CPD Anaesthesia, 2001; 3(3): 103-108
Educational Seminars
Neurophysiology of pain
Part I: Mechanisms of pain in the peripheral nervous
system
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.
Introduction
The International Association for the Study of
Pain has defined pain as “an unpleasant sensory
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103
Paul R Wilkinson
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 affective-
motivational and cognitive-evaluative
components of pain. This article is concerned
primarily with what we know about the
neurophysiology of pain and therefore is focused Paul R Wilkinson
FRCA MRCGP B Med Sci
on the sensory-discriminative aspects of pain.
Consultant in Anaesthesia
and Pain Management
Definitions in pain
Following a mild, painful stimulus such as a Paul Wilkinson graduated
from the University of
pinprick, the pain experience is brief, closely related Newcastle upon Tyne.
to the stimulus and often associated with ref lex Staring life with general
withdrawal of the affected limb part. However, with practice, he is now a
Consultant with a specialist
increasing stimulus, tissue injury and inf lammation
interest in pain
may occur and the pain persists. Nociceptive pain management.
refers to pain associated with potential tissue injury His interests include
and serves to warn the organism of tissue damage. education and he has a
research interests in
One associated feature is hyperalgesia, which is neurophysiology
defined as an increased response to a normally
painful stimulus. Hyperalgesia is often classified as Correspondence:
Paul Wilkinson
primary or secondary. Primary hyperalgesia Pain Management Unit
occurs immediately around the site of the injury and Royal Victoria Infirmary
is interpreted as being due to changes in the Queen Victoria Road
peripheral pain receptor. Secondary hyperalgesia Newcastle upon Tyne
Tel: 0191 282 4412
occurs over a wider area, is longer lasting and E-mail:
generally involves mechanisms remote from the site p.r.wilkinson@ncl.ac.uk
104 CPD Anaesthesia, 2001; 3(3): 103-108

Mechanisms of pain in the peripheral nervous system

of injury for example in the dorsal horn of the spinal
cord.
A second type of pain is distinguished in clinical
practice where nerve injury is assumed to have occurred.
This pain is known as neuropathic pain and can be
initiated by a primary lesion or a dysfunction within the
nervous system. Clinical features may include a
“burning”quality”, hyperalgesia and allodynia.
Allodynia is pain that arises from stimuli that do not
normally evoke pain. Thus, allodynia involves a change
in the quality of the sensation for example tactile or
thermal stimuli becoming painful. Allodynia may also be
associated with nociceptive pain for example following
sunburn or tissue injury and is not exclusively a feature
of neuropathic pain.
Pain is commonly divided into acute and chronic.
Whilst acute and chronic pain could be viewed as
differing only on a temporal axis, it is becoming clear
that there are broader differences. Acute pain is closely
related to stimulus, serves the biological function of
protecting the organism and is largely associated with an
undamaged nervous system. Therefore, acute pain
allows the organism to minimise tissue damage and
promote healing. In chronic pain, there is often no
active tissue damage and the relationship between pain
and injury (“hurt” and “harm”) is less clear. As this
article will emphasise, the nervous system itself becomes
“damaged” after injury and profound
neurophysiological, anatomical and even genetic
changes ensue. These changes serve no protective
function and the perception of pain is uncoupled from
stimulus.
The Cartesian model of pain transmission describes
the process of pain perception in terms of discrete
pathways linking peripheral stimulus to the sensory
cortex. Though this process is known to be more
complex, this simple model will be used to introduce the
neurophysiology of pain transmission.
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. Nociceptors are receptors that detect sensations
associated with actual or potential tissue damage and
respond to noxious thermal, chemical and mechanical
stimulation. They are located in skin as well as deeper
structures. Nociceptors are fine nerve endings that
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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CPD Anaesthesia, 2001; 3(3): 103-108
Mechanisms of pain in the peripheral nervous system
in membrane electrical potential. If threshold is reached
action potentials are generated. Action potentials are small
all-or-nothing depolarisations in the membrane potential
and pain signals are encoded in the pattern of action
potential firing. 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. The sensory nerves that conduct
noxious impulses to the spinal cord mainly belong to Aδ
and C groups. This classification is based on the size,
speed of conduction and degree of myelination. Aδ fibres
are small, myelinated fibres 2-5 µm in diameter and have
conduction velocities of 5-30 m/s while C fibres are
smaller, unmyelinated fibres 0.5-1 µm with lower
conduction velocities of 0.5-2m/s. The different rates of
conduction along these two types of axons may contribute
in part to the biphasic perception of pain. 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.
Anatomically, the cell bodies of these afferent
(because they conduct signals towards the spinal cord)
neurones are situated in the dorsal root ganglion. This
arrangement is unusual, in that the cell body sits off the
main conducting axon. 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. 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”.
Nociceptive pain
Nociceptors and inflammation
Following peripheral tissue injury, a variety of local
inf lammatory substances are released which include
histamine, prostaglandins, bradykinin and substance P.
These result in changes in local blood flow and vascular
permeability, activation of immune cells and some, such
as bradykinin, may even produce pain directly. The
characteristic features of tissue inflammation result
from the release of these inflammatory mediators and
include pain, oedema and erythema.
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. 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, by the sensory fibres to which they are
associated (C or Aδ) or by their responsiveness to different
stimuli e.g. mechanical or thermal stimuli.
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Receptors associated with C fibres are usually
polymodal in that they respond to heat, mechanical and
chemical stimuli but some are relatively insensitive to
mechanical stimulation. Aδ fibres carry information
from at least two types of sensory transducers which may
respond to heat and mechanical stimuli with differing
thresholds.
Thresholds of C and Aδ associated transducers to
particular stimuli may vary.
Some receptors, which respond to low intensity
mechanical or thermal stimulation (low threshold), are
responsible for normal nerve conduction, while others,
which are stimulated only at higher intensities (high
threshold), may be more important to noxious
stimulation. Other receptors are normally activated only
at very high stimulation intensities but may be recruited
during inf lammation. These are known as silent
receptors because they are dormant in unsensitised
states.
Tissues such as muscle, tendon, 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. In visceral
tissue, the density of sensory receptors is much lower,
the localisation of pain imprecise and often referred to
areas of skin away from the viscera. Also, only particular
types of stimuli such as distension or ischaemia produce
pain. Though pain is often conducted along small,
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.
Peripheral sensitisation
Following inf lammation, recordings from single
sensory nerves have demonstrated an increased
sensitivity of peripheral sensory neurones. Such
experiments have shown that many of the chemical
mediators of inf lammation increase the responsiveness
or decrease the threshold of peripheral sensory nerves.
Thus, sensory nerve endings close to the area of injury
acquire a state of hyper-responsiveness known as
peripheral sensitisation. Specifically, 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.
Peripheral sensitisation may explain primary
hyperalgesia but not all hyperalgesia can be explained by
peripheral mechanisms. Secondary hyperalgesia is also
due to changes remote from the peripheral pain receptor
including changes in the spinal cord known as central
sensitisation.
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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
This section considers the pathological processes in
the peripheral nervous system that underlie
neuropathic pain. It considers also treatments which may
be useful in the treatment of such pain.
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, for
example, by cutting completely (neuroma model) or by
placing a tight suture round the nerve (nerve
constriction model). A completely transected nerve
exhibits a variety of pathological changes which include
demyelination, inf lammatory changes, neuronal
degeneration and nerve regrowth in the form of tiny
sprouts which may become entangled and form a
swelling known as a neuroma. The nerve end may
become painful to touch.
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. 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. Similar findings were confirmed in painful
human neuroma of amputees which gave a potential
explanation for pain and paraesthesia following nerve
injury. Volleys of spontaneous electrical impulses arise
from areas of nerve damage and are sent to the spinal
cord and thereafter perceived as pain.
Subsequently it was shown that the excitability of
such “injured fibres” could be increased by: -
1) Mechanical stimuli e.g. gentle probing of nerve,
2) Physiological stimuli e.g. stimulation of sympathetic
ganglia,
3) Chemical substances e.g. adrenaline and
noradrenaline,
Thus, 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. The additional finding of increased
excitability in nerve cell bodies in the dorsal root
ganglion might amplify these effects further.
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). There are other potential factors
contributing to the hyperexcitability but, arguably, the
most interesting discovery relates to changes in sodium
channels in injured nerves.
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Sodium channels and neuropathic pain
A number of drugs used in the management of
neuropathic pain are known to block sodium channels, a
property which may be important, but not exclusive, to
their clinical effects. These agents that can block sodium
channels include drugs used normally as anticonvulsants,
membrane stabilising agents and antidepressants. 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.
It is logical to ask whether sodium channels are
important in the observed hyperexcitability in injured
peripheral nerves. There is emerging evidence for this
view. First, sodium channels are found concentrated at
the injured end of axons. Second, ectopic electrical
activity is abolished most reliably by sodium channel
blockers. Significantly, 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. It is now apparent
that there are a number of different sub-types of sodium
channels. 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.
Sympathetic mechanisms and neuropathic pain
It is well known that immobilisation or nerve injury
can result in a clinical syndrome where ongoing pain,
allodynia and hyperalgesia are associated with oedema,
changes in local blood f low, altered sweating and trophic
changes. 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.
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.
2) Baskets of fine new sympathetic nerve sprouts grow
and spread round sensory cell bodies in the dorsal
ganglia.
3) There is a demonstrable increase in hyperexcitability
of injured neurones following sympathetic
stimulation and application of catecholamines.
Thus, 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
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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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