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Chapter summary
1. Pain is a multidimensional sensory modality. The perception and
interpretation of pain involve the peripheral nervous system, and several
subcortical and cortical areas in the central nervous system. This is
commonly referred to as the pain matrix.
2. Pain has an essential protective function after acute injury, but under
conditions of non-resolved inflammation or injury and following persistent
damage to the nervous system, it can become profoundly maladaptive.
Persistent neuropathic pain associated with injury in the central nervous
system is linked to plastic adaptations of neural circuits, which involve
peripheral and central sensitization that exacerbate pain.
3. Pain can be modulated through exogenous and endogenous mechanisms.
Exogenous mechanisms often involve pharmacological or cognitive
treatments, whereas endogenous mechanisms comprise two key
processes: (a) a gating of nociceptive input at the first synapse in the
spinal cord or brainstem and (b) by activation of descending pathways,
which can modify the ascending nociceptive pathway transmission. This is
done by presynaptic or postsynaptic inhibition.
5PAIN AND ANALGESIA
4. The pain matrix circuitry involves multiple neurotransmitters, including
peptides such as the enkephalins and substance P, purines such as ATP, and
monoamines such as noradrenaline and serotonin, and glutamate.
Management of pain is based on the use of non-opioid drugs and opioid
drugs, whose use is titrated, so that therapy is based on a gradual
escalation (known as the analgesic ladder), for example from nonsteroidal anti-inflammatory drugs to low strength opioids and finally
strong opioids. The mu opioid receptors are a major target for the
modulation of pain, using agonists such as morphine or related
compounds. However, long- term use of these agents is associated with a
risk of tolerance and dependence. For chronic neuropathic pain, other
drugs such as antidepressants, anticonvulsants, cannabinoid- based drugs
or other interventional strategies are used.
5
Chapter summary—cont’d
5. Migraine is a distinct form of pain. It is a primary headache disorder
whose pathophysiology is neurovascular. The trigeminovascular activation
involved in migraine leads to release of vasodilatory agents, which trigger
the specific pain that characterizes migraine attacks. Management
involves treatment for the attacks and also prophylaxis, as needed. Drugs
modulating 5- HT transmission (e.g. triptans) and calcitonin gene- related
PAIN AND ANALGESIA
peptides (e.g. gepants) are specific therapies for the management of this
condition.
6. Non-pharmacological approaches can also be used to control pain.
They could involve surgical interventions (e.g. cordotomy) or various
forms of neurostimulation such as transcutaneous electrical stimulation,
vagus nerve stimulation, deep brain stimulation or remote electrical
neuromodulation. Biofeedback, relaxation and distraction strategies can
also help alleviate pain.
Box
Case history
5.1
A South- East Asian male was involved in an industrial accident when he was 18 years old; his shirtsleeve got caught in a
machine, dragging his arm into the equipment. Surgeons tried
to repair the arm but the blood supply was severely compromised and eventually the right arm was amputated above the
elbow. Since the accident he has experienced phantom limb
pain sensations that radiate up the right arm and appear to
originate from the non-existent right hand. He describes the
pain as shooting, burning and stabbing sensations, and it feels
worse when it is cold. He rates it as 7 out of 10 on a visual analogue pain rating scale. Intermixed with these are sensations
of hyperalgesia and allodynia when the skin over the stump
is touched, and spontaneous pain that occurs sporadically
and feels like electric shocks in the arm. When he is shaving
he feels tingling sensations in the phantom hand. He describes
the phantom hand as contorted, with the fist closed and the
nails digging into the palm skin.
His GP initially prescribed mild analgesics to relieve the
pain but these were largely ineffective. He sought alternative treatments such as transcutaneous electrical nerve stimulation (TENS) and acupuncture, but these have had mixed
results; TENS made the pain worse and acupuncture only
partially alleviated the pain. Likewise, anticonvulsant and
tricyclic antidepressant drugs, such as carbamazepine and
amitriptyline, had a limited effect, and stronger opiate drug
treatment, such as morphine, was initially effective but now
much higher doses are required to achieve the same effect.
He is referred to a pain clinic where the consultant tries
a sympathetic nerve blockade that has limited effect. After
unsuccessfully trying several new drug combinations, he
prescribes the drug gabapentin. After a couple of months
of treatment, the patient reports that suddenly the pain in
his phantom limb has regressed to a point where he hardly
notices it (pain rating, 1/10). The only side effect of this latest
treatment was a mild dizziness that occurred during the first
few days of treatment.
This case gives rise to the following questions:
1. What pathways transmit pain from the periphery to
the brain?
2. Why were TENS and acupuncture ineffective?
3. How does morphine reduce pain and why did it
become ineffective in this case?
4. What is the rationale for the other pharmacological
and non-pharmacological treatments that were tried?
5. What are the mechanisms that may contribute to
phantom limb pain?
