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

Educational Seminars

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

Paul R Wilkinson

Abstract and emotional experience associated with actual or

The traditional view of pain in terms of “hard-wired” potential tissue damage, or described in terms of
conduction of pain signals to the sensory cortex has been such damage”. This definition emphasises that pain
modified following extensive research into the physiological, is not a predicted physiological response to stimulus
pharmacological and even genetic changes that accompany nor based on third party observation but is always
pain. It is now established that pain whether neuropathic or subjective with each individual learning about pain
inflammatory is accompanied by profound and long-lasting through experiences relating to tissue injury in
changes both at the primary site of injury and at distant sites early life when pain is reported in terms of its
in the central nervous system for example, in the dorsal horn intensity, location and sometimes quality. This is
of the spinal cord. referred to as the sensory-discriminative
This together with the second article in the next edition component of pain. Many people report pain in the
explains how pain may be worsened by the phenomena of absence of tissue injury and this pain may be
peripheral sensitisation, wind-up and central sensitisation amplified by psychological, emotional, cognitive
and changes in the sympathetic nervous system. and social factors as well as learned behaviours.
Additionally pain may be reduced by descending inhibitory This pain cannot be distinguished from pain
and endogenous control mechanisms while anatomical links associated with tissue damage and should therefore
exist to areas of the brain controlling emotion and be accepted as pain. These extra dimensions of pain
autonomic function. The practical value of this knowledge are sometimes referred to as the affective-
is highlighted with reference to current and potential motivational and cognitive-evaluative
methods of treating pain. components of pain. This article is concerned
primarily with what we know about the
Keywords neurophysiology of pain and therefore is focused Paul R Wilkinson
FRCA MRCGP B Med Sci
Pain mechanisms, neurophysiology, hyperalgesia. on the sensory-discriminative aspects of pain.
Consultant in Anaesthesia
and Pain Management
This is the first of two articles introducing the Definitions in pain
reader to aspects of neurophysiology, Following a mild, painful stimulus such as a Paul Wilkinson graduated
from the University of
neuropharmacology and neuroanatomy involved in pinprick, the pain experience is brief, closely related Newcastle upon Tyne.
the perception of pain. Where possible the modes of to the stimulus and often associated with ref lex Staring life with general
action of current therapeutic approaches are withdrawal of the affected limb part. However, with practice, he is now a
Consultant with a specialist
highlighted and areas of recent discovery or future increasing stimulus, tissue injury and inf lammation
interest in pain
interest f lagged to allow the reader to explore further may occur and the pain persists. Nociceptive pain management.
what is a fascinating and rapidly expanding area. In refers to pain associated with potential tissue injury His interests include
this first article, important definitions are reviewed and serves to warn the organism of tissue damage. education and he has a
research interests in
and mechanisms underlying nociceptive and One associated feature is hyperalgesia, which is neurophysiology
neuropathic pain in the peripheral nervous system defined as an increased response to a normally
considered. The second article deals with painful stimulus. Hyperalgesia is often classified as Correspondence:
Paul Wilkinson
mechanisms in the spinal cord and supraspinal primary or secondary. Primary hyperalgesia Pain Management Unit
mechanisms. occurs immediately around the site of the injury and Royal Victoria Infirmary
is interpreted as being due to changes in the Queen Victoria Road
Introduction peripheral pain receptor. Secondary hyperalgesia Newcastle upon Tyne
Tel: 0191 282 4412
The International Association for the Study of occurs over a wider area, is longer lasting and E-mail:
Pain has defined pain as “an unpleasant sensory generally involves mechanisms remote from the site p.r.wilkinson@ncl.ac.uk

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Mechanisms of pain in the peripheral nervous system

of injury for example in the dorsal horn of the spinal and injury (“hurt” and “harm”) is less clear. As this
cord. article will emphasise, the nervous system itself becomes
A second type of pain is distinguished in clinical “damaged” after injury and profound
practice where nerve injury is assumed to have occurred. neurophysiological, anatomical and even genetic
This pain is known as neuropathic pain and can be changes ensue. These changes serve no protective
initiated by a primary lesion or a dysfunction within the function and the perception of pain is uncoupled from
nervous system. Clinical features may include a stimulus.
“burning”quality”, hyperalgesia and allodynia. The Cartesian model of pain transmission describes
Allodynia is pain that arises from stimuli that do not the process of pain perception in terms of discrete
normally evoke pain. Thus, allodynia involves a change pathways linking peripheral stimulus to the sensory
in the quality of the sensation for example tactile or cortex. Though this process is known to be more
thermal stimuli becoming painful. Allodynia may also be complex, this simple model will be used to introduce the
associated with nociceptive pain for example following neurophysiology of pain transmission.
sunburn or tissue injury and is not exclusively a feature
of neuropathic pain. Functional anatomy of peripheral sensory
Pain is commonly divided into acute and chronic. nerves
Whilst acute and chronic pain could be viewed as Pain transmission begins with transduction of the
differing only on a temporal axis, it is becoming clear pain stimulus at receptors in peripheral tissues where
that there are broader differences. Acute pain is closely painful stimuli are converted into a series of electrical
related to stimulus, serves the biological function of signals. Nociceptors are receptors that detect sensations
protecting the organism and is largely associated with an associated with actual or potential tissue damage and
undamaged nervous system. Therefore, acute pain respond to noxious thermal, chemical and mechanical
allows the organism to minimise tissue damage and stimulation. They are located in skin as well as deeper
promote healing. In chronic pain, there is often no structures. Nociceptors are fine nerve endings that
active tissue damage and the relationship between pain respond to stimulation usually by small, graded changes

Figure 1. Anatomy of pain transmission to the spinal cord which is shown in diagrammatic cross-section. Pain signals are transmitted
from peripheral receptors by A delta and C-fibres which have their cell bodies in the dorsal root ganglion. These ganglia from a swelling
associated with the posterior root of the spinal nerve. Fibres enter the spinal cord via the posterior root and synapse in the dorsal
horn(DH). Second order neurones then decussate and ascend mainly in the spinothalamic tracts to the thalamus. The dorsal horn was
divided into various lamina by Rexed (I-V are shown on the diagram).

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Mechanisms of pain in the peripheral nervous system

in membrane electrical potential. If threshold is reached Receptors associated with C fibres are usually
action potentials are generated. Action potentials are small polymodal in that they respond to heat, mechanical and
all-or-nothing depolarisations in the membrane potential chemical stimuli but some are relatively insensitive to
and pain signals are encoded in the pattern of action mechanical stimulation. Aδ fibres carry information
potential firing. It is important to realise that sensory from at least two types of sensory transducers which may
nerves conducting these signals are not modality specific respond to heat and mechanical stimuli with differing
and no individual sensory nerves are identifiable that thresholds.
conduct just pain signals. The sensory nerves that conduct Thresholds of C and Aδ associated transducers to
noxious impulses to the spinal cord mainly belong to Aδ particular stimuli may vary.
and C groups. This classification is based on the size, Some receptors, which respond to low intensity
speed of conduction and degree of myelination. Aδ fibres mechanical or thermal stimulation (low threshold), are
are small, myelinated fibres 2-5 µm in diameter and have responsible for normal nerve conduction, while others,
conduction velocities of 5-30 m/s while C fibres are which are stimulated only at higher intensities (high
smaller, unmyelinated fibres 0.5-1 µm with lower threshold), may be more important to noxious
conduction velocities of 0.5-2m/s. The different rates of stimulation. Other receptors are normally activated only
conduction along these two types of axons may contribute at very high stimulation intensities but may be recruited
in part to the biphasic perception of pain. Cutaneous Aδ during inf lammation. These are known as silent
fibres are associated with reflex withdrawal and are receptors because they are dormant in unsensitised
responsible for an initial pricking pain so-called first or states.
fast pain while conduction along C-fibres is equated with Tissues such as muscle, tendon, joints and cornea are
second or slow pain which is burning or dull. similar to skin in that various sensory receptors have
Anatomically, the cell bodies of these afferent been identified with most pain signals being transmitted
(because they conduct signals towards the spinal cord) along myelinated and unmyelinated fibres. In visceral
neurones are situated in the dorsal root ganglion. This tissue, the density of sensory receptors is much lower,
arrangement is unusual, in that the cell body sits off the the localisation of pain imprecise and often referred to
main conducting axon. Axons from these sensory nerves areas of skin away from the viscera. Also, only particular
finally reach the dorsal horn of the spinal cord (Figure 1) types of stimuli such as distension or ischaemia produce
and synapse with cell bodies of so-called second order pain. Though pain is often conducted along small,
neurones. The arrangement of the connections within myelinated or unmyelinated afferents (usually
the spinal cord and the projections to the cerebral cortex autonomic fibres) the understanding of the mechanisms
is discussed in the section on “central anatomy of pain”. involved and the relationships to specific receptors is not
as well understood as in skin.
Nociceptive pain
Peripheral sensitisation
Nociceptors and inflammation Following inf lammation, recordings from single
Following peripheral tissue injury, a variety of local sensory nerves have demonstrated an increased
inf lammatory substances are released which include sensitivity of peripheral sensory neurones. Such
histamine, prostaglandins, bradykinin and substance P. experiments have shown that many of the chemical
These result in changes in local blood flow and vascular mediators of inf lammation increase the responsiveness
permeability, activation of immune cells and some, such or decrease the threshold of peripheral sensory nerves.
as bradykinin, may even produce pain directly. The Thus, sensory nerve endings close to the area of injury
characteristic features of tissue inflammation result acquire a state of hyper-responsiveness known as
from the release of these inflammatory mediators and peripheral sensitisation. Specifically, sensitisation
include pain, oedema and erythema. occurs where a peripheral receptor (or a central neurone)
For many years it was unclear whether the sensation of responds either to stimuli in a more intense fashion than
pain was simply an increase in the intensity of normal it would under baseline conditions or to a stimulus to
sensation producing more activity at existing sensory which it would normally be insensitive.
receptors or whether different populations of receptor Peripheral sensitisation may explain primary
exist for painful stimuli. It is now known that there are hyperalgesia but not all hyperalgesia can be explained by
several species of pain receptor in the skin which can be peripheral mechanisms. Secondary hyperalgesia is also
classified in various ways for example by threshold of due to changes remote from the peripheral pain receptor
activation, by the sensory fibres to which they are including changes in the spinal cord known as central
associated (C or Aδ) or by their responsiveness to different sensitisation.
stimuli e.g. mechanical or thermal stimuli.

