Review Article

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Pathophysiology of pain
Sheng-Xi Wu, Ya-Yun Wang, Juan Shi, Yu-Lin Dong, Guo-Hong Cai

Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi’an 710032,
China
Correspondence to: Sheng-Xi Wu, MD, PhD, Professor; Ya-Yun Wang, MD, PhD, Associate Professor; Juan Shi, PhD, Associate Professor; Yu-Lin
Dong, MD, PhD, Associate Professor; Guo-Hong Cai, Postgraduate Student. Department of Anatomy, Histology and Embryology, K. K. Leung
Brain Research Centre, The Fourth Military Medical University, No. 169 West Changle Road, Xi’an 710032, China. Email: xym@amegroups.com.

Abstract: Pain can be defined as an unpleasant sensory and emotional experience of actual or potential
tissue damage or an experience expressed in such terms. It is a major symptom of many different diseases and
a subjective result of nociception, and can be classified in various ways such as by physiological, etiology and
temporal. Pathophysiological mechanisms including pain pathways, peripheral and central mechanisms that
are involved in pain will be described in this article.

Keywords: Pathophysiology; pain; mechanism

Received: 08 June 2016; Accepted: 23 June 2016; Published: 29 June 2016.

doi: 10.21037/xym.2016.06.05
View this article at: http://dx.doi.org/10.21037/xym.2016.06.05

Introduction contains acute and chronic pain (2).

Pain can be defined as an unpleasant sensory and emotional
experience of actual or potential tissue damage or an
experience expressed in such terms. Both excitatory
and inhibitory physiologic and pathologic mechanisms
are involved in its generation and maintenance. Recent
research has uncovered important pathophysiological
mechanisms that are underlying different clinically relevant
pain disorders. This chapter will briefly describe types of
pain, pain pathways, peripheral and central mechanisms
that are involved in pain. A better understanding of
pain, particularly the translation of pathophysiological
mechanisms into sensory signs, will lead to a more effective
and specific mechanism-based treatment approach.
Types of pain
Pain is a major symptom of many different diseases and a
subjective result of nociception. Nociception is the encoding
and processing of noxious stimuli in the nervous system that
can be measured with electrophysiological techniques (1).
Pain may be classified in various ways: physiologically, it
contains nociceptive and neuropathic pain; by etiology, it
contains malignant and nonmalignant pain; temporally, it
Acute pain often lasts less than 3 months (3), and is often
associated with an identifiable injury or trauma. Thus, it
responds to relatively simple analgesic therapy, and it will
be resolved as the area of injury heals or is treated. Acute
physiological nociceptive pain is elicited when a noxious
stimulus is applied to normal tissue. Because withdrawal
reflexes are usually elicited, this pain would protect tissue
from being further damaged. When the tissue is inflamed
or injured, pathophysiologic nociceptive pain will occur,
which is one of the most frequent reasons why patients seek
medical care. This kind of pain may appear as spontaneous
pain, hyperalgesia, and/or allodynia (4).
Chronic pain lasts longer than 3 months and exceeds
the typical recovery time for the initial injury. It may or
may not be explained by low levels of identified underlying
pathology (1). It is often accompanied by neuroendocrine
dysregulation, fatigue, increased irritability, depression,
social withdrawal, emotional stress, loss of libido, disturbed
sleep patterns and weight loss (5). Although injury may
elicit chronic pain, factors remote from its cause may
perpetuate it. Environmental and affective factors can also
exacerbate and perpetuate chronic pain. Interestingly, the
causal relationship between nociception and pain may not

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be clear in many chronic pain states and certain pain states
may not reflect tissue damage.
Chronic pain
Chronic pain may also be categorized by its character. It can
be nociceptive, neuropathic, or both. It may be caused by
cancer, inflammation, or a variety of non-life-threatening
conditions such as arthritis, fibromyalgia, and neuropathy (2).
Chronic pain may result from a chronic disease and then
actually result from persistent nociceptive processes.
Cancer pain
Most chronic cancer-related pains are caused directly by the
tumor. Bone metastases and compression of neural structures
are the two most common causes (6). Bone metastases could
potentially cause pain by many mechanisms, including
endosteal or periosteal nociceptor activation or tumor growth
into adjacent soft tissue and nerves (7). In fact, there is no
homogenous entity of “cancer pain”; pain in cancer, which
is often tied up with concomitant psychosocial upheaval and
existential anxiety, can be inflected by a multitude of emotional,
psychological and spiritual factors (8). To many cancer
sufferers, their pain has a “sinister meaning” over and above its
inherent unpleasantness as a sensory experience (8). Chronic
cancer pain rarely involves medicolegal or disability issues and
is distinct from acute physiological pain. It has a significant
effect on every aspect of a person’s life, including daily physical
activities, mood, social relationships, sleep patterns, cognition
and existential beliefs (whether the person’s life has meaning,
purpose or value in relation to mortality) (2). The patients with
cancer may become withdrawn and unable to focus if the pain
is not managed well.
Neuropathic pain
Neuropathic pain is thought to arise from abnormal physiology
of the peripheral or central nervous systems and may be
unrelated to ongoing tissue damage or inflammation (9).
There are numerous causes of nervous system injury,
including exposure to toxins, infection, viruses, metabolic
disease, nutritional deficiencies, ischemia, trauma (surgical
and nonsurgical), and stroke (10). Some patients with
neuropathic pain may have severe pain without obvious
clinical signs of nerve injury, whereas others may have
significant nerve injury without pain. In addition,
neuropathic pain may be precipitated by a relatively minor
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Xiangya Medicine, 2016
physical insult, and the severity of pain may be much greater
than the extent of damage might suggest. Although the
mechanism underlying neuropathic pain is not completely
understood, it is considered to be complex, multifactoral,
and could evolve over time. Normally, peripheral and central
sensitization phenomena would dissipate as tissue heals and
inflammation subsides. However, neuropathic pain may be
elicited when changes in primary afferent function persist
after disease or injury of the nervous system (9).
Inflammation pain
Chronic inflammation is a feature of a large number of painful
chronic degenerative diseases, such as arthritis, low back
pain, and inflammatory bowel disease (11). Unfortunately, it
may be the single greatest cause of pain, which is the result of
activation and sensitization of primary afferent nerve fibers.
Inflammation pain is experienced predominantly when the
inflamed site is mechanically stimulated by being moved
or touched. The stimulation-induced pain is thought to
be referred to as inflammatory hyperalgesia. Inflammatory
hyperalgesia has been shown to be produced by inflammatory
mediators released from circulating leucocytes and platelets,
vascular endothelial cells, immune cells resident in tissue and
sensory and sympathetic nerve fibers. Since the first mediator
bradykinin was reported in 1953 (12), researchers have
identified a number of inflammatory mediators which can
produce hyperalgesia, including prostaglandins, leukotriene,
serotonin, adenosine, histamine, interleukin-1, interleukin-8
and nerve growth factor (NGF).
Pathways for pain
Pain is a sensation that evokes an emotional response and
involves a complex interaction between the periphery, the
spinal cord, the brainstem and higher cortical centers.
Nociceptors
Nociceptive afferents do not have specialized receptors;
they use free nerve endings and most are polymodal (13).
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. Aδ fibers mediate the “fast” pain,
whereas C-fibers signal the “slow” pain. Not all Aδ and
C fibers are nociceptors. Some respond to low threshold
stimuli such as sensual touching or brushing the skin. Many
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C fibers are thermoreceptors, and respond to warm or cold,
providing homeostatic responses via emotional tagging of
sensations. 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.
There are several differences between cutaneous and
muscle or visceral nociceptors (14-16). 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. Lastly,
as most visceral organs have very few low threshold
myelinated fibers and comprise mostly of Aδ and C fibers,
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.
Cutaneous 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 perception. 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 signaled
by the STT, and the homeostatic and affective qualities of
pain are signaled by the SRT and SPBT (17-19). 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 to act as a warning system by signaling the exact location
and severity of the injury and the duration of the pain.
Fast pain predominantly arises from STT neurons in the
laminae IV–V of the spinal cord. Slow pain is mediated by
C-fibers and signals the emotional aspects of pain. It reaches
the thalamus indirectly via connections with the brainstem
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reticular formation. The slow pain axons innervate the
non-specific intrathalaminar nuclei of the thalamus, and
the autonomic centers of the reticular formation in the
brainstem. 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 (20).
The projections to the reticular formation underlie the
arousal effects of the 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 system (21).
Thalamocortical axons transmit the information from
the thalamus to the cortex. There is no one specific cortical
region that can be designated as “pain cortex”. Rather,
functional brain-imaging studies have revealed several
regions that are active when a pain stimulus is sensed and
these are associated with different functional components
of pain (22,23). “Where and how much it hurts” involves
the somatosensory cortex whereas “I do not like it or stop
it” are associated with the limbic regions, such as cingulate
cortex or insula. Parts of the prefrontal motor cortex are
also involved in cognitive evaluative process.
Visceral and muscular pain pathways
Considering that muscle and visceral pain evoke distinct
sensations, it would be logical to expect to find cells in
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 also have a separate cutaneous receptive field. This
means that convergence occurs within the spinal cord.
The central terminals of visceral and muscle nociceptors
terminate in laminae I and V but also laminae II, unlike
skin nociceptor afferents. In lamina I, these fibers converse
onto projection neurons of the STT and SPBT, which then
project to the brainstem and thalamus and from there to
the somatosensory cortex (24,25). Visceral afferents also
terminate on SPT neurons and onto cells that project to
the dorsal column nuclei and 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 reflex functions than visceral
pain (26). Lesions of the dorsal columns effectively relieve
chronic visceral pain and have led to new clinical treatments
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for managing visceral cancer pain.
Spinal dorsal horn loco circuits for pain modulation
The initial integration of noxious information occurs in
the superficial dorsal horn (SDH) of the spinal cord, which
is very important for understanding pain sensation and
developing effective analgesic strategies (27).
Peripheral nociceptors transmit noxious information
to spinal neurons that further project afferents through
ascending tracts, such as the STT, and neurons located in
the SDH (including laminae I and II). These secondary and
third order axons then synapse with sensory relay nuclei
in the thalamus and then onto the cerebral cortex. SDH
neurons (including projection neurons and interneurons)
receive nociceptive information conveyed by the thinly
myelinated (Aδ) and unmyelinated (C) primary afferent
fibers (PAFs) (28,29). Additionally, SDH neurons and PAFs
receive dense descending inputs, including serotonergic
and noradrenergic components mainly originating from
the raphe magnus and locus ceruleus in the brain stem
respectively (30). The sole noxious output of SDH
projection neurons to the higher brain structures are likely
modulated by complicated interneuronal interactions within
the SDH. Thus the integration of nociceptive transmission
within the SDH is very important for understanding pain
sensation and developing effective analgesic strategies. The
platform for such complicated integrations is the circuits
formed by pools of neurons that are highly plastic under
conditions of inflammatory or neuropathic pain.
Descending pain control pathways
The idea of descending control systems dates back to
the 1970s and 1980s when its original version was that
structures in the brain stem send impulses that ‘‘descend’’
and thus inhibit the nociceptive transmission in SDH
(31,32). A simplified descending inhibitory system was
depicted as the following: the PAG projects to the rostral
ventromedial medulla (RVM), which includes the serotonin-
rich nucleus raphe magnus (NRM) as well as the nucleus
reticularis gigantocellularis pars alpha and the nucleus
paragigantocellularis lateralis (33). Serotonergic (34) and
some GABAergic or glycinergic (35,36) neurons in RVM
then project along DLF to terminate in SDH, where
they inhibit nociceptive transmission. Besides RVM,
locus coeruleus and subcoeruleus nucleus are important
supraspinal descending inhibitory structures which contain
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Xiangya Medicine, 2016
the majority of noradrenergic neurons with projections
to SDH (37). These supraspinal structures together form
the descending control system of the spinal nociceptive
transmission.
Complicated circuits can be formed between those
key elements within SDH, thus facilitating or inhibiting
nociceptive transmission. These circuits can be delineated
according to different criteria. However, they are not hard-
wired since they are capable of dynamic change under
different pain states. Furthermore, depending on the
membrane properties (e.g., different receptor types on the
membrane), the same classic neurotransmitter can function
inhibitorily or excitatorily.
Peripheral mechanisms of pain
At the peripheral level, a “pain” signal is initiated when
physicochemical stimuli of high intensity or a particular
quality are detected by a subpopulation of sensory
neurons termed nociceptors. Traditionally, nociceptors are
noncapsulated nerve endings of thin myelinated (Aδ-type)
and nonmyelinated (C-type) fibers in the tissue, which can
sense the actual or potential tissue damage and convert
the energy into a changed membrane potential that is
sufficient to generate an action potential, a cognizable
“language” of nervous system. Most of the nociceptors
respond to mechanical, chemical and/or cold stimuli and
thus are polymodal. During the pathophysiological process,
however, the nociceptor per se also undergoes functional or
structural changes in response to the tissue damage. These
changes may amplify the effect of initial stimulus to make
pain either a powerful defense system for individual safety
(nociceptive pain) or even a diseased condition torturing
patients (chronic pain). Due to the limited space, we will
focus on reviewing the main peripheral mechanisms of pain,
which have been proved to be effective targets for clinical
therapy.
Peripheral sensitization
During tissue injury or inflammation, polymodal nociceptors
undergo decreased excitation thresholds, increased
response to suprathreshold stimuli, such that even light
or normally innocuous stimuli can activate the receptors.
Such phenomenon is referred to as peripheral sensitization
or nociceptor sensitization (38). As a consequence, noxious
stimuli applied to the injured tissue area evoke more severe
pain (primary hyperalgesia) than in the non-sensitized state
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and innocuous stimuli such as mechanical and cold stimuli
also cause pain (allodynia). Thus, peripheral sensitization is
a neuronal mechanism correlating with behavioral changes,
i.e., hyperalgesia and allodynia. In addition to triggering the
increased sensitivity of nociceptor to stimuli, inflammation
also causes the recruitment of so-called “silent nociceptors”.
Silent nociceptors are A- or C-fibers that are unexcitable
or hard to excite with a high mechanical threshold under
healthy conditions. During inflammation, however, these
fibers are sensitized and become susceptible to applied
stimuli (39).
Nociceptor sensitization is initiated by the action
of numerous inflammatory mediators released upon
tissue injury from surrounding cells such as mast cells,
keratinocytes, macrophages and immune cells (4). Important
among these inflammatory mediators or cytokines are
bradykinin, serotonin, histamine, prostaglandin, adenosine,
interleukins, tumor necrosis factor alpha as well as
neurotrophins like NGF (40). A mixture of these substances
forms the “sensitizing soup” and modulates the sensitivity
of nociceptors to thermal, mechanical or chemical stimuli.
Primary afferent neurons express receptors for all these
substances (however not all receptors are expressed in
each nociceptor). The binding of specific ligands to these
receptors leads to either the activation of nociceptors
directly or indirectly via second messenger cascades which
in turn influence the functional state or the expression of
ion channels in the cell membrane (38). Through such
exogenous processes, the excitability of primary afferent
neurons can be greatly enhanced with lowered threshold
and increased action potential frequency by suprathreshold
stimulation. Nerve cells are highly innervating cells at
any time; in addition to passive alteration by micro-milieu
substances, they are able to release neuropeptides from their
peripheral terminals. The typical examples are calcitonin-
gene related peptide (CGRP) and substance P (SP). CGRP
causes vasodilation and SP induces protein extravasation,
both effects being deteriorating inflammatory processes (41).
Ectopic discharge
As mentioned above, sensory discharges originate from
nerve endings in somatic and visceral tissues where the
receptor potential is transduced into action potential. When
injury occurs to peripheral nerves, however, other cellular
compartments such as the proximal parts of injury and the
dorsal root ganglia (DRG) cell bodies turn to generate
action potential, an electrophysiological phenomenon
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referred to as ectopic discharge (ectopia) (42). A feature
of ectopic discharge is its mechanosensitivity, e.g., gentle
and instantaneous touch of the injured nerves or spinal
roots generates intense and outlasting discharges, which
causes the sensation reminiscent of the stabbing or shock
like sensation in patients with neuropathic pain. Thus, it
is currently regarded that ectopic discharges of differential
afferent fibers likely underlie the clinical manifestations
called burning pain (C-fiber), dysesthesias (Aδ-fiber) or
paresthesias (Aδ-fiber) resulting from nerve injury (10).
Interestingly, a growing body of evidence suggests that the
intact nerve neighboring injured axons may also develop
ectopic activities (43).
Ectopia, which is characterized by tonic, burstic or
irregular firing pattern, results from secondary changes
that develop in hours and days following nerve injury (42).
The cellular mechanisms of ectopic impulse generation is
not simply a decreased spike threshold but rather complex
alterations in DRG neurons involving gene transcription,
protein trafficking and ion channel kinetics.
One plausible example for these changes in DRG neurons
is altered expression and location of Na+ channels. After
nerve injury, Nav1.3 and Nav2 increased while Nav1.1, 1.2,
1.6, 1.7, 1.8, 1.9 decreased in primary afferent neurons (44).
The distribution of Na+ channels also tends to accumulate
in neuroma endbulbs and sprouts, rather than in the sensory
nerve endings and intra-segmental parts of the node of
Ranvier. The kinetics of Na+ channels are also modulated
by proinflammatory cytokines and other downstream
mediators such as protein kinases (PKA and PKC) (44). In
addition to Na+ channels, N-type Ca2+ channels are also
found to decrease in expression in DRG neurons (42).
