BASIC SCIENCE

The anatomy and not providing the person with a useful signal since the likelihood
of injury occurring with the activity has ceased. In fact lack of

physiology of pain activity may now be becoming physically and psychologically

bad for the patient. The continuing pain is distressing for the
patient and the dissociation between pain and tissue damage is
Charlotte E Steeds confusing.
The IASP definition avoids tying pain to the stimulus. In this
article, although we will look at nociceptive pathways, it is
Abstract important to recognize that the whole experience of pain is far
Pain is an unpleasant experience that results from both physical and more than physical stimuli triggering neural signals.
psychological responses to injury. A complex set of pathways trans-
mits pain messages from the periphery to the central nervous system, Pain pathways
where control occurs from higher centres. Primary afferent pain fibres
synapse with second-order neurons in the dorsal horn of the spinal Pain receptors and primary afferents
cord. Ascending spinothalamic and spinoreticular tracts convey pain Nociceptors are receptors in tissues which are activated specif-
up to the brain, where pain signals are processed by the thalamus ically by painful stimuli. This ‘noxious’ information is trans-
and sent to the cortex. Descending tracts, via the midbrain periaqua- duced by the receptors into an electrical signal and transmitted
ductal grey and nucleus raphe magnus, have a role in pain modulation. from the periphery to the central nervous system along axons.
When nerves are damaged, neuropathic pain results and various There are two types of nociceptors:
mechanisms have been proposed for how this takes place. These  high-threshold mechanoreceptors (HTM), which respond
mechanisms involve both peripheral and central sensitization. to mechanical deformation
 polymodal nociceptors (PMN), which respond to a variety
Keywords Central sensitization; gate-control theory; neuropathic
of tissue-damaging inputs:
pain; nociception; pain pathways; peripheral sensitization; somatic
 hydrogen ions (protons)
pain; visceral pain
 5-hydoxytryptamine (5-HT)
 cytokines
 bradykinin
What is pain?
 histamine
In 1996 the International Association for the Study of Pain (IASP)  prostaglandins
defined pain as ‘an unpleasant sensory and emotional experience  leucotrienes.
associated with actual or potential tissue damage, or described in These inflammatory mediators bathe the nociceptors, acti-
terms of such damage’. This statement requires further expla- vating and sensitizing them. Prostaglandins and bradykinin
nation as it encompasses some important concepts. Pain is a sensitize nociceptors to activation by low-intensity stimuli. His-
subjective experience, which cannot be easily measured. It re- tamine and 5-HT cause pain when directly applied to nerve
quires consciousness. Describing pain as an ‘experience’ sepa- endings. Hydrogen ions and 5-HT act directly on ion channels on
rates pain from ‘nociception’. Nociception is the neural process the cell membrane, but most of the others bind to membrane
involving the transduction and transmission of a noxious stim- receptors and activate second-messenger systems via G proteins.
ulus to the brain via a pain pathway. Pain is the result of a Nociceptors are therefore the free nerve endings of nerve fi-
complex interplay between signalling systems, modulation from bres. There are two main fibre types: Ad and C fibres. A com-
higher centres and the unique perception of the individual. parison of the properties of these pain fibres is shown in Table 1.
We learn about pain when we experience injury in early life. These primary afferent nerve fibres have cell bodies in either the
Scientists recognize that stimuli that cause pain are likely to be dorsal root ganglia or trigeminal ganglion and terminate in the
damaging to (or likely to damage) tissue. However, many people dorsal horn of the spinal cord. Although all pain fibres terminate
report pain in the absence of tissue damage or any likely patho- in the dorsal horn, their route to this end-point varies. Most enter
physiological cause; usually this happens for psychological the dorsal horn in the ventro-lateral bundle of the dorsal root
reasons. Patients misunderstand the relationship between tissue (Figure 1). They travel just lateral to the larger-diameter
damage and pain, but sometimes healthcare professionals get it myelinated Ab fibres, which respond to non-painful stimuli
wrong too. If someone says they are in pain, regardless of whether such as vibration and light touch. However, 30% of the C fibres
a damaging stimulus can be identified, or not, what they are enter the spinal cord via the ventral root. Once they have entered
experiencing should be accepted as pain. the spinal cord the nerve roots may bifurcate into ascending and
If a person experiences pain as a result of a particular activity, descending branches, which can enter the dorsal horn one or two
they usually stop doing that activity, because they identify pain segments higher or lower than the segment of origin.
as a warning sign that harm is occurring. However, if the pain
continues, the person can do less and less. At this point pain is The spinal cord and the gate-control theory
The dorsal horn of the spinal cord is the site where the primary
afferent fibres synapse with second-order neurons. It is also
where complex interactions occur between excitatory and
Charlotte E Steeds BSc MBBS FFARSCI is a Locum Consultant in inhibitory interneurons and where descending inhibitory tracts
Anaesthesia and Pain Medicine at University Hospitals Bristol, UK. from higher centres exert their effect (Figure 2).

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 BASIC SCIENCE

Characteristics of primary afferent fibres Excitatory and inhibitory interactions at the spinal
cord level
Higher centres
Fibre type Ad (finely myelinated) C (unmyelinated)
NA
5-HT
Fibre diameter 2e5 mm <2 mm
Conduction velocity 5e15 m/second 0.5e2 m/second y
Other sensory + –
Control Perception
Distribution Body surface, Most tissues input +
neuron
muscles, joints
Pain sensation Rapid, pricking, Slow, diffuse, GABA
E
Enkephalin
well localized dull, aching
Position of synapse Laminae I and V Lamina II
within dorsal horn (substantia –
of spinal cord gelatinosa) +
Pain
neuron Substance P
Table 1
Glutamate
NA, noradrenaline; 5-HT, 5-hydroxytryptamine;
GABA, γ-aminobutyric acid.
Spinal and supraspinal pathways of pain
Figure 2

The dorsal horn is divided into laminae (called Rexed

Cerebral cortex Forebrain
laminae). There are numerous connections between the laminae.
Lamina II is also known as the substantia gelatinosa and this
Thalamus extends from the trigeminal nucleus in the medulla, to the filum
terminale at the caudal end of the spinal cord. C fibres terminate
Fibres to in lamina II and Ad fibres terminate in laminae I and V. Ab fibres
hypothalamus
(light touch and vibration) enter the cord medial to the dorsal
Midbrain horn and pass without synapse to the dorsal columns. They give
Fibres to periaqueductal
Periaqueductal off collateral branches to the dorsal horn which terminate in
grey matter
grey matter several laminae (IIIeV). They also synapse directly with termi-
Fibres to nals of unmyelinated C fibres in lamina II. Laminae II and V are
Locus coeruleus
reticular formation
important areas for the modulation and localization of pain.
There are three types of second-order neurons in the dorsal
horn:
Medulla
 nociceptive specific (NS)
Nucleus
- respond selectively to high-threshold noxious stimuli
reticularis giganto-
cellularis (NA) - found in laminae II and III
 wide dynamic range (WDR)
Nucleus raphe
Neospinothalamic
magnus (5-HT)
- respond to a range of sensory stimuli
tract (fast pain) - found in laminae V and VI
Inhibitory dorsal columns  low-threshold (LR)
Palaeospinothalamic
tract (slow pain) - respond solely to innocuous stimuli.
Spinal cord
Dorsal horn At the spinal cord level the passage of pain information from
(laminae I–VI) Dorsal root periphery to central areas is controlled by a number mechanisms
ganglion
that modulate the pain signals:
C fibres
 inhibitory control by higher centres
Aδfibres  activity in Ab collaterals
 segmental (spinal) modulation by a variety of mechanisms
including endogenous opioid and cannabinoid systems,
inhibitory amino acids, for example g-aminobutyric
acid (GABA), galanin, cholecystokinin and nitric oxide
(Table 2).
Ascending nociceptive fast (red) and slow (green) pathways. The first two of the above mechanisms act to ‘close the gate’
Descending inhibitory tracts (blue). on the onward transmission of C fibre activity. Melzack and Wall
NA, noradrenaline; 5-HT, 5-hydroxytryptamine. initially proposed the gate-control theory in 1965. They proposed
that lamina II inhibitory interneurons can be activated directly or
Figure 1 indirectly (via excitatory interneurons) by stimulation of non-

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 BASIC SCIENCE

Chemicals involved in the transmission of pain

Class Chemical Comments

Amines Noradrenaline Involved with descending modulation of pain

5-HT
Endogenous Enkephalins Produced in cell body and transported to nerve terminal. Widespread in
opioid peptides b-Endorphin CNS, but especially in sites associated with pain. Bind to opioid receptors
with inhibitory effect
Non-opioid peptides Substance P Widespread especially in DRG of C fibres. Associated with inflammation.
Galanin Widespread. Involved with antinociception
Cholecystokinin Occur in DRG, dorsal horn and spinal tracts. May be involved with visceral
and others pain. Become depleted in nerve injury
Excitatory amino acids Glutamate Act on NMDA and non-NMDA receptors. Involved in development, memory
and neuronal plasticity
Inhibitory amino acids GABA Regulate behaviour associated with non-noxious stimuli
Glycine
Others Cannabinoids CB1 receptors in SC and on primary afferent neurons: involved in antinociception.
Nitric oxide In sensory neurons and dorsal horn. Involved in peripheral and central
sensitization. Linked with NMDA activity

CNS, central nervous system; DRG, dorsal root ganglia; NA, noradrenaline; NMDA, N-methyl-D-aspartate; 5-HT, 5-hydroxytryptamine; GABA, g-aminobutyric acid.

Table 2

noxious large sensory afferents from the skin (Ab fibres) that are located in the anterolateral white matter of the spinal cord
would then suppress transmission in small unmyelinated (Figure 1). The properties of these tracts are highlighted in
(C fibre) afferents and therefore block the pain. Thus rubbing a Table 3.
painful area relieves the pain. This is the working mechanism
behind transcutaneous electrical nerve stimulation (TENS) in The brain
pain control. The thalamus is the key area for processing somatosensory in-
formation. Axons travelling in the lateral and medial spinotha-
Ascending tracts lamic tracts terminate in their respective medial and lateral
nuclei and from here neurons project to the primary and sec-
Second-order neurons ascend to higher centres via the contra- ondary somatosensory cortices, the insula, the anterior cingulate
lateral spinothalamic and spinoreticular tracts, which cortex and the prefrontal cortex. These areas play various roles in

Properties of the spinothalamic and spinoreticular tracts

Spinothalamic tract Spinoreticular tract

More recently evolved More phylogenetically ancient

Contains axons of neurones in laminae I and V (where Ad fibres terminate) Arises from cells deeper in grey matter including lamina V
Lateral tract Medial tract
‘Neospinothalamic’ ‘Paleospinothalamic’
Projects to ventral posterior lateral nucleus Projects via medial thalamus Projects to thalamus and hypothalamus via nuclei of
of thalamus, then to post-central gyrus brainstem reticular formation. Some fibres project diffusely
to the whole cerebral cortex
Axons are somatotopically ordered Little somatotopic organization
(caudal elements are more lateral)
Sends collateral branches to the periaqueductal grey (PAG) matter in
the midbrain
Involved in the sensory-discriminative Involved in autonomic Involved in perception of diffuse, emotionally disturbing pain
aspect of pain and affective part of pain

