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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2679_Библиотеки_им_академика_М_И_Перельмана
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36 Chronic Pain: New Molecular Insights into Pain and Treatment
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such distinct lines of pain pathways are unlikely, especially in case of
pathological pain or central pain. Thus, it becomes critical to distinguish
physiological pain from pathological pain. While it is true that under
physiological conditions, some proteins are selective in pain transmission,
chronic pain is likely mediated by a network.
In addition to selective lines of involvement, the contribution of
peripheral sensitized activity and central plasticity to chronic pain may be
simple additive or liner (see Figure 1). For certain types of pain, the central plasticity may be driven, and even maintained, by peripheral sensitized inputs. Thus, the removal or inhibition of abnormal inputs will lead
to a significant reduction in chronic pain. However, in other cases, while
peripheral inputs may still play minor roles, central potentiation may take
over and play a major role in ongoing chronic pain. In such cases, inhibiting peripheral inputs may be insufficient, and in some cases, it is difficult
to clearly identify which peripheral inputs are responsible for chronic
pain.
Peripheral nerves and DRG cells
There are two major classes of peripheral nociceptors: unmyelinated C
fibers and small-myelinated Aδ fibers. C fibers are small-diameter unmyelinated fibers with small-diameter cell bodies. Whereas, Aδ fibers have
medium-diameter unmyelinated fibers. Each nociceptor can be divided
into different subgroups according to their responses to different forms of
sensory stimuli (thermal, mechanical, and chemical) or the chemicals they
express. The cell bodies of nociceptors are generally located in the DRG.
For the facial sensory nociceptors, they are located in trigeminal and
nodose ganglia. Although the sizes of DRGs have often been used to identify nociceptors, it may not be appropriate to be used in case of visceral
pain. Many somas of visceral nociceptors are larger than the DRG somas
of somatic nociceptors. Performing electrophysiological recordings from
nerve fibers and cells is the most reliable way to study the function of
peripheral nociceptors.
Peripheral noxious stimuli activate peripheral nociceptive transducer
receptors and/or ion channels causing membrane depolarization in
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sensory DRG cells. Recent studies indicate that not all nociceptors have a
response threshold as high as previously believed. Some nociceptors have
lower thresholds, just like non-nociceptors. Recent studies indicate that
transducer proteins include a family of proteins: TRPV1-4, TRPM8, and
different subtypes of ATP receptors. It becomes clear that no single protein or gene is responsible for a specific sensory process, such as heat pain
or cold sensation (see Table 1).
Under physiological conditions, noxious stimuli stimulate both nonnoxious and nociceptive fibers. It is almost impossible to deliver a selective noxious stimulus without activating some form of non-nociceptive
receptors. In pathological pain conditions, typical allodynia — triggered
by non-noxious stimulation — is also unlikely due to the selective activation of nociceptive fibers (Figure 1). Two voltage-gated sodium channel
alpha subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals. Deleting Nav1.7 has no effect on the development of
neuropathic pain, and double knockouts of both Nav1.7 and Nav1.8 also
develop normal levels of neuropathic pain. Inflammatory pain and
mechanical and thermal acute pain were altered [1]. A recent study by
Peirs et al. provides strong evidence that the neural circuits conveying
mechanical allodynia in the dorsal horn differ by the nature of the injury
[2]. Calretinin neurons in lamina II inner convey mechanical allodynia
induced by inflammatory injuries, while protein kinase C gamma (PKCγ)
neurons at the lamina II/III border convey mechanical allodynia induced
by neuropathic injuries. It is safe to say that each sensory modality, or
sensation, is a function of a specially organized neuronal circuit and network, from the periphery to the cortex with some of the key proteins playing major roles.
Table 1. Peripheral nociceptors for spinal transmitters for nociceptive pain and itch
Sensory modality Peripheral receptors Primary afferent fibers
Nociceptive heat
Nociceptive cold
Nociceptive mechanical
Itch
Visceral pain
TRPV1, TRPV2-4,
TRPM8, TRPA1, TRAAK/TREK-1
ASIC1-3; Cav3,2; P2X3, TRAAK
H1,4; interlukin-31 receptors; PAR2
ASIC1-3; TRPV1; TRPV4
Aδ; C fibers
Aδ; C fibers
Aδ; C fibers
C fibers
Visceral afferent fibers
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Molecular biology of sensory receptors
Identification of heat receptor TRPV1 has greatly facilitated the discovery
of many other sensory receptors [3]. Research into the expression of these
genes in cell lines has provided the first direct evidence of their sensitivity
to sensory stimuli. Development of selective inhibitors and gene knockout
mice have further helped us to understand the physiological studies of
these sensory receptors, although some of the results are complicated and
different from the expectation (e.g., cold receptor knockout and mouse
behavioral responses to cold). At the cellular level, the thermal threshold
of TRPV1 is found to be similar to that of human thermal threshold for
heat pain. In addition to the heat, TRPV1 is also activated by capsaicin
and acids (protons). Knockout mice lacking the TRPV1 receptors not only
avoid water with capsaicin in it but also have a diminished response to
heat, providing strong evidence for its roles in sensory process in behavioral animals [4].
In addition to TRPV1, there are other types of heat receptors in the
skin. They are all transmembrane proteins in the plasma membrane that are
permeable to calcium ions and sodium ions when they are open. Between
them, they cover a range of temperatures: TRPV4 Warm (~27–34°C),
TRPV3 Warmer (~31–39°C), and TRPV2 Painfully hot (>52°C). Since the
discovery of TRPVs, there has been a great interest in developing drugs that
inhibit these proteins. The hypothesis is that by applying these receptor
blockers, we may reduce the pain in patients with chronic pain. While it is
true that some thermal hyperalgesia may be reduced, these inhibitors will
also reduce normal thermal sensation in normal skin areas and thus may
cause secondary damage in daily life due to the changed threshold.
Cold-sensitive thermoreceptors give rise to the sensations of cooling,
cold, and freshness [5–7]. There are two candidate receptors for this: One,
designated TRPM8, is a channel that admits Ca2+ and Na+ in response to
moderate cold (<26°C) or menthol (the ingredient that gives mint its
“cool” touch and taste). However, knockout mice lacking the gene encoding the TRPM8 receptor do not avoid cold places as normal mice do, suggesting that its function can be compensated by other sensory proteins in
vivo. A second candidate, designated TRPA1, responds to lower temperatures (<18°C). It also responds to several irritant chemicals eliciting
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signals that the brain interprets as pain. However, TRPA1 knockout mice
respond normally to cold so the precise role of these receptors is still
uncertain for those stimuli.
Recent physiological studies using gene knockout mice lacking
TRPV1 or TRPM8 have nicely demonstrated that neither heat pain nor
cold pain is mediated by a single protein/an ion channel. In mice lacking
TRPV1, behavioral deficits in responses to noxious heat applying to the
tail or hind paw are only partial. In mice lacking TRPM8, behavioral
responses to noxious cold are partially affected or not affected at all. In
some subpopulation of nociceptors, other ion channels such as voltagegated K+ channel may also contribute to cold responses. Thus, it is possible that a peripheral sensory protein may contribute to multiple sensory
processes, such as heat, cold, itch, and touch. One common concern is that
many reports only employed behavioral studies using gene-manipulated
mice. Therefore, most of the conclusions are indirect and inconclusive.
Electrophysiological experiments may be very difficult in some cases and
are needed in future studies (Figure 2).
While the roles of TRPM8/TRPA1 in behavioral responses to physiological cold are inconclusive, recent studies found that they may contribute to cold stimuli after tissue inflammation or cold allodynia [8–12]. It is
great of interest to confirm these findings at the cellular level (using electrophysiological recordings of fiber activity) and investigate the possible
molecular mechanisms. Mechanical nociceptors respond to excess pressure or mechanical deformation. They also respond to incisions that break
the skin’s surface. The reaction to the stimulus is processed as pain by the
cortex, just like chemical and thermal responses. Many times, these
mechanical nociceptors have polymodal characteristics. Therefore, it is
possible that some of the transducers for thermal stimuli are the same for
mechanical stimuli. The same is true for chemical stimuli since TRPA1
appears to detect both mechanical and chemical changes.
Visceral nociceptors
Visceral receptors are less studied as compared with somatosensory nociceptors [13]. Recent studies from visceral nociceptors clearly show that
it is unlikely that there is a common mechanism for nociceptors in
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Figure 2. Molecular identity of thermosensitive afferents based upon the expression of
TRPM8 and TRPA1. TRPM8 and TRPA1 are found in distinct and non-overlapping populations of sensory afferents, with TRPA1 expressed exclusively in some, but not all, neurons that express the heat-gated channel TRPV1. These thermosensitive TRP channels
respond to a number of naturally occurring pungent compounds, such as menthol (mint),
allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), and capsaicin (‘hot’ chili
peppers), thus providing a molecular explanation for how these compounds provide distinct sensations of cold, heat, or spiciness. Based upon in vitro characterizations of these
channels, along with their distinct expression patterns, thermal stimuli activating TRPM8expressing afferents elicit the sensation of cool to potentially noxious cold, while TRPA1
afferents will merge both noxious cold and noxious heat, due to the expression of TRPV1
(adapted from McKemy [8]).
cutaneous tissues vs visceral organs. For example, some of the visceral
nociceptors have large cell bodies of DRG as compared with typical
somatic nociceptors. Unlike somatic nociceptors, visceral nociceptors are
low-threshold mechanoceptors suggesting that they also respond to nonnociceptive stimuli. Recent studies reveal that different subtypes of ATP
receptors are important for transducting visceral pain information [14,15].
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Itching and pain: Two separate transmitter systems?
Research on itch has gained more interest recently. Similar to pain, one
major theory is that itch may be mediated by selective, independent ‘itch’
transmitters and receptors, at least at the periphery [16,17]. The studies of
mice lacking gastrin-releasing peptide (GRP) provide interesting findings
that show selective reduction in ‘itch’ responses, while most of the pain
responses remain intact. Considering the expression of GRP in selective
DRG cells, it has been proposed that GRP may act as selective transmitter
for itch. However, there is one key piece of evidence missing to support
the theory of GRP as the neurotransmitter in the spinal cord for itch. It is
essential to demonstrate that sensory-evoked responses between primary
afferent fibers and GRP-responsive dorsal horn neurons are mediated by
GRP itself. Without this direct evidence, it is impossible to distinguish
GRP as a transmitter or neuromodulator for itch. The hypothesis of GRP
as a selective itch transmitter is also questioned by recent studies using
gene-mutant mice lacking VGLUT2 or BHLHB5 [18]. In the study of
BHLHB5 mutant mice, loss of inhibitory interneurons in the spinal dorsal
horn contributes to elevated itch responses in behavioral animals. In
VGLUT2 conditional null mice — in which vesicle glutamate transport
type 2-dependent synaptic release of glutamate was abolished — behavioral responses to itch stimuli were either significantly reduced or
enhanced. Electrophysiological studies showed that while GRP activated
certain dorsal horn neurons that received C fiber inputs, excitatory synaptic responses onto the same neurons are purely mediated by glutamatergic
receptors, suggesting that glutamate is also the major transmitter for itching at the level of the spinal cord [19] (Figure 3). These conflicting results
raise new questions about whether GRP serves as a selective transmitter
of itch or GRP and/or glutamate may serve as transmitters in spinal itch
synapses (Figure 4).
Peripheral sensitization
It is well known that nociceptor neuron sensitivity is modulated by a large
variety of mediators in the extracellular space [20,21]. Peripheral sensitization represents a form of functional plasticity of the nociceptor. The
nociceptor can simply change from a noxious stimulus detector to a
42 Chronic Pain: New Molecular Insights into Pain and Treatment
(A)
(B)
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(a)
(b) (c) (d)
(e)
Figure 3. C fiber-evoked responses in GRP-positive neurons are blocked by glutamate
antagonists. (A) The experimental procedure to identify the transmitter between C fibers
and GRP-positive neurons in rats. (B) In a GRP-sensitive neuron (a), a monosynaptic C
fiber-evoked EPSCs (b) was totally blocked by a bath application of CNQX (25 µM), an
AMPA/KA receptor antagonist (c–e, n = 4) (adapted from Koga et al. [19]).
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Figure 4. Itching and pain pathways. Under normal physiological conditions, noxious
stimuli activate nociceptive afferent fibers (Aδ and C fibers). Incoming action potentials
trigger a release of excitatory transmitter glutamate in the spinal dorsal horn. In addition,
some neuropeptides are also released including substance P (SP) and neurokinin A (NKA).
Glutamate and neuropeptides activate spinal dorsal horn neurons, including those that send
projection terminals to supraspinal structures. Neurons in the thalamus play key roles in
relaying these ascending inputs. Five major cortical areas, the ACC, IC, S1, S2, and PFC,
are activated and contribute to different aspects of pain perception, including the unpleasantness of pain. Recent studies have suggested that glutamate may also serve as a key fast
excitatory transmitter for itch, and a peptide GRP plays modulatory role in the transmission of itch.
44 Chronic Pain: New Molecular Insights into Pain and Treatment
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detector of non-noxious stimuli. The result is that low-intensity stimulus
from regular activity initiates a painful sensation. This is commonly
known as hyperalgesia and allodynia. Inflammation is one common cause
that results in the sensitization of nociceptors. Normally, hyperalgesia
ceases when inflammation goes down, however, sometimes genetic
defects and/or repeated injury can result in allodynia: where a completely
non-noxious stimulus like light touch causes extreme pain. It becomes
clear that no simple factor is involved in peripheral sensitization. Instead,
different factors and cells are involved. It is believed that peripheral sensitization may contribute to behavioral hyperalgesia and/or allodynia in
chronic pain state. It is unlikely that there is one universal mechanism for
all kinds of peripheral sensitization.
cAMP as a key messenger for peripheral sensitization
cAMP is a key second messenger for cellular signaling process. cAMP is
generated by the activation of adenylyl cyclases (ACs), and there are at
least 11 different isoforms of ACs in neuronal cells. These different isoforms of ACs allow the coupling of different receptors/ion channels to the
production of cAMP in postsynaptic cells. For example, subtypes AC1 and
AC8 link activation of NMDA receptors to the cAMP production in an
activity-dependent manner in central synapses. The activation of NMDA
receptors leads to an increase in postsynaptic calcium, then that calcium
binds to calmodulin and activates AC1 and AC8 which both are regulated
by calcium calmodulin. At the peripheral, non-selective activators of
ACs — forskolin as well as cAMP analogs — trigger peripheral nociceptor sensitization (i.e., causing behavioral hyperalgesia or allodynia). At
least one major mechanism is enhancing responses of primary afferent
fibers to sensory stimuli. Interestingly, opioid receptor agonists produced
their analgesic effects at least in part by reducing the intracellular cAMP
level by different types of G protein-related signaling pathways.
In addition to cAMP and PKA pathways, another major protein kinase
PKC has also been found to be important for peripheral sensitization.
Interestingly, among different isoforms of PKCs, only calcium-independent PKCε is mainly involved in peripheral sensitization. It can be activated
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by different types of inflammation-related mediators, such as bradykinin,
epinephrine, tumor necrosis factor, and carrageen.
Sensitization of TRPV1 receptor
Among many different possible target proteins that may be sensitized or
enhanced in peripheral sensitization, the modulation of TRPV1 receptor
function is an attractive target (Figure 5) [22,23]. Due to its important role
in processing thermal heat transmission, it is obvious that its sensitization
will significantly enhance the responses of nociceptors to thermal stimuli
and contribute to thermal hyperalgesia. It may also contribute to thermal
allodynia if the responsive threshold is also reduced. The cAMP-PKA
pathway that is known to be critical for peripheral sensitization has been
reported to enhance the function of TRPV1 receptors in nociceptors [24].
Capsaicin responses in nociceptors are enhanced by the activation of
PKA. One possible major mechanism is that PKA phosphorylates TRPV1
at Ser 116, and this phosphorylation reduces the desensitization of
TRPV1.
Figure 5. Plasticity of TRPVR1 receptors. The capsaicin receptor, TRPVR1, is a sensory
neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. ATP potentiates the TRPVR1 currents evoked by capsaicin
through metabotropic P2Y1 receptors in a protein kinase C (PKC)-dependent pathway.
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