PAIN
The anatomy of pain
David G Gore
Abstract
Pain is a sensory and emotional experience that is personal and
unique to an individual. Nociception is different from pain and con-
siders the neural process of encoding and processing noxious stimuli.
Anatomically noxious stimuli are transduced by nociceptors to an
electrical signal carried by first-order neurons to the dorsal horn of
the spinal cord. From the spinal cord second-order neurons project
in tracts to the thalamus, where third-order neurons continue to higher
cerebral centres. There is no known primary pain processing centre in
the brain, instead multiple different areas activate and interact in
response to noxious stimuli. The brain centres associated with pain
perception overlap with those involved in depression. The brain regu-
lates the nociceptive information it receives and can exert both anti-
and pro-nociceptive influence. Pathology in the peripheral and central
nervous systems can contribute to nociception and pain, as can
changes in the interaction of higher cerebral centres. Appreciating
the anatomical structures involved in pain and nociception
affords an understanding of where different therapies may be applied
to alleviate pain.
Keywords Anatomy; modulation; nociception; nociceptor; pain
Royal College of Anaesthetists CPD Skills Framework: Pain
The most widely accepted definition of pain is that of the Inter-
national Association for the Study of Pain (IASP) updated in
2020: ‘Pain is an unpleasant sensory and emotional experience
associated with, or resembling that associated with, actual or
potential tissue damage’. In their key notes the IASP emphasize
the personal nature of pain and that pain and nociception are
different phenomena. Nociception is defined as ‘the neural pro-
cess of encoding and processing noxious stimuli’.
Pain is well known as a protective mechanism that can both
identify and minimize tissue damage. Pain can however, also be
pathological leading to physical and psychosocial harm when it
exists or persists beyond an original injury or due to changes in
nociceptive pathways. Pain is commonly subclassified into
nociceptive pain (mediated by sensory receptors), inflammatory
pain (mediated by tissue damage) and neuropathic pain (caused
by disease or damage to the nervous system).
Given that pain is influenced by biological, psychological and
social factors, examining the anatomy of nociception is a more
attainable focus of this article. To consider the anatomy of
nociception it is useful to consider the process and pathway by
which a peripheral painful stimulus reaches the brain. This
David G Gore MBChB BSc(Hons) MSc(Dist) FRCA FFPMRCA completed his
advanced pain training at Oxford University Hospitals, UK, and will
undertake a post CCT pain fellowship in Queensland, Australia.
Conflicts of interest: none declared.
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Learning objectives
After reading this article, you should be able to:
C understand somatic and visceral nociceptive transduction
C explain nociceptive signal transmission to the spinal cord and
higher cerebral centres
C recall the cerebral centres involved in processing nociceptive
signals and the experience of pain
C acknowledge that nociceptive transmission and pain can be
modulated at the spinal cord and higher cerebral levels
pathway typically involves transduction, transmission and
perception. A noxious stimulus activates a nociceptor, which
converts this signal (via transduction) into an electrical signal
that is transmitted by nerves to the spinal cord and then onto the
higher processing centres where perception takes place.
Nociceptors
The transduction of a painful stimuli into an electrical afferent
action potential, conducted by nerves, takes place in free nerve
cell endings called nociceptors. Nociceptive fibres arise from cell
bodies in the dorsal root ganglia or trigeminal ganglia. Nociceptors
can be activated by mechanical, thermal and chemical stimulation
and their threshold for activation can be modified by inflamma-
tory and biomolecular influences in the local extracellular envi-
ronment. Such modification or sensitization can be defined as ‘a
reduction in the threshold and an increase in the magnitude of a
response to noxious stimulation’. Sensitization is a physiological
process that typically occurs due to tissue injury or inflammation.
Nociceptors have been described in the skin, joints, muscles,
bones and viscera. Cutaneous nociceptors are present in the skin
and deep nociceptors are present in muscles, bones and joints.
Deep nociceptors are less sensitive to noxious stimuli than their
cutaneous counterparts but are easily sensitized by inflamma-
tion. Nociceptors can be further classified according to their
associated axons, the type of information they relay and stimu-
lation thresholds. Ad myelinated nociceptors are often referred to
as high-threshold mechanoreceptors (HTM). Type I HTM are
activated by heat (>50 C) and noxious mechanical distortion
(such as stretching, cutting or pinching). Type II HTM have a
higher mechanical threshold and activate at a lower temperature
(>45 C). C fibres are phylogenetically older unmyelinated Poly-
modal Nociceptors (PMN) and have been linked to survival and
procreation. High-threshold C fibres respond to thermal, me-
chanical and chemical stimuli. Low-threshold ‘tactile’ C fibres
carry non-nociceptive sensations associated with pleasure.
Within joints, a silent nociceptor, that only becomes responsive
after tissue damage or inflammation, has been described.
As illustrated in Table 1 the primary afferent nociceptors