Table 3

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 BASIC SCIENCE

the perception of pain and also interact with other areas of the Abnormal pain and how the nervous system responds to
brain, for example the cerebellum and basal ganglia (which are injury
areas more traditionally known to be associated with motor
Definitions
function rather than pain).
So far we have considered nociceptive pain, that is pain arising
from an identifiable lesion causing tissue damage, accompanied
Descending tracts
by stimulation of nociceptors in somatic or visceral structures.
These pathways (Figure 1) have a role in the modulation of pain. However, sometimes pain signalling goes wrong. This gives
Noradrenaline and 5-HT are the key neurotransmitters involved rise to abnormal pain, which is described using a range of terms
in descending inhibition. Two important areas of the brainstem that can be confusing.
are involved in reducing pain: the periaquaductal grey (PAG) and
the nucleus raphe magnus (NRM). Neuropathic pain: pain or abnormal sensation initiated or
caused by a primary lesion or dysfunction of the nervous system.
Periaquaductal grey This can be a motor, sensory or autonomic dysfunction. Patients
This region surrounds the cerebral aqueduct in the midbrain and can report spontaneous pain, in the absence of an obvious pe-
is important in the control of pain. Electrical stimulation of the ripheral stimulus. The pain may be paroxysmal or continuous
PAG produces profound analgesia and injection of morphine and is often described as a ‘burning’, ‘tingling’, ‘shooting’,
here has a far greater analgesic effect than injections anywhere ‘stabbing’ or ‘numb’ sensation.
else in the central nervous system. The PAG receives inputs from Neuropathic pain is also characterized by evoked pains:
the thalamus, hypothalamus and cortex and also collaterals from  Allodynia e painful response to a normally innocuous
the spinothalamic tract. PAG (anti-nociceptor) neurons excite stimulus.
cells in the NRM that in turn project down to the spinal cord to  Hyperalgesia e pain of abnormal severity following a
block pain transmission by dorsal horn cells. noxious stimulus.
 Hyperpathia e exaggerated and prolonged response to
Nucleus raphe magnus stimulation. May be delayed in onset and after repeated
A second descending system of serotonin-containing neurons ex- stimulation. Often an explosive onset.
ists. The cell bodies of these neurons are located in the raphe  Hyperaesthesia e increased sensitivity to stimulation.
nuclei of the medulla and, like the noradrenalin-containing neu-  Dysaesthesia e evoked or spontaneous altered sensation.
rons, the axons synapse on cells in lamina II. They also synapse on Discomfort rather than pain.
cells in lamina III. Stimulation of the raphe nuclei produces a
powerful analgesia and it is thought that the serotonin released by Mechanisms in neuropathic pain
this stimulation activates inhibitory interneurons even more
powerfully than noradrenaline and thus blocks pain transmission. Pain can result from damage to either the peripheral or the
Brainstem neurons may control nociceptive transmission by: central nervous system. Traditionally, abnormal pain from pe-
 direct action on dorsal horn cells ripheral nerves has been termed ‘neuropathic’ and pain from
 inhibition of excitatory dorsal horn neurons damage to central nerves has been called ‘central pain’. How-
 excitation of inhibitory neurons. ever, in clinical practice, the symptoms and signs can be the
same for both conditions and it is not always easy to tell where
Visceral pain the injury is occurring.
The nervous system has the ability to adapt to injury and can
This is the pain arising from internal organs. In comparison to change its response to stimulation. The pathways described
somatic pain, visceral pain is poorly localized, because the density above are not hard-wired, but instead display the phenomenon
of nociceptors on viscera is lower and afferent fibres are less well of plasticity. Several mechanisms to explain how these changes
represented in cortical mapping. Just as with somatic pain, the take place have been proposed and some are summarized
fibres that transmit pain from visceral nociceptors are Ad and C below.
fibres and travel with autonomic afferents. Visceral pain pathways
are shared with somatic pathways in the same ascending tracts of Peripheral sequelae of nerve injury
the spinal cord. The result is that pain from an internal organ can When an Ad or C fibre is cut or partially damaged (e.g. in post-
be interpreted as arising from converging somatic afferents and herpetic neuralgia), it tries to repair itself. In doing so it does
therefore visceral pain may be referred to the corresponding so- not heal in its original form but instead a neuroma, or swelling,
matic tissue. Visceral pain can also be referred to a site far away develops around the joined axon. Spontaneous electrical activity
form the source of stimulation. An example of this is when deep can be seen around neuromata, thought to be due to altered
pain from the bladder is referred in a segmental fashion to the distribution, expression and gating properties of sodium chan-
superficial S2-4 dermatomes in the perianal region. nels. Ectopic impulse generation can also be seen at the spinal
Visceral pain also differs from somatic pain in that it is often cord level in dorsal root ganglia.
colicky in nature and is accompanied by nausea and autonomic In addition, peripheral nociceptors become sensitized by
disturbance. Whereas somatic pain is caused by stimuli such as injury so that they:
cutting and crushing, visceral structures do not show a painful  have a lower threshold for firing
response to these, but instead respond to distension as well as to  increase their response to noxious stimuli
inflammation and ischaemia.  can fire in response to non-noxious stimuli.

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 BASIC SCIENCE

Thus damaged nerves become the foci of hyperexcitability prolonged dorsal horn response. This phenomenon has been
and ectopic discharge. Ectopic firing is influenced by physical termed ‘wind-up’.
stimuli (e.g. heat or cold) and the metabolic and chemical Within the dorsal horn there is a reduction in local inhibition
environment of the nerve. by the neurotransmitters GABA and glycine and evidence of
Injury also causes changes in the Schwann cells and glia that excitotoxic death of inhibitory interneurons. At the same time
surround axons. These are non-neuronal cells that provide sup- there is a strengthening of excitatory synaptic connections.
port and nutrition to nerves. Injury causes phenotypic shifts Incoming axons develop ectopic activity and output to the spi-
leading to changes in growth factor, breakdown of the myelin nothalamic tract neurons is increased. This process involves
sheaths surrounding nerves and a resultant change in axonal neurochemical changes mediated via N-methyl-D-aspartate
function. Furthermore, uninjured axons can spread into areas of (NMDA), neurokinins, and nitric oxide. The result of all of these
injury and, particularly if this involves central neurons, the result changes is that the sensory threshold for pain signalling is low-
is the spread of pain to uninjured areas and development of ered and there is spread of the receptive field.
‘mirror’ pain. In addition it has been shown that structural rewiring occurs
in the dorsal horn of the spinal cord in response to injury. C fibre
The role of the sympathetic nervous system terminations in the substantia gelatinosa (lamina II) degenerate
The sympathetic nervous system can play a role in some painful and Ab (fine touch) fibres, which are usually located in laminae
conditions, such as complex regional pain syndrome. It is III and IV, sprout into lamina II. This may explain allodynia,
responsible for both causing and maintaining the pain. Injury where light touch is perceived as painful. These changes seem to
(usually to a limb) can cause abnormal processing of information be triggered by loss of nerve growth factor.
in the spinal cord, which in turn leads to abnormal sympathetic Finally, there are changes at a supraspinal level. Following
outflow to the injured extremity. The result is neuropathic pain, injury there is evidence of cortical remapping and reorganization
which is often resistant to treatment and the following changes in in both the primary somatosensory and motor cortices and in the
the limb: subcortical areas. This is well recognized following limb ampu-
 abnormal regulation of vasculature tation where lack of afferent input from the amputated limb leads
 oedema to less occupation of the corresponding area of the somatosen-
 discolouration sory cortex. As a result the neighbouring cortical area (repre-
 changes in sweating senting a different anatomical site) expands. The clinical
 temperature changes manifestation of these changes is that the patient not only de-
 trophic changes in skin velops phantom limb pain very soon after amputation, but also
 reduced motor activity in the affected part. that the phantom limb can sometimes be mapped out by
Primary afferents from nociceptors can be influenced by touching a very different site of their body (e.g. pain in phantom
sympathetic neurons. The sympathetic postganglionic neuro- hand felt by touching side of face). Reduction in the intensity of
transmitter noradrenaline can exert its effect anywhere along the the phantom limb pain by effective treatment can be shown to
pathway from the free nerve endings to the dorsal root ganglion. reverse the cortical changes.
In response to injury, nociceptor neurons can show increased
expression of a-adrenoceptors, making them more responsive to Summary
the chemical influence of noradrenaline. In addition, sympathetic
terminals sprout into the dorsal root ganglia (DRG) after nerve This article gives a broad overview of the anatomy and physi-
injury and may come into contact with sensory neurons here. ology of pain. It explains pain as a complex experience involving
Alteration of the blood supply to afferent nerve terminals may both physical and psychological adaptations. The normal pain
also contribute to their sensitivity to the effects of sympathetic pathways are described in some detail in a systematic fashion
stimulation. from nociceptor to central nervous system and back to periphery.
It concludes with an explanation of some of the mechanisms
Central sensitization involved with pain transmission. A
Changes occur in the dorsal horn of the spinal cord after nerve
injury. Repetitive C fibre activation by noxious stimuli leads to a

SURGERY 34:2 59 Ó 2016 Published by Elsevier Ltd.