All these quantitative and qualitative changes of channel
proteins contribute to the altered electrophysiological
phenotype of injured nociceptive neurons. In support
of this, some clinically effective analgesics such as local
anesthetic lidocaine and anticonvulsant gabapentin actually
act as modulators of Na+ and Ca2+ channels, respectively (45).
Sympathetically maintained pain
Spinal nerve comprises four types of nerve fibers, i.e.,
somatic afferent and efferent, and visceral afferent and
efferent (sympathetic or parasympathetic) fibers. Normally,
the sympathetic nervous system does not activate somatic
primary afferents, while in the nerve-injured conditions,
such cross-talk might occur. The responsiveness of afferent
neurons to sympathetic transmitters (noradrenaline and
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adrenaline) is likely to contribute to causalgia, the burning
pain in patients with injury in the main nerve of a limb
(46-48). This is evidenced by the effectiveness of systemic
injection of phentolamine, the α-adrenoceptor blocker,
in alleviating the pain (49). Such pain depending on the
activity of sympathetic neurons is termed sympathetically
maintained pain (SMP). SMP is a symptom characterized
by spontaneous pain and/or pain evoked by mechanical or
thermal stimuli and may be present in the complex regional
pain syndrome (CRPS) type I and II (50).
The mechanisms for SMP are not well understood
despite long exhaustive efforts of researchers over tens of
years. Several experimental models are, however, suggestive
and influential. Following nerve section or ligation,
electrical stimulation of lesioned or intact sympathetic
supply excites unmyelinated and myelinated afferent fibers.
This coupling is chemical and may occur via noradrenaline
acting on the α2-adrenoceptors, as the ephaptic coupling
between sympathetic fibers and afferent fibers has not been
experimentally validated so far (51). In addition to this
chemical coupling mechanism, aberrant structural changes
can also occur between sympathetic and afferent neurons.
Under healthy conditions, most sympathetic postganglionic
fibers project distally to peripheral target cells via gray rami
and a small quantity of fibers project proximally and usually
target along blood vessels. After nerve injury, however,
many proximally projecting perivascular catecholamine-
containing axons start to sprout in the DRG and even form
“baskets” along the cell bodies of injured nerve fibers (52).
The mechanisms underlying this collateral sprouting of
postganglionic sympathetic fibers is partially due to the
neurotrophic signals and their receptors enriched along
the afferent cells with lesioned axons (50,53). Whether
such pathological changes in structure are related to pain
behavior in patients after peripheral nerve lesions is still
uncertain and further investigations are expected.
Central mechanisms of pain
Although peripheral mechanisms play an important role in
the induction and transmission of nociceptive information,
it alone cannot explain all the characteristics of pathological
pain. Pathological nociceptive inputs also induce central
sensitization.
Central sensitization
The spinal cord is a pivotal gateway where the primary
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Xiangya Medicine, 2016
central sensory neurons exist and peripheral noxious
inputs are transmitted. In chronic pain states, modification
and plasticity of local neural circuits in the spinal dorsal
horn (SDH) were induced. As a result, ongoing noxious
information to the brain is amplified and prolonged, a
phenomenon which we call central sensitization. Central
sensitization is the abnormal hyperexcitability of nociceptive
related neurons in the SDH following intense peripheral
noxious stimuli, tissue injury or nerve damage (54-56).
Nociceptive information is transmitted from peripheral sites
to the SDH via unmyelinated (type C) and myelinated (type
Aδ) fibers. Usually, central sensitization disappears when
the peripheral input is reduced. However, in some serious
pathological pain, central sensitization can be isolated
from the peripheral nociceptive transmission. At this time,
the central sensitization exists even when the peripheral
stimulation and inputs disappear. Processes that are known
to contribute to hyperexcitability of dorsal horn neurons
include: changes in neurotransmitters and tachykinins and
in their receptors (56-59), aberrant remodeling of peripheral
afferent fibers and the synaptic dendrites in the SDH (60,61),
and the loss of inhibitory GABAergic inputs (62,63).
Central mechanisms on the spinal cord
Neurotransmitters and tachykinins are released from the
central prominence of the nociceptive neurons in the DRG.
Glutamate is the main transmitter in the DRG neurons (57).
