Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2679_Библиотеки_им_академика_М_И_Перельмана
.pdf
46 Chronic Pain: New Molecular Insights into Pain and Treatment
(a)
(b)
https://t.me/medicina_free
Hyperalgesic priming and its related molecular
mechanism
The peripheral sensitization mechanism for hyperalgesia has been greatly
improved by the discovery of hyperalgesia priming in the periphery. In
this form of peripheral nociceptor plasticity, acute inflammatory insult can
trigger long-lasting hypersensitivity of nociceptors to inflammatory
cytokines (Figure 6). This form of priming depends on one form of protein
kinase C (PKCε). cAMP signaling pathway has been known to contribute
Figure 6. Chronic hyperalgesia associated with inflammation-induced hyperalgesic
priming. (a) In the normal (unprimed) paw, a small intradermal injection of prostