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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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16 Chronic Pain: New Molecular Insights into Pain and Treatment
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(b)
(c)
Figure 10. Feedback control as key mechanism. Models for spinal sensory transmission
and modulation by postsynaptic regulation (a), presynaptic regulation (b), heterosynaptic
regulation (c), autoregulation (d), and retrograde messenger (e). In case of heterosynaptic
regulation, glutamate released from the central terminals of the primary afferent fibers may
regulate spinal local inhibitory transmission through activation of presynaptic KA
receptors.
receptors leads to changes in AMPA/KA receptor-mediated synaptic
(e)
responses. They include acetylcholine, serotonin, opioids, norepinephrine, and oxytocin.
Presynaptic regulation: DRG–dorsal horn synapses
Sensory transmitters or neuromodulators bind to their target receptors on
the central terminals of DRG cells in the spinal cord dorsal horn.
Activation of these presynaptic receptors will lead to changes in the
release of sensory transmitters in response to peripheral sensory stimulation. Many neurotransmitters and peptides have been reported to produce
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presynaptic regulatory effects in the DRG–dorsal horn synapses, such as
ATP, serotonin, and opioids.
Heterosynaptic regulation: DRG–spinal inhibitory
neurons
In the spinal cord dorsal horn, glutamate-containing sensory fiber terminals come into close proximity with the GABA- and glycine-containing
boutons of local interneurons at synaptic glomeruli. In a recent study, we
provided evidence that glutamate released from primary afferent sensory
fibers can regulate spinal inhibitory transmission by activating KA receptors. These data suggest that heterosynaptic regulation of transmitter
release by presynaptic ligand-gated ionic channels may be reciprocal
between sensory fibers and dorsal horn interneurons. Because synaptically released glutamate suppressed evoked inhibitory transmission,
itsuggests that with sufficiently high levels of sensory input, inhibitory
tone may be reduced, possibly facilitating the relay of sensory information
to higher brain centers.
Autoregulation
In addition, neurotransmitters can act on their target receptors also
expressed in the presynaptic terminals. These can be either excitatory
glutamate or inhibitory GABA synapses. In case of glutamate synapses,
glutamate may act on presynaptic KA receptor expressed on the central
terminals of primary afferent fibers and regulates the release of glutamate.
Similar autoregulation of GABA releases is also reported in the spinal
cord.
Retrograde messengers
In central synapses, activation of postsynaptic receptors often leads to the
production of diffusible messengers, such as nitric oxide (NO) and carbon
monoxide (CO). In the spinal cord dorsal horn, enzymes that produce
retrograde messengers are found in dorsal horn neurons. It is very likely
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that diffusible retrograde messengers affect presynaptic release of glutamate and/or neuropeptides.
Mice and humans
The use of mouse model for human studies is supported by the fact that
human and mouse genes are similar as they share the same number of
genes (97.5%), and the genome is organized similarly (Figure 11). Recent
studies using genetically manipulated mice found that mutant genes that
Figure 11. Conserved synteny between the human and mouse genomes. Regions from
different mouse chromosomes (indicated by the colors of each mouse in b) show conserved synteny (gene order) with the indicated regions of the human genome (a). For
example, the genes present in the upper portion of human chromosome 1 (orange) are
present in the same order in a portion of mouse chromosome 4. Regions of human chromosomes that are composed primarily of short, repeated sequences are shown in black.
Mouse centromeres (indicated in black in b) are located at the ends of chromosomes; no
known genes lie beyond the centromere on any mouse chromosome. For the most part,
human centromeres, indicated by constrictions, occupy more internal positions on chromosomes (adapted from Sinha and Meller [49]).
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caused diseases in humans had similar effects in mice. The use of the
mouse model for human diseases — including CNS diseases — has several
advantages: the low cost of investigation, the short lifespan of mice, and the
easy manipulation of genes/proteins before any selective drug is used.
Genetic approaches: A new light for molecular
and cellular mechanism of pain
Genetically modified mice and other organisms are an essential tool
in identifying the molecular pathways mediating pain transmission,
modulation, and plasticity. Identification of the neurotransmitters and
receptors involved has been possible using pharmacological techniques.
However, most of the pharmacological agents have side effects, as well as
unexpected interactions with molecules other than their targets, and the
development of a selective pharmacological agent takes time. The possibility of genetically ablating or overexpressing a specific molecule has
allowed for rapid progress in the identification of the molecular mechanisms of pain. Behavioral and electrophysiological examinations of
mutant mice are necessary to identify specific deficits, or lack thereof, and
their mechanisms. Therefore, a thorough study must include an analysis at
the behavioral, electrophysiological, and molecular levels.
Ascending pain transmission
Noxious stimulation is detected by primary afferent fibers called nociceptors located in the skin and internal organs. Several types of afferent fibers
are distinguished according to their conduction velocity. The large Aδ
fibers respond mostly to innocuous stimuli, whereas the slower Aδ fibers
and the thin unmyelinated C fibers primarily contribute to painful stimuli.
We need to point out that the selective involvement of Aδ and C fibers in
pain transmission only holds up under normal physiological conditions.
Recent studies indicate that non-nociceptive fibers such as Aβ fibers may
contribute to persistent pain after tissue or nerve injury.
Neurons in the spinal dorsal horn and related areas receive sensory
inputs, including noxious stimuli, and convey them to supraspinal
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structures. Identifying molecules that are selectively involved in pain
transmission is a major research focus and holds hope for the treatment of
pain conditions, including persistent pain. Studies using pharmacological
and behavioral approaches showed that glutamate and neuropeptides —
including substance P (SP) — are likely transmitters of pain [5–8].
Electrophysiological investigations of sensory synaptic responses between
primary afferent fibers and dorsal horn neurons provide evidence that
glutamate was the principal fast excitatory transmitter and that synaptic
responses were mediated by postsynaptic glutamate receptors. While
AMPA receptors mediated most of the synaptic currents, KA receptors
preferentially contribute to synaptic responses induced by higher or noxious intensities [6]. Consistent with this, receptor antagonists blocking KA
and AMPA receptors yield greater analgesic effects in adult animals than
AMPA receptor-selective antagonists. These novel findings suggest that a
sensory modality may be coded by postsynaptic transmitter receptors.
Not all sensory synapses are functional, or effective, under normal
conditions. In young animals, silent glutamate synapses containing only
NMDA receptors were found in dorsal horn neurons and sensory afferent
fibers [5]. Conversion of such ‘silent’ synapses contributes to the enhancement of synaptic responses by serotonin (5-HT), an important transmitter
of descending projecting pathways. Furthermore, pure NMDA receptors
were also reported in the spinal dorsal horns of adult animals. These
NMDA synapses are functional due to possible distal dendrite locations of
NMDA receptors and/or the insensitivity of NMDA receptors to magnesium blockade.
In addition to glutamate, several neuropeptides including SP are
alsothought to serve as sensory neurotransmitters. For many years, electrophysiological evidence for the monosynaptic nature of SP-mediated
synaptic responses has been lacking, since SP-mediated responses have a
very slow onset. Recent studies using whole-cell patch-clamp recordings
revealed a rather fast SP- and neurokinin A (NKA)-mediated synaptic
current at synapses between primary afferent fibers and dorsal horn
neurons [7]. The currents summated upon repetitive stimulation at high
frequencies. In sum, spinal sensory synapses are far more diverse and
complicated than we previously believed.
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Dorsal horn neurons project to the thalamus via the spinothalamic
tract located in the anterolateral tract. Two pathways appear: a lateral one
and a medial one. The lateral pathway consists of the lateral thalamic
nuclei (ventroposterior lateral and medial) and their projection to the
somatosensory cortices (S1 and 2). This pathway codes for the intensity
of the stimulus from innocuous touch to noxious pinch. Receptive fields
are small, allowing accurate localization of the stimulus. On the other
hand, the ACC receives sensory input via the medial thalamic nuclei
[9,10]. Human imaging experiments have shown that activity in the ACC
correlates to the emotional, affective component of pain [11]. ACC
responses to noxious stimulation are also recorded in other species [12].
Pain can be modulated
Sensory transmission within the dorsal horn is subject to biphasic modulation, including descending facilitatory and inhibitory regulation [13–20].
Alteration of spinal sensory transmission modulates both the behavioral
responses to noxious stimulation and the information transmitted to
supraspinal areas. Based on electrophysiological and pharmacological
data, Melzack and Wall suggested the “gate control theory” in the 1960s
[21]. Although Aβ fibers do not contribute directly to pain processing, they
can inhibit nociceptive transmission, as they synapse onto both projection
neurons and local inhibitory interneurons. Recent studies have shown that
glutamate released by primary afferent fibers can act on the presynaptic
terminals of inhibitory interneurons to inhibit evoked GABA release. This
effect is mediated by presynaptic glutamate KA receptors, suggesting that
KA receptor antagonists would have an analgesic effect [22].
In addition to the interactions between different types of sensory afferent fibers, spinal sensory transmission, including pain transmission, is
strongly modulated by inputs from various supraspinal areas. Dorsal horn
neurons receive direct and indirect descending projections from numerous
supraspinal areas, including the ACC, amygdala, hypothalamus, periaqueductal grey (PAG), and rostral ventral medulla (RVM). Among them, a
major descending pathway consists of the PAG, RVM, and spinal cord
connections (Figure 12). Many other central nuclei interact with this
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Figure 12. Cortex-endogenous pain control. Neurons in the rostroventral medulla
(RVM) project to the spinal dorsal horn and modulate sensory synaptic transmission in the
spinal cord. Serotonin is the most likely transmitter for mediating this facilitatory effect.
The facilitation induced by serotonin likely requires activation of specific subtypes of serotonin receptors and coactivation of cAMP signaling pathways to induce facilitation in adult
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endogenous analgesia system and produced antinociceptive or analgesic
effects. As the last step of relay nuclei, neurons in several nuclei in the
brainstem play important roles in descending inhibition of spinal sensory
transmission. In addition to descending inhibition, descending facilitatory
influences from the brainstem and forebrain have also been characterized.
Biphasic modulation of spinal sensory transmission affects not only inputs
from somatosensory areas but also visceral organs. Biphasic modulation
of spinal nociceptive transmission from the RVM, consistent with different
types of neurons identified in this area, offers fine regulation of spinal
sensory thresholds and responses. While descending inhibition is involved
primarily in regulating the suprathreshold responses to noxious stimuli,
descending facilitation reduces the neuronal threshold to nociceptive
stimulation.
The ACC is a further source of descending facilitation (Figure 12).
Electrical or chemical stimulation of the ACC facilitates the spinal nociceptive tail-flick (TF) reflex [23]. This effect is mediated by the RVM,
as it is abolished following lidocaine inactivation of that area. This
facilitation is clinically relevant because plastic changes occur in the
ACC following injury. Many other more minor areas also contribute to
modulation of pain. For instance, the hypothalamus projects directly to
the dorsal horn and also releases hormones, which could alter nociceptive transmission. Relatively little is known regarding the exact roles of
hormones and hypothalamic projections in sensory processing. Although
more detailed data concerning the influence of gender on nociceptive
and antinociceptive pathways are emerging, their mechanisms of action
remain unknown. The use of knockout mice should shed some light on
these mechanisms.
Figure 12. (Continued) spinal dorsal horn neurons. Due to enhanced synaptic efficacy
between primary afferent fibers and dorsal horn neurons, spike (action potential) responses
to stimulation of afferent fibers were enhanced, as were behavioral nociceptive responses
(e.g., decrease in response latencies). Stimulation of neurons in the ACC also activated
descending facilitation, and activity within the RVM is required for mediating descending
facilitation from the ACC to the spinal dorsal horn (adapted from Zhuo [49]).
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Physiological pain versus pathological pain
Physiological pain is a very important physiological function for survival.
Depending on the pain experience, animals and humans gain knowledge
of potentially dangerous stimuli in their environments, and that painrelated unpleasantness helps form long-term avoidance memory in order
to protect themselves long term [24]. Although animals have the capacity
to enhance their sensitivity as well as their motor responses to subsequent
noxious stimuli, animals’ ability to distinguish pain from other sensations
is intact or at least not permanently altered. Pathological pain happens
only after injury (e.g., tissue or nerve injury) and is not the result of the
repetitive application of physiological pain. Long-term changes are likely
to occur after injury, both peripherally and centrally. Consequently, the
injury and injury-related areas undergo long-term plastic changes, and
pain sensations are significantly enhanced (hyperalgesia) or non-noxious
stimuli cause pain (allodynia). It should be pointed out that allodynia is
one of the major problems in pathological pain. Because it is induced by
non-noxious stimuli, it is most likely that central plastic changes play
important roles.
Central plasticity is most likely mechanism for
pathological pain
Pathological pain is likely the result of long-term plastic changes along
somatosensory pathways from the periphery to the cortex. Due to longterm plastic changes in the central regions, pain specificity is lost in the
somatosensory pathway, at least in areas where allodynia was reported
[25–30]. Thus, drugs developed based on physiological pain mechanisms
may not be used for treating pathological pain. Understanding pathological pain requires an understanding of plastic changes in somatosensory
pathways, mainly the CNS.
Pain plasticity: Key mechanisms underlying
persistent pain
Prolonged nociceptive stimulation following tissue or nerve injury induces
long-lasting changes at most levels of the nociceptive pathways. In the
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dorsal horn of the spinal cord, neurons exhibit increased responses to
noxious stimulation. As mentioned previously, the selective activation of
Ad and C fibers by nociceptive stimuli is selective in situations of ‘normal’
acute noxious stimulation. After tissue or nerve injury, such rules do not
exist anymore. It is quite common that non-noxious stimuli such as a gentle touch or warm temperatures become very painful. Corresponding
anatomical and chemical alterations have been reported. The synapses
between the primary afferents and dorsal horn neurons further undergo
plastic changes, which are partly dependent on NMDA receptors. Longlasting changes of dorsal horn synaptic responses have been shown to
occur in vivo following altered nerve activation.
Descending modulatory systems are also altered in persistent pain,
leading to modification of spinal sensory transmission [20,31]. Both
descending facilitatory and inhibitory modulation from the RVM may
participate in the development and maintenance of hyperalgesia following
inflammation and tissue injury. Following inflammation, reversible spinal
inactivation produced greater increases in dorsal horn neuronal activity,
receptive field, and response to noxious stimuli. Lesions of the dorsolateral funiculus, which mediates descending inhibition from the RVM,
potentiated inflammation-induced hyperalgesia. This indicates that
descending inhibition of dorsal horn nociceptive transmission from
supraspinal structures is increased during inflammation. RVM lesions
furthermore revealed that increased descending facilitation could contribute to the development and maintenance of secondary hyperalgesia. Longterm changes in RVM neuronal activity have been observed in polyarthritis.
Studies using microinjections of excitatory amino acids or opiate receptor
agonists suggest that RVM neuronal excitability and sensitivity to opiates
are altered following persistent hind paw inflammation. Our recent study
shows that changes in RVM neuronal activity and descending modulation
occur rapidly (within 15 min) following formalin-induced injury [32].
One potential synaptic mechanism for descending facilitation during persistent pain is the recruitment of silent spinal synapses [20,33,34].
Plasticity can occur in cortical areas, even in adults. It has been proposed that use-dependent changes in synaptic strength may serve as key
synaptic mechanisms of such cortical changes, although more direct evidence is needed. Cortical and subcortical reorganization occurs after limb
or digit amputation [35]. Most human amputees experience phantom limb
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