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Mechanisms of pain in the peripheral nervous system

Neurosubstance Possible main targets of action

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

Neuropathic pain –Peripheral mechanisms Sodium channels and neuropathic pain

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

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Mechanisms of pain in the peripheral nervous system

injured nerves. Blocking this sympathetic drive might be However, many of the long-term effects of chronic
expected to improve pain but there is still considerable pain result from profound changes in the central nervous
debate whether the results of such clinical practice meet system remote from the site of the injury including
the theoretical expectation. central sensitisation in the dorsal horn of the spinal cord.
This is discussed in the next article.
Summary Nociceptive Neuropathic
Tissue and nerve injury produce pain with different Pain
pathological features (Table 2), notably nociceptive and Nature of Injury Tissue Nerve
neuropathic pain. However, both result in extensive Peripheral nerve terminal +++ +/-
changes
changes in the peripheral nervous system (Table 3). Ectopic neuronal activity - Often
Nociceptive pain occurs as a consequence of Neurone structure Intact Neuronal
inf lammatory changes resulting from tissue injury and degeneration
Sympathetic +/- +++
the peripheral sensitisation which results. Neuropathic hyperexcitability
pain implies nerve injury and injured nerves become Central sensitisation Yes Yes
hyperexcitable. This may be worsened by an increased
Table 2. Summary of some of the important differences between
sympathetic drive.
nociceptive and neuropathic pain.
References
A) Tissue injury
1. Berde C, Sundrel R: Cox-2 Inhibitors: A status report. IASP
Local Inflammatory Newsletter. Seattle 1998. IASP press. Sept/Oct 1998; 3-6.
Inflammatory mediator activation and release 2. Waxman SG, Dib-Hajj, Cummins et al; Sodium channels and pain. Proc
Changes in local blood flow Natl Acad Sci USA 1999; 96: 7635-7639.
Altered vascular permeability
3. Bennet GJ. Scientific basis for the evaluation and treatment of
Migration and activation of white blood cells
Trophic changes RSD/CRPS syndromes: Laboratory studies in animals and man, Max
M, editor: Pain 1999 – An updated review. 1999; 331-337. IASP Press,
Peripheral sensory neurones Seattle.
Sensitisation of afferent nerves endings
Activation of silent nociceptors
Further Reading

B) Nerve injury • Craig AD. Functional anatomy of supraspinal pain processing with
reference to the central pain syndrome, Max M, editor: Pain 1999 – An
Anatomical updated review. 1999 IASP Press, Seattle.
Proximal axonal degeneration • Borsook D, editor: Molecular Neurobiology of Pain. 1999, IASP Press,
Neuronal death
Seattle.
Myelin sheath disruption
Neuroma formation • Elgen RM, Hunter JC, Dray A. Ions in the fire: recent ion-channel
Formation of axonal sprouts which may form “microneuromas” research and approaches to pain therapy. Trends in Pharmacological Sciences
or reinervate target tissue 1999; 20: 337-342.
Invasion of nerve sprouts into new areas of dorsal root ganglia • Melzack R. From the gate to the neuromatrix. Pain, Supplement 6.
August 1999, S121-126.
Electrophysiological
• Yaksh TL. Spinal systems and pain processing:development of novel
Spontaneous neuronal firing
Abnormal sensitivity of neurones analgesic drugs with mechanistically defined models. Trends in
Abnormal sympathetic coupling Pharmacological Sciences 1999; 20: 329-337.
Ephaptic transmission
Increased activity of dorsal root ganglia cells

Table 3. Summary of changes in the peripheral nervous system in

A) Tissue injury and B) Nerve injury.

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