bennet GJ. IASP press. 3-6. Sodium channels and pain. 331-337. August 1999. many of the long-term effects of chronic pain result from profound changes in the central nervous system remote from the site of the injury including central sensitisation in the dorsal horn of the spinal cord. However.

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