90
Introduction
Pain is one of humanity’s oldest and most dreaded fears.
Pain is a sensation that evokes an emotional response
and involves a complex interaction between the periphery, spinal cord, brainstem and higher cortical centres.
SYSTEMS OF THE BODY
Intense pain is an extreme sensation that commands the
person’s attention and rapidly dominates the mind. To
the neuroscientist, pain is a sensory phenomenon based
on perception; to the psychologist, it may be a learned or
conditioned behaviour, but to the doctor, it is a warning
sign to be decoded for diagnosis and treatment. People
go to see their doctors most often because they are in
5
pain. Thus it is important that doctors have a sound
knowledge of pain and its pathways, and of the treatments that are effective in alleviating pain. Pain is a
learned experience, the perception of which depends on
the emotional interpretation of pain, recall of past pain
and social and genetic factors.
Pain is defined by the International Association for the
Study of Pain (IASP) as ‘an unpleasant sensory or emotional experience associated with, or resembling that associated with, actual or potential tissue damaging stimuli’.
The definition includes the sensory- discriminative and
motivational- affective components that make up the complex experience of pain. Among somatovisceral sensations, pain is arguably the most important. Although pain
is used to define generically all sensations that hurt or are
unpleasant, there are three distinct types of pain. The first
two types of pain are examples of ‘good’ pain; the third is
deemed ‘bad’ pain.
1. Nociceptive acute pain is elicited by a brief
noxious stimulus such as a pinprick that induces a
flexion withdrawal response to the stimulus. This
type of pain is an adaptive sensation whose
primary function is to protect the body from
injury; it is an early warning alarm system. Loss of
this type of pain through disease or injury can lead
to life- threatening situations. People who have
congenital insensitivity to pain with anhydrosis
(CIPA)—a rare autosomal- recessive disorder—
have recurrent episodes of unexplained fever,
anhydrosis and absence of reaction to noxious
stimuli, as well as mental retardation. Children
with this condition often have to have their
fingernails and teeth removed to stop selfmutilation (autotomy) behaviour, and many die
young. Mutations in the sodium channel subunit
NaV1.7 also result in abnormal pain sensations;
loss of the subunit results in analgesia, whereas
increased expression results in conditions such as
paroxysmal extreme pain disorder and
erythromelalgia (Mitchell’s disease). Pain also has
a homeostatic function. A low level of pain is
necessary to inform us when activities put
excessive strain on the body, such as during certain
movements or altered posture. Even when we
sleep, nociceptors work to cause us to toss and
turn during the night to prevent bedsores or
musculoskeletal strain.
2. When pain is prolonged (e.g. sunburn), injury to
the body has already occurred and the biological
function of pain is to prevent further damage,
assist healing and tissue repair. It does this by the
development of areas of hypersensitivity in and
around the injury site, which are the result of a
decreased activation threshold of nociceptors—a
phenomenon called peripheral sensitization. The
pain recedes once healing has occurred.
3. Chronic pain is pain that has persisted for at least
2–3 months. Such pain is often neuropathic, due to
damage of the nervous system. Chronic pain is
defined by the IASP as ‘pain resulting from disease
or damage to the peripheral or central nervous
systems, and from dysfunction of the nervous
system’. Thus, it is a ubiquitous term covering a
wide range of conditions such as pain in irritable
bowel syndrome (a visceral pain disorder),
through to muscle and joint pain disorders such as
fibromyalgia and back pain, where there is no
obvious nervous system damage, and to pain in
diseases such as arthritis, diabetes, cancer and
HIV/AIDS. The quality of pain sensations is
distinct from that seen in acute pain (Table 5.1). In
neuropathic pain, the pain persists in the absence
of the initial injury. Chronic pain often results from
abnormal sensitivity of nociceptors and nonnociceptors and pathological changes at multiple
levels in the nervous system (Table 5.2). Pain,
rather than the original injury, becomes of greatest
concern and is often very difficult to treat.
Statistics suggest that the prevalence of chronic pain
in the UK adult population is 35%–51%, with nearly twothirds of those aged >75 years suffering from chronic
pain. In 2018 in the United States, 50 million people were
reported to suffer from chronic pain. The worldwide
prevalence is about 30% of the population. Statistics from
the United States suggest that the annual cost of chronic
pain is $560–653 billion, with indirect costs (disability
compensation and lost productivity) adding another
$261–300 billion annually. These estimates do not include
other costs such as legal fees, childcare, lost earning
potential or personal suffering. Chronic pain costs more
than heart disease ($309 billion), cancer ($243 billion) or
diabetes ($188 billion). Chronic pain is expensive to diagnose, expensive to treat acutely, and expensive to live
with long- term.