convey information from different areas, at different speeds and
synapse at different locations within the dorsal columns.
The spinal cord
Nociceptive sensory afferents terminate in the ipsilateral dorsal
horn where they synapse with second-order neurons directly or
355 Ó 2022 Published by Elsevier Ltd.
 PAIN
Features of primary afferent nociceptors
Fibre type Ad
Myelinated Yes - lightly
Diameter 2e5 micrometres
Conduction velocity 5e30 m/second
Receptive Field Small
Distribution Skin, muscles and joints
Pain sensation Rapid, sharp/stabbing and localized
Synapse location in dorsal Lamina I and V
horn of spinal cord
Role Initial alert to the presence of pain
Respond to Mechanical pressure
Temperature
Table 1
via interneurons. Termination occurs at the level of entry into the
spinal cord or up to two spinal segments higher or lower via
collateral branches (named the dorsolateral fasciculus or Lissa-
uer’s tract). Collateral branch presence is more frequent in the
cervical region.
The dorsal horn is divided into six laminae (named Rexed
laminae) or layers that have discrete electrophysiological char-
acteristics; they take part in nociceptive transmission. Table 2
describes the different laminae associated with nociception. C
fibres terminate in the outermost laminae I and II. Ad fibres
terminate primarily in laminae I and V, with a small subset ter-
minating in lamina III.
Three types of second-order neurons have been described in the
dorsal horn. Nociceptive specific (NS), low threshold (LT) and wide
dynamic range (WDR). NS neurons are found in laminae II and III
and respond selectively to high threshold noxious stimuli. LT neu-
rons respond selectively to innocuous stimuli. WDR neurons are
found in laminae II, V and VI and respond in a graded manner to
noxious stimulation, that is the magnitude of their response
increases with repeated stimulation (a process known as ‘wind up’).
This can facilitate neuroplasticity and sensitization.
In laminae I and V, nociceptors synapse to second-order
neurons forming the ascending spinothalamic and spinor-
eticulothalamic (spinoreticular) tracts. Nociceptors terminating
in laminae II predominantly synapse with WDR interneurons that
project into lamina V. In addition to nociceptive input WDR
neurons receive sensory input from Ab fibres and are involved in
nociceptive modulation via lamina II inhibitory interneurons.
Laminae V also receives descending corticospinal fibres.
To facilitate muscular reflexes associated with pain, dorsal
horn neurons synapse with anterior horn motor neurons. They
also project to and synapse with sympathetic neurons in the
intermediolateral column. Sympathetic stimulation typically
causes vasoconstriction and the release of catecholamines.
Central nervous system e ascending tracts and cerebral
processing
There is no known primary nociceptive processing area or region
within the brain that receives ascending nociceptive input.
Instead, in response to pain, neuroimaging studies demonstrate
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C
No e unmyelinated
<2 micrometres
0.5e2 m/second
Large
Most tissues
Dull, aching, burning and diffuse
Lamina I and II (substantia gelatinosa)
Relay pain intensity
Chemical (including hydrogen ions, cytokines,
histamine, prostaglandins), thermal and mechanical
activation of multiple areas involved in sensory discrimination,
emotion and behaviours e the ‘pain neuromatrix’ (see Figure 1
and Table 3). These areas both process nociceptive signals and
facilitate the conscious experience of pain.
Three ascending tracts carry nociceptive signals in second-order
neurons to higher processing centres e the neospinothalamic,
paleospinothalamic and archispinothalamic tracts. Most third-
order neurons begin in the thalamus (Figure 2).
Neospinothalamic tract
The neospinothalamic tract or lateral spinothalamic tract is
responsible for immediate awareness and location of painful
stimuli. Evolved more recently, it originates primarily in laminae
I and V (where Ad fibres terminate). Second-order neurons
decussate in the anterior white commissure and ascend in the
anterolateral white matter of the spinal cord. The majority of the
fibres in the body (below the neck) terminate in the ventral
posterolateral lateral (VPL) and ventral posteroinferior (VPI)
nucleus of the thalamus. Axons of the lateral spinothalamic tract
are somatotopically ordered with caudal elements being more
lateral.
Paleospinothalamic tract
The more medial, deeper, paleospinothalamic tract is phyloge-
netically older than the neospinothalamic tract and is involved in
the experience of diffuse pain and emotional aspects of the pain
experience. Most, but not all, second-order neurons decussate
and ascend in the anterior spinal thalamic tract which lacks
somatotopic organization. The anterior spinal thalamic tract can
be subdivided into three smaller tracts that synapse in different
locations. The spinoreticular tract synapses in the reticular for-
mation and periaqueductal grey. The spinotectal (spinomedul-
lary) tract synapses in the tectum. Finally, the spinothalamic
tract synapses in the thalamus. From their synapses most fibres
travel to the somatosensory cortex. The paleospinothalamic
pathway is thought to be involved in the emotional processing of
pain via its extensive connections with limbic areas (such as the
insular cortex and cingulate gyrus). The limbic system facilitates
the processing of sensory input with cognition. Whilst connec-
tions to the frontal cortex enable sensory experiences to impact
on behaviour and planning.
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 PAIN

Nociceptive input from the head

Principle Rexed laminae of the dorsal horn involved in The majority of nociceptive neurons from the head synapse in
nociception the trigeminal ganglion before travelling to the spinal trigeminal
Rexed Lamina Description nucleus, where they decussate and ascend to the thalamus as the
trigeminal thalamic tract. From the thalamus fibres then travel to
I Receives incoming nociceptive fibres from the the somatosensory cortex. Nociceptive input from the facial,
dorsal root and contributes to axons of contra- glossopharyngeal and vagus nerves synapse in the geniculate
lateral spinothalamic tract. ganglion, superior and petrosal ganglion, and jugular (somatic)/
II Substantia gelatinosa. Receives noxious and ganglion nodosum (visceral), respectively.
non-noxious sensory stimuli, collaterals of
dorsal root fibres and also input from the Nociceptive modulation and the descending tracts
descending reticulospinal tracts (involved in
It has been observed and demonstrated that the pain experience
pain modulation). Extends from medulla to the
can be modulated by activities that activate sensory Ab fibres
filum terminale.
local to a pain source and activation of higher cerebral centres.
III Consists mainly of interneurons and low-
This is attributed to the presence of inhibitory interneurons
threshold (LT) neurons, receives input relating
within the dorsal horn and inhibitory pathways within the cen-
to proprioception
tral nervous system. The brain therefore regulates the nocicep-
IV The long dendrites of tract cells in this lamina
tive information it receives and can exert both anti- and pro-
receive sensory input from the dorsal horn and
nociceptive influence. This is thought to be a survival advantage
decussate to the contralateral spinothalamic
as in situations of serious mortal threat, such as injuries in war,
tract.
pain suppression may facilitate escape.
V These two laminae consist of interneurons
Inhibitory interneurons were first postulated in 1965 when
VI e present in that receive both primary afferent fibres and
Melzack and Wall explained their gate control theory of pain.
cervical and descending (corticospinal) fibres. Wide
The gate control theory predicts that at the spinal cord level (in
lumbosacral dynamic range neurons are also present in
the substantia gelatinosa) non-noxious, sensory stimulation,
enlargements lamina V
inhibits dorsal root nociceptive fibres e closing the gate to
Table 2 noxious signalling. Transcutaneous electrical nerve stimulation
(TENS) is thought to exploit this mechanism.
In addition to spinal cord inhibitory interneurons, anti-
Archispinothalamic pathway nociceptive cerebral structures and descending pathways have
The archispinothalamic pathway is phylogenetically the oldest been described. The periaqueductal grey matter (PAG) and
tract and carries non-specific noxious information involved in nucleus raphe magnus (NRM) are known to be involved in
visceral, autonomic and emotional aspects of pain. After syn- nociceptive modulation. Direct electrical stimulation of both
apsing in rexed lamina II (substantia gelatinosa) and ascending areas is known to produce analgesia whilst preserving non-
to laminae IV and VII, fibres further ascend via the multisynaptic nociceptive sensation. The PAG, located in the midbrain, re-
propriospinal pathway. Upon reaching the medial reticular for- ceives input from the thalamus, hypothalamus and cortex and
mation and periaqueductal grey, further fibres travel to the expresses a large number of opioid receptors. It is proposed that
thalamus, hypothalamus and limbic system nuclei. antinociceptive neurons in the PAG stimulate the NRM. This
same system has also been shown to enhance spinal trans-
Areas of the brain involved with pain processing mission of nociception.
The NRM of the medulla contains cell bodies of neurons
which project down the spinal cord to synapse in laminae II and
III. It also expresses a high number of both opioid and cannabi-
noid receptors. Serotonin released by stimulation of the NRM is
thought to activate inhibitory interneurons and activate both
opioid and a-2 adrenergic receptors in the dorsal horn, thereby
modulating nociception at a spinal cord level to reduce thalamic
input. Such stimulation produced analgesia continues after
stimulation has terminated, however can be blocked by
naloxone, indicating the involvement of opioid receptors.
Activation of the PAG and NRM is associated with the pro-
nociceptive nucleus reticularis gigantocellularis (RCG) and
dorsolateral funiculus (DLF). The RCG innervates both the PAG
and NRM and is activated by noxious stimuli. It has been
demonstrated that lesions to the DLF (which is composed of
fibres from many brainstem nuclei) block analgesia produced by
Figure 1 electrical stimulation and opioid injection into PAG and NRM.

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Higher centres involved in or activated by afferent nociceptive input

Structure Location Role/function

Ventral posterolateral, ventral posteroinferior The thalamus is situated between the cerebral Relay centre and initial processing of
and ventral medial nucleus of the thalamus cortex and midbrain nociceptive sensory information before
distribution to cerebral cortex
Primary (S1) and secondary (S2) Located in the postcentral gyrus in the parietal Sensory discriminative processing e intensity,
somatosensory cortex lobe localization and character of pain
Insula Deep in lateral sulcus (the fissure separating Consciousness, self-awareness and
the frontal and parietal lobes from the homeostatic emotions such as hunger and
temporal lobe) sensory perception of pain
Anterior cingulate cortex Front of the cingulate cortex, which is located Emotion and subjective pain experience
medially in the cerebral cortex Attention allocation, decision making, impulse
control
Amygdala Front of temporal lobe close to hippocampus Memory modulation, reward and emotional
responses, fear and anxiety
Hippocampus Deep in the temporal lobe Episodic (short-term) memory, consolidation
of memory, emotion and learning
Hypothalamus Base of the brain close to pituitary gland Maintains homeostasis and connects to
endocrine system. Modulates response to
stress
Pre-frontal cortex In frontal lobe Behaviour, decision making, emotion
regulation, processing of risk and fear
Cerebellum Located posteriorly beneath the temporal and Motor responses
parietal lobe
Periaqueductal grey Around cerebral aqueduct in the midbrain Autonomic function, behavioural responses,
controls descending pain modulation
Nucleus accumbens Basal forebrain anterior to the hypothalamus Motivation, reward and reinforcement of
learning. Role in addiction

Table 3

Visceral nociception Neuropathic pain is itself defined as being caused by a lesion