Tachykinins include SP and neurokinin and neurotension
(45,64). In addition, different kinds of receptors are also
involved in the induction and maintenance of central
sensitization. There are three kinds of glutamate receptors
in the SDH: the ionotropic N-methyl-D-aspartate (NMDA)
receptor, non-NMDA receptors, and metabotropic
glutamate receptors. When glutamate binds to non-
NMDA receptors, the receptors are opened and sodium
influx depolarizes the neurons. However, under normal
conditions or during weak stimulation, the channels of
NMDA receptors are closed because of the presence of
magnesium. When pathological pain occurs, the magnesium
ion is removed by the tonic nociceptive stimulation. At
this time, the increased glutamate releasing can activate
the NMDA receptor in the SDH, which causes large
amounts of calcium flow into the neuron (65,66). Calcium
ions induce second-messenger cascades that increase
neuronal excitability. Thus, the NMDA receptors and their
downstream molecules play an important role in nociceptive
information transmission, central sensitization induction
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and maintenance as well as the chronic pain deterioration.
Laboratorially and clinically, administration of the NMDA
receptor antagonist can prevent central sensitization and
inhibit pain responses of animals or patients (67). After
central sensitization occurs, the neuronal excitability and
sensitivity is increased and the response to nociceptive
stimuli is exaggerated. This phenomenon is called “wind
up” (68,69).
Neuropeptides also play critical roles in the induction
and maintenance of central sensitization. SP and CGRP
released from the central terminals of nociceptive neurons in
the DRG can bind to receptors expressed on the neurons of
SDH and contribute to the persistent hyperalgesia. CGRP
can facilitate glutamate release through the activation of
CGRP receptors on terminals of primary afferent neurons
(59). Additionally, SP activates neurokinin receptors which
couple to phospholipase C and several kinds of intracellular
messengers. After binding to receptors, SP’s downstream
effects include depolarizing the membrane and facilitating
the function of α-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid receptor (AMPA) and NMDA receptors (59).
In addition, both CGRP and SP can activate transcription
factors and then increase the expression of related genes
that contribute to long-term changes in the excitability
of SDH neurons and maintain hyperalgesia. The changes
abovementioned finally induce the plasticity of the SDH
which is another important factor of central sensitization.
With augmented noxious inputs and prolonged activation
of pain pathways, neural plasticity is occurs and remodeling
of synapses in the SDH is induced. Type A-beta fibers, which
originally transmit peripheral proprioceptive information,
can release SP and are involved in the nociceptive
inputs transmission under the pathological pain (70).
More than 70% excitatory synapses are located on the
dendritic spine in the CNS, specifically on pyramidal cells
and neurons in the SDH. Dendritic spines can receive
highly convergent inputs from different origination (71),
and then regulate synaptic transmission (72). After disease
and injury, such as the pathological pain discussed here, the
dendritic spine morphology can change. Mushroom shape
dendritic spines are increased, which indicates the increased
synaptic efficacy. New dendritic spines grow from the
dendrites of neurons, which can provide more postsynaptic
binding sites (71). All the changes of dendritic spines
contribute to the hyperexcitibility and central sensitization
of spinal neurons.
The third mechanism underlying the central
sensitization is the disinhibitatory action of GABAergic
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input in the SDH (63). The reduction of GABA release
from the presynaptic terminals occurs during pathological
pain, which finally induces a functional loss of GABAergic
inhibition to excitatory neurons in the SDH (73).
Central mechanisms on supraspinal level
Recently, using an integrative research approaches in animal
models, genetically manipulated mice or human patients,
accumulated evidences have consistently suggested that
chronic pain is due to long-term plastic changes along
sensory pathways. Plastic changes not only take place in
peripheral nociceptors and SDH but also in cortical areas
and subcortical areas that are involved in the processing
of painful information. The region of the brain activated
by noxious stimuli is termed the “pain matrix”, and is
comprised of the primary/secondary somatosensory cortex,
insular cortex, prefrontal cortex (PFC), anterior cingulate
cortex (ACC), thalamus, limbic system, basal ganglia and
brainstem. Neuroimaging studies reveal neuronal activity
in these regions during pathological pain (74). The ACC,
PFC, insular and amygdala are pain-related structures with
a close morphological and functional interconnection. It
is reported that synaptic plasticity occurs in these cortical
or subcortical areas, such as in the ACC and amygdala
(75,76). In addition, neuronal activities in the ACC and
IC are believed to be important for pain perception and
unpleasantness. Cortical manipulations can modulate pain
behavior and pain-related memory traces. Thus, treating
chronic pain requires an understanding of plastic changes in
somatosensory pathways.
Acknowledgements
None.
Footnote
Conflicts of Interest: This article has been originally published
in the book The Art and Science of Palliative Medicine.
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