Table 5.1 Clinical features of neuropathic pain
Abnormal pain quality—burning, stabbing, gnawing and sickening
Sensory loss with associated hyperalgesia (increased painful
response to a noxious stimulus), allodynia (pain in response to
an innocuous stimulus) and hyperpathia (delayed perception,
summation and painful after- sensations)
Paroxysmal pain (electric shock-like) episodes are common
Radiating dysaesthesia (non-painful abnormal sensations)
Pain is poorly localized and diffuse
Pain intensity is altered by emotion and fatigue
Onset of pain is immediate or delayed after injury
Sympathetic nervous system dysfunction may be present
Vasomotor (regulation of blood vessels) and sudomotor
(stimulation of sweat glands) changes can occur
PAIN AND ANALGESIA
THE NERVOUS SYSTEM
91
5
Table 5.2 Summary classification of some major characteristics of different types of pain
Temporal
Type Duration
features in
relation to cause Sensation
Nerve fibre class
involved Adaptive value Example
Acute Seconds Instantaneous
PAIN AND ANALGESIA
Prolonged Hours to days Resolves on
Chronic Months to years Persistent;
Despite much research regarding the molecular and
cellular aspects of nociception, pain therapy continues to
be only partially effective and may be accompanied by
distressing side effects or have abuse potential. For most
acute pain conditions, non-steroidal anti-inflammatory
drugs (NSAIDs) or opioids remain the first line of treatment, while these drugs are largely ineffective in neuropathic pain. Chronic pain can respond well to drugs
whose primary use was not intended for pain, for example, antidepressants, anticonvulsants and local anaesthetics. It is becoming clear that no one class of drug is
effective in treating all forms of pain. Moreover, different
types of pain may involve common or dissimilar mechanisms. Therefore treatment, which traditionally was
based on empirical measures such as symptom or temporal properties, may be improved by therapies targeting
with more precision the underlying mechanisms. In the
past 20 years, rapid progress has been made in uncovering new mechanisms, pathways, brain areas and drugs
involved in pain perception, and modulation. However,
we are still putting all the pieces of the pain puzzle
together. This chapter aims to provide an overview of
some of the pathways and mechanisms of nociception
and pain, current therapies for pain management and
new therapeutic concepts.
Nociceptors
Nociceptive afferents do not have specialized receptors;
they use free nerve endings and most are polymodal, that
is, they respond to more than one kind of stimulus such
as chemical, thermal or mechanical stimuli. Free nerve
endings are found in all parts of the body, except the interior of the bones and the brain itself. Acute pain is characterized by activation of nociceptors for a limited duration.
Pain sensations can be broadly divided into bright, sharp,
stabbing types of pain, and dull, throbbing, aching types.
Aδ fibres mediate the former, or ‘fast’ pain, whereas C
fibres signal the latter or ‘slow pain’. Not all Aδ and C
fibres are nociceptors. Some respond to low- threshold
Simultaneous
recovery
exceeds repair
of injury
Pain C/Aδ Preventive Pinprick, muscle
ache, visceral
distension
Hyperalgesia,
allodynia
Hyperalgesia,
allodynia,
spontaneous
pain
C/Aδ
Aβ
C/Aδ
Aβ
Aβ/δ/C
CNS cells
Table 5.3 Comparison of pain characteristics from different target
organs
Peripheral target Sensation
Skin Pricking
Muscle Aching
Viscera Dullness
Protective
Recovery
None
Maladaptive
Stabbing
Burning
Soreness/tenderness
Cramping
Vagueness
Fullness
Nausea
Inflamed wound
Arthritis
Neuropathy
Central pain
Localization
of pain
Well localized
Poorly localized
stimuli such as sensual touching or brushing the skin;
recent evidence suggests that these fibres contribute to
pathological pain perceptions such as mechanical allodynia after injury. Many C fibres are thermoreceptors
and respond to warm or cold, providing homeostatic
responses via emotional tagging of sensations. For example, think how pleasant a cool shower feels after sunbathing for a while, and conversely, how unpleasant a cool
shower feels first thing in the morning when the skin is
cool! Additionally, there is a population of ‘silent’ nociceptors that reside in most tissues and are normally
insensitive to mechanical and thermal stimuli. They
become active under pathological conditions such as
inflammation and nerve injury.
Interestingly, most of our knowledge about the neurophysiology of pain comes from the study of cutaneous
nociceptors. Pain from each target organ has its own distinct perceptual quality, as shown in Table 5.3. However,
cutaneous pain is clinically less common than muscle
and visceral pain. Among the most common reasons for
visiting the doctor are chest pain, neck pain, abdominal
pain, headache and back pain. For example, back pain is
extremely common, with up to 80% of the population
92 SYSTEMS OF THE BODY
5
suffering at some point in their life; it is the world number one chronic pain. Visceral pain represents a major
clinical challenge, as its occurrence is not always correlated with disease severity. For example, bowel cancer
produces little or no pain, whereas passing a kidney
stone, or a stool in a patient with irritable bowel syndrome, can be excruciating.
There are several differences between cutaneous and
muscle or visceral nociceptors. The first is that cutaneous
sensation is well localized, and the pain is usually constant. Visceral and muscle pain is poorly localized due to
the lower innervation densities of these tissues, and is
often periodic. Secondly, visceral afferents are insensitive
to direct trauma but very sensitive to distension (of
hollow- walled muscular organs), whereas muscle and
skin are not. In fact, early 20th century surgeons could
perform abdominal surgery using only local anaesthesia
of the body wall, as healthy organs are largely insensitive
to direct mechanical trauma such as cutting or burning.
All are sensitive to ischaemia and inflammation. Lastly,
as most visceral organs have very few low- threshold
myelinated fibres and comprise mostly of Aδ and C
fibres, their stimulus response properties differ from
cutaneous and muscle afferents, which have specialized
receptors to detect innocuous stimuli. Visceral afferents
encode a stimulus response in an intensity-dependent
manner—the more painful the stimulus, the greater the
number of action potentials and frequency of discharge.
Although acute pain results from damage to these free
nerve endings; in reality, the pain is a result of substances
released by damaged tissues such as prostaglandins, histamine, bradykinin, cytokines, peptides and H+ ions.
These activate specific receptors located on the free nerve
endings. Nociceptors have more than 30 different ion
channels or receptors and the list is functionally diverse
and still growing! (see Table 5.4). Moreover, the molecu-
lar composition of the receptors and their relative ratios
can change after injury.
Pain pathways
Cutaneous nociceptor afferents terminate mainly in laminae I, II and V of the spinal cord dorsal horn and synapse
on second order neurons that carry the signal to either the
brainstem or the thalamus. It is only when the nociceptive
signal reaches the brainstem that it is translated into a conscious sensory percept. Three ascending pathways are
concerned with pain transmission: the spinothalamic tract
(STT), the spinoreticular tract (SRT) and the spinoparabrachial tract (SPBT). Each appears to be concerned with a
particular aspect of pain processing. Simplistically, the
sensory discriminative aspect is signalled by the STT, and
the homeostatic and affective (emotional) qualities of pain
by the SRT and SPBT (Fig. 5.1). Therefore fast and slow
pain travel by different pathways to different areas of the
brain. The fast pathway connects directly to the thalamus,
which then relays the information to the primary sensorimotor cortices for analysis and response. Its function is
Table 5.4 Function of some of the receptor types and ion channels
located on nociceptors
Receptor family Function
P2X = purinergic ATP receptor
ASIC = acid-sensing ion channel (chemical
and mechanical stimuli)
TRP = transient response potential receptors
(temperature sensitive)
Voltage- gated Na+ channels (tetrodotoxin
resistant or tetrodotoxin sensitive)
Voltage- gated Ca2+ channels
α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid + N-methyl-
D-aspartate (AMPA + NMDA) =
ionotropic glutamate receptors; mGluR =
metabotropic glutamate receptors
Voltage- gated K+ channels
γ-aminobutyric acid (GABA) receptors
5- HT3 = serotonin receptor
CB1 = cannabinoid receptor
H1 = histamine receptor
EP = prostanoid receptors for prostaglandins
IL- 1R = receptor for interleukin 1 (cytokine)
TrkA = tyrosine kinase A receptor for the
neurotrophin nerve growth factor (NGF)
BK2 = bradykinin receptor
Involved in signal
transduction
Involved in
membrane
excitability
Involved in
peripheral
sensitization
to act as a warning system, by signalling the exact location
and severity of the injury and duration of the nociceptive
signal. Fast pain predominantly arises from the STT cells
in laminae IV–V of the spinal cord. Slow pain is mediated
by C fibres and signals the emotional aspects of pain. It
reaches the thalamus indirectly via connections with the
brainstem reticular formation. The slow pain axons innervate the non-specific intralaminar nuclei of the thalamus
and the autonomic centres of the reticular formation in the
brainstem. For example, axons of lamina I cells of both the
STT and SPBT are more concerned with stimulus intensity
than stimulus location. They form part of the forebrain
pain pathways associated with the affective quality of
pain (unpleasantness and fear of further injury) and
involve the prefrontal cortex and amygdala. Slow pain
may remind the brain that pain has occurred, that protective attention to the injury site is required, and that normal
activity may need to be restricted while healing occurs.
The projections to the reticular formation underlie the
arousal effects of painful stimuli, via activation of the
ascending reticular activating system that projects to all
areas of the brain. Activation of the reticular formation
stimulates noradrenergic neurons in the locus coeruleus
and thus decreases the pain transmission by activating
the descending pain modulating systems (see below).
Thalamocortical axons transmit the information from
the thalamus to the cortex. There is no one specific cortical region that is designated as ‘pain cortex’ (Box 5.2).
Rather, functional brain- imaging studies have revealed
PAIN AND ANALGESIA
93THE NERVOUS SYSTEM
5
Midbrain
B
SRT
C
SPBT
A
STT
PAIN AND ANALGESIA
Amygdala
Pons
Medulla
Thalamus
Hypothalamus
PAG
LC
PBN
RVM
SI cortex
Association
cortex
SI cortex
Pontine RtF
CST
Fig. 5.1 Schematic representation of anterolateral pain pathways: (A) Spinothalamic tract (STT), (B) Spinoreticular tract (SRT), and (C)
Spinoparabrachial tract (SPBT). Information is also transmitted to the amygdala and hypothalamic areas of the limbic system. CST, Corticospinal
tract; LC, locus coeruleus; PAG, periaquductal grey; PBN, parabrachial nucleus; RtF, reticular formation; RVM, rostroventral medulla; SI, primary
somatosensory cortex.
several regions that are active when a pain stimulus is
sensed, and these are associated with different functional
components of pain. The discriminative qualities (i.e.
‘where and how much it hurts’) involve the somatosensory cortex, whereas the affective- motivational aspects
(e.g. ‘I don’t like it, or stop it!’) are associated with the
limbic regions (cingulate cortex, insula). Parts of the prefrontal motor cortex are also involved in cognitive evaluative processes, for example, attention to, anticipation of,
memory of or escape from pain.
the spinal cord that respond only to muscle or visceral
stimulation. Interestingly, no such cells exist in the spinal
cord. All cells that have either a visceral or muscle receptive field (RF) also have a separate cutaneous RF. This
means that convergence occurs within the spinal cord. It
provides an explanation for referred pain. Referred pain
is a pain that is localized in one part of the body that is
remote from its source. In contrast to cutaneous pain,
which is well localized, visceral and muscle pains are
poorly localized and are often sensed as somatic pain.
This is because of afferent convergence onto spinal cord
cells that have a cutaneous RF. The area of referral is
Visceral and muscular pain pathways
related to the segmental dermatome and is often referred
to skin or muscle. The classic example is angina in which
Considering that muscle and visceral pain evoke distinct
sensations, it would be logical to expect to find cells in
ischaemic heart muscle causes pain over the skin and
radiating down the left arm. Another example is stomach
94 SYSTEMS OF THE BODY
Box
Pain in the brain
5.2
5
PAIN AND ANALGESIA
The role of the cortex in pain has been debated for almost 100
years. Based on a careful study of patients with cortical or thalamic lesions, Dr. Henry Head showed that ablation of the thalamus eliminated all pain sensations, whereas cortical lesions
did not. However, converging clinical, experimental and, more
recently, functional imaging evidence, has now altered this view,
to show that several brain regions are active, either directly or
indirectly, in response to a painful stimulus but that they process
different aspects of the stimulus (Table 5.5). These include the
primary (SI) and secondary (SII) somatosensory cortex and the
adjacent insula region, the anterior cingulate cortex and the ventromedial prefrontal cortex. Some regions, such as the anterior
cingulate cortex and the ventromedial prefrontal cortex, directly
feedback to the periaqueductal grey to stimulate anti-nociceptive
pathways. Furthermore, pain perception modulation by hypnosis
has been shown to alter activity in many of these brain areas.
Damage to the prefrontal cortex affects the evaluative cognitive responses to pain. For example, patients with frontal lobe
damage which disconnects it from the thalamus rarely complain
about the severity of pain. They acknowledge the presence of the
pain but state that it does not bother them. Cingulotomy selectively decreases the emotional components of pain perception,
although it fails to provide significant pain relief in approximately
25% of patients. It appears that the cingulate cortex may not
pain which can cause visceral organ spasm, muscle
spasm, and a skin flare response due to autonomic activity. Referred pain is consistent enough to be of diagnostic
value, for example, lower right quadrant abdominal pain
can be used to diagnose appendicitis (Fig. 5.2). Another
important feature is that the referral site may show signs
of hyperalgesia due to a preexisting condition such as
ischaemia, injury, disease or inflammation.
The central terminals of visceral and muscle nociceptors terminate in laminae I and V, but not lamina II, unlike
skin nociceptor afferents. In lamina I, these fibres converge onto projection neurons of the STT and SPBT,
which then project to the brainstem and thalamus, and
from there to the somatosensory cortex. Visceral afferents
also terminate on SRT neurons and onto cells that project
to the dorsal column nuclei; recent research suggests that
this latter pathway is exclusively involved in visceral
pain, whereas the STT and SRT visceral pathways are
more concerned with autonomic (visceral) reflex functions. Dorsal column lesions relieve chronic visceral pain
and provide a new clinical treatment for managing visceral cancer pain.
Given that muscle, viscera and skin converge onto
projection neurons that utilize common ascending tracts,
how then does the brain know whether the pain is from
skin, muscle or viscus? The answer is unknown but most
likely involves differences in the temporal and spatial
coding of inputs onto cells, inducing a differential processing of information by the brain.
modulate some forms of chronic pain, for example, neuropathic
pain. Patients with ischaemic damage to SI and SII areas show a
loss of pain sensation with preservation of pain affect. Similarly,
patients with damage to the insula and SII cortex have elevated
pain thresholds to thermal stimuli. Table 5.5 summarizes the presumed functional roles of these cortical areas in pain perception.
Table 5.5 Presumed functional roles of cortical areas in pain
perception
Cortical area Presumed function
SI Pain localization
SII Pain intensity; spatially directed attention
(touch, visual) to pain
Insula Regulation of pain- related autonomic activity;
pain intensity
Anterior
cingulate
Prefrontal
cortex
Response selection, attention, affect, motor
suppression, anticipatory appraisal of pain;
pain modulation
Affect, emotion, memory, anticipatory
appraisal of pain; pain modulation
How does the central nervous system
interpret a stimulus as painful?
As lesion studies have confirmed the role of the STT in pain
transmission, it might be expected that STT cells would be
nociceptive specific (NS), that is, specifically responding to
tissue- damaging stimuli. However, it is one of the paradoxes of pain that most of the cells of the STT are excited
by non-noxious stimulation of the skin! Low- threshold sensory skin afferents synapse upon the proximal dendrites of
the lamina IV and V neurons. These low- threshold inputs
are the only inputs to lamina IV cells (i.e. they have no
nociceptive inputs). The same low- threshold afferents also
synapse on the dendrites of the lamina V cells. However,
cells of lamina V extend some dendrites into laminae I–II
where C/Aδ fibres contact the distal dendrites. Thus the
lamina V cells receive convergent inputs from both nociceptor and non-nociceptor afferents (i.e. they are wide
dynamic range cells). Therefore, the STT has axons of three
different kinds of neurons: those that are nociceptorspecific (lamina I), those that are non-nociceptive (lamina
IV) and those that have both nociceptive and nonnociceptive inputs (lamina V). The presence of this convergence of
sensory modalities on the lamina V cells presents a problem. The forebrain can only know that action potentials are
arriving in the axons of the STT. How can it tell which
types of primary afferents are activating the lamina V cells,
nociceptors (C/Aδ) or low- threshold Aβ afferents?
95THE NERVOUS SYSTEM
5
Gallbladder
Gallbladder
PAIN AND ANALGESIA
Liver
Appendix
(T10)
Bladder
(T11 – L2)
Fig. 5.2 Common cutaneous areas of referred pain from visceral organs; dermatomes of referred pain are in parentheses. C, Cervical; L, lumbar;
T, thoracic. (Adapted from Moore KL, Agur AMR. (2002) Essentials of clinical anatomy, third ed. Lippincott Williams and Wilkins.)
Diaphragm
(C3 – 4)
Oesophagus
(T1 – 3)
Heart
(T1 – 4)
Stomach
(T6 – 9)
Spleen
(T6 – 8)
Small intestine
(T5 – 9)
Colon
(T10 – 12)
Kidney and ureter
(T11 – 12)
(T6 – 9)
Liver
(T6 – 9)
One theory is that the lamina V cells make up the
majority of the STT and have small RFs that signal the precise location of stimulus. However, because of the afferent
input convergence in lamina V, they are non-specific in the
type of stimulus that they register. The lamina I cells
unequivocally signal that a noxious stimulus has
occurred. However, these cells are fewer in number and
have large RFs that cannot indicate the precise location of
the painful stimulus. It is thought that the pain is signalled
by the lamina I and V neurons acting together. If lamina I
cells are not active, the detailed information about the
type and location of a stimulus provided by the lamina V
axons is interpreted as innocuous. If, however, a lamina I
cell is active, the stimulation is recognized as painful.
Thus, the lamina V cells provide the details about the location of a stimulus and the lamina I cells specify whether it
is painful or not. This theory has been confirmed in recent
animal studies where lamina I cells were selectively
ablated using a neurotoxin, which led to a significant
reduction in the behavioural hyperalgesia associated with
tissue injury, without affecting the ability to locate the
stimulus.
Physiology of pain modulation
The transmission of information from primary afferents
to secondary neurons in the spinal cord is not simply a
passive process but is dynamic, involving excitation,
inhibition and modulation. The variable nature of pain
responses also suggests that modulatory systems must
exist in the CNS that regulate pain. Neurons in the
superficial dorsal horn are subject to modulation that
‘gates’ the flow of information to the CNS. Nociceptive
sensory information is gated in the substantia gelatinosa
(lamina II of the spinal cord) where nociceptors synapse,
by tonic or phasic inhibitory control mechanisms. Gating
is of two kinds:
1. Local—‘segmental antinociception’ regulated by
primary afferent inputs.
2. Widespread—‘supraspinal antinociception’, which
utilizes descending pathways from the brainstem.
In attempting to explain various clinical pain phenomena such as allodynia, referred pain and the variable relationship between tissue injury and pain response, a
theory about how pain is perceived—the ‘gate control’
theory—was proposed by Patrick Wall and Ronald
Melzack in 1965 (Fig. 5.3, top). This theory states that
pain is a function of the balance between the information
traveling into the spinal cord through large (non-nociceptive) nerve fibres and information travelling into the
spinal cord through small (nociceptive) nerve fibres.
Without any stimulation, both sets of nerve fibres are
inactive and the inhibitory neuron (I) blocks the signal in
the projection neuron (P) that connects to the brain. The
gate is ‘closed’ and therefore no pain is sensed. With nonpainful stimulation, large nerve fibres are activated. This
activates P but it also activates I, which then blocks the
signal in P that connects to the brain. As the gate is
‘closed’, no stimulation is perceived by the brain. With
noxious stimulation, nociceptive fibres become active.
They activate P and according to the original theory,
block I (it is now known that this does not occur). Since
activity of the inhibitory neuron is blocked, it cannot
block the output of the projection neuron that connects
with the brain. Therefore if the relative amount of
96 SYSTEMS OF THE BODY
5
Original theory
Actual circuitry
C/Aδ
I
Aβ
Central control
Aβ
Aδ/C
E
I
Fig. 5.3 Gate control theory—original circuit shown on the top.
The bottom part of the figure shows the actual circuitry involved.
Nociceptors do not have an inhibitory effect on the inhibitory neuron
as proposed in the original theory; they activate the P cell either
directly or via an excitatory interneuron (E). The Aβ fibres have the
connections as proposed in the original theory. I, Inhibitory neuron; P,
projection neuron.
P
P
Pain
activity is greater in large nerve fibres, there should be
little or no pain. However, if there is more activity in
small nerve fibres, then pain ensues, because the gate is
‘open’. Wall and Melzack also recognized that the brain
could exert descending modulatory influences on the
spinal cord. Their theory generated vigorous scientific
debate; little was known about the neuroanatomy and
neurochemistry of the dorsal horn back then. While the
gate control theory can explain some observations seen
in pain patients during therapy, it does not explain
everything. Over the past 65 years, as new techniques
such as transgenic models, genomics and, more recently,
optogenetics, have explored and probed the functional
neuroanatomy of the dorsal horn, the theory has undergone significant modification (see Fig. 5.3, bottom). For
example, there is no evidence for an inhibitory connection to interneurons from small fibres, and the complexity and diversity of neuronal types and transmitters
involved has exploded. Despite its limitations in the proposed circuitry, its most important contributions to pain
research have been the appreciation that the CNS is intimately involved in pain modulation and that the brain
has a dynamic role in pain processing. Psychological factors that had been previously thought of as reactions to
pain are now considered integral to pain processing.
Moreover, it offered new sites for pain modulation by
pharmacotherapy rather than surgery. Lastly, as a direct
result, the theory has led to the production of counterstimulation devices such as trans- cutaneous electrical
nerve stimulators (TENS) and spinal cord stimulators, as
well as other techniques that can alleviate pain.
Counter- stimulation analgesia
A bump on the head or kick in the shin by accident elicits acute pain. However, if the injury site is rubbed, the
pain immediately subsides and it feels better. This reaction can be explained by the ‘gate control’ theory.
Rubbing the head or shin stimulates the non-nociceptive
afferents that send impulses into the spinal cord.
According to the ‘gate control’ theory, lamina II inhibitory interneurons are activated either directly or indirectly by stimulation of these afferents from the skin that
would then block the projection neuron and therefore
block the pain. This may explain why ‘counterstimulation’ techniques are sometimes effective at relieving pain. For example, this can be done simply by
rubbing the skin over a sore muscle or may involve specially designed battery- powered devices designed to
electrically stimulate nerves through the skin. The aim of
these TENS machines is to stimulate the large (Aβ) sensory fibres in peripheral nerves in the hope that they will
in turn activate the inhibitory neurons of lamina II and
block pain transmission. Importantly, these devices work
best when placed on/near the skin of the injured/painful region. They are commonly used by physiotherapists
or midwives during labour and use high frequency, low
intensity stimuli to activate the low- threshold fibres;
recent evidence suggests that it is the Group 1 (Aα) afferents that are most effective at producing this effect. They
are ineffective if they are positioned far away from the
painful site. In practice, most counter- stimulation techniques require the use of ‘near noxious’ stimulation
intensities (felt as a buzzing or tingling sensation), which
recruit Aδ afferents to be maximally effective. From the
spinal cord, the messages go directly to several places in
the brain, including the thalamus, midbrain and reticular formation. It may be that Aδ fibres, rather than Aαβ
fibres, are best at exciting lamina II inhibitory interneurons because the Aδ fibres are able to recruit the supraspinal control systems (described in next section). TENS
is often used in the treatment of acute pain. It is not
always useful in chronic pain, because some forms of
chronic pain involve phenotypic changes in the properties of low- threshold afferents so that they behave more
like nociceptors. In such cases, their activation may actually increase the pain rather than alleviate it.
Supraspinal (descending) analgesia
The ‘gate control’ theory introduced the concept that
pain perception could be modulated in the spinal cord. It
also became clear that pain could be modulated at each
PAIN AND ANALGESIA
97THE NERVOUS SYSTEM
5
stimulus
Opioids
PAIN AND ANALGESIA
Fig. 5.4 Supraspinal control of pain and its pharmacological modulation by opioids. The periaqueductal grey (PAG) region can be stimulated
by input from other regions. In turn, it causes activation of the nucleus raphe magnus (NRM) cells in the rostroventral medulla. Nucleus raphe
magnus paragigantocellularis (NRPG) can also stimulate NRM. The NRM sends inhibitory enkephalinergic (ENK) and serotonergic (5- HT) axons via
the dorsolateral funiculus (DLF) to the dorsal horn to inhibit substantia gelatinosa cells or nociceptors. Opioids excite cells of the PAG and NRM,
as well as having a direct inhibitory effect in the dorsal horn on primary afferents and dorsal horn cells. The locus coeruleus (LC) sends separate
noradrenergic (NA) inhibitory inputs to the dorsal horn via the DLF.
NRPG
Opioids
Cortex
PAG
NRM
5-HT
Dorsal horn
Amygdala
HypothalamusThalamus
LC
ENK
NA
DLF
Painful
synapse along the pain pathways. Brain regions that are
involved in pain perception and emotion project back to
the brainstem and spinal cord, and these connections can
change or modify information that is coming to the
brain. This is one way that the brain can reduce pain by a
mechanism known as supraspinal (descending) analgesia. It uses feedback loops that involve several different
nuclei in the brainstem reticular formation (Fig. 5.4).
There are now several lines of evidence to corroborate
the involvement of brain mechanisms in analgesia, such
as the fact that direct deep brain stimulation suppresses
nociception, and the discovery of central endogenous
opioid and cannabinoid transmission, which have modulatory roles.
Areas of the brainstem that are involved in reducing
pain are the periaqueductal grey (PAG), nucleus raphe
magnus (NRM), and locus coeruleus (LC). The PAG is very
important in the control of pain. This region surrounds the
cerebral aqueduct in the midbrain. Stimulation of parts of
the PAG produces more pronounced analgesia than stimulation of either the NRM or LC. Neurosurgeons can implant
stimulating electrodes near the PAG of intractable pain
patients so that a small electrical shock can be delivered.
The patient can control the level of self- stimulation and
hence the level of analgesia. This is known as stimulusinduced analgesia. The PAG contains enkephalin- rich neurons that excite the NRM and/or LC neurons by inhibiting
gamma-aminobutyric-acid or γ-aminobutyric acid (GABA)
ergic interneurons in the PAG. This allows PAG (antinociceptor) neurons to excite amine- containing cells in the
NRM and LC that in turn project to the spinal cord to block
pain transmission by dorsal horn cells. They can exert this
inhibition by different mechanisms:
1. Direct presynaptic inhibition of neurotransmitter
release from primary afferent terminals. This
involves, for example, activation of G proteinlinked receptors that cause calcium channels to
close, thus reducing transmitter release (Fig. 5.5A).
2. Direct postsynaptic inhibition of projection cells
causing hyperpolarization of the membrane, due
to activation of G protein- linked receptors that
cause potassium channels to open (see Fig. 5.5B).
3. Indirect inhibition via activation of local
enkephalinergic and/or GABAergic inhibitory
interneurons by the descending serotonergic and
noradrenergic axons. These interneurons can act
both postsynaptically on projection cells by
opening potassium channels or presynaptically by
closing calcium channels. Enkephalins bind to the
same family of receptors as opiate drugs such as
morphine and heroin. Therefore it seems likely that
opiate drugs may act by mimicking the activity of
the interneurons of lamina II.
Stimulation of the NRM causes activation of enkephalin and 5- HT- containing neurons. Like noradrenalinecontaining neurons, the majority of NRM axons synapse
on lamina II cells. They also synapse on cells in laminae I
and III. Stimulation of the raphe nuclei produces a powerful analgesia, and it is thought that the 5- HT released
98 SYSTEMS OF THE BODY