Some organs such as the heart, lungs, testis and bile duct appear
to have specific nociceptors. On the contrary other organs, such
as the brain where only the meningeal covering contains noci-
ceptors, have no nociceptors.
Visceral nociceptors are polymodal and respond primarily to
distension and stretching, smooth muscle spasm and chemical
stimulation (ischaemia and inflammation). They do not respond
to cutting or burning during surgery. Ad and C visceral noci-
ceptive fibres travel with autonomic afferents, however the
density of nociceptors on viscera is low. Visceral pain fibres
share ascending somatic pathways within the spinal cord. This
results in visceral pain often being interpreted as somatic pain
corresponding to shared afferents or ‘referred’ away. Visceral
pain can also involve an autonomic element and nausea.
Anatomical sources of pain
Pathology in the peripheral or central nervous systems can, un-
derstandably, contribute to nociception. Thalamic and central post
stroke pain can occur following the interruption of blood supply
and ischaemic insult to the CNS. Thalamic lesions are commonly
associated with contralateral intracranial pain and central post-
stroke pain is characterized by pain and allodynia in the areas of
the body corresponding to the cerebrovascular lesion.
or disease of the somatosensory nervous system. It is associated
with a host of inflammatory, degenerative and ischaemic con-
ditions such as diabetes.
Where nerves may be subject to direct trauma, such as in
amputation, tangled new nerve growth (neuromas) can gradually
develop and be a source of pain. In phantom limb pain,
involvement of peripheral nerves, the spinal cord and cortical
structures have all been implicated.
Autonomic nervous system
In addition to playing a role in visceral nociception the auto-
nomic nervous system, via its sympathetic arm and noradrena-
line, can influence nociception. Noradrenaline has been shown
to influence primary afferent neurons and in injury, a-
adrenoceptor expression is increased in nociceptive neurons,
increasing sensitivity. The influence of the autonomic nervous
system on pain processing may be reduced by mindebody
therapies such as guided relaxation and meditation.
Anatomical changes in chronic pain
Chronic pain is typically defined as pain that exists beyond the
healing process, lasting greater than 3 months, frequently
impairing both function and quality of life. It is recognized as a

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Functional imaging observations in chronic pain and

their possible interpretation
Observation in chronic pain Possible Interpretation/Impact

Attentional hypervigilance The fear of pain, common to chronic

for pain increases pain
related activations in the
somatosensory cortices,
thalamus and insula.
Negative emotions can
increase activity in the
amygdala, anterior cingulate
cortex and anterior insula.
Bilateral activation of the
somatosensory cortex
compared to unilateral
activation in acute pain.
More widespread activation
of the insular cortex
Hyperactivity of prefrontal
cortex and impaired function
pain patients, may enhance the
experience of pain
This heightened neural processing
may prime nociceptive pathways and
enhance nociception. Furthermore,
these emotions can impair pre-
frontal cortex function (see below)
This change may contribute to the
more widespread and less well-
defined nature of chronic pain
Increased sensory discrimination
and blunting of emotional
‘suffering’ response due to
increased input. This shift to
increased sensory processing may
contribute to states such as
allodynia and hyperalgesia.
Reduced ability to perform other
tasks and engage in cognitive pain
management strategies

Table 4

reward circuits are frequently noted to overlap with those seen in

depression.

Figure 2
pan-nervous system disorder. In addition to emotional, cognitive
and behavioural elements, a number of pathophysiological
changes observed in chronic pain are associated with anatomical
features. It is unclear whether the anatomical changes observed
in chronic pain are the result of continuous nociceptive input or
have a role in transition to chronic pain.
Neuroimaging studies have started to report activation of
cerebral centres and interaction between these centres in chronic
pain. Such observations include increased functional connectiv-
ity between the pre-frontal cortex and nucleus accumbens
(associated with motivation and reward), reduced grey matter in
areas such as the hippocampus and amygdala and smudging of
sensory-motor homunculus.
A common theme across many neuroimaging studies is
the increased activation of brain centres associated with pain
perception and emotional processing in chronic pain. Some ob-
servations and their possible interpretation are listed in Table 4.
These neurobiological changes to emotional, motivational and
Summary
Understanding and knowledge of the anatomy underpinning
nociceptive transduction, transmission, perception and modula-
tion is rapidly evolving. As research techniques, such as func-
tional imaging, move forward it is likely new targets, treatments
and therapies will follow. It is also likely that the link between
depression and chronic pain will be further elucidated. A
FURTHER READING
Garland EL. Pain processing in the human nervous system: a selective
review of nociceptive and biobehavioral pathways. Prim Car 2012;
39: 561e71.
Hohenschurz-Schmidt DJ, Calcagnini G, Dipasquale O, et al. Linking
pain sensation to the autonomic nervous system: the role of the
anterior cingulate and periaqueductal gray resting-state networks.
Front Neurosci 2020; 14: 147.
Yang S, Chang MC. Chronic pain: structural and functional changes in
brain structures and associated negative affective states. Int J Mol
Sci 2019; 20: 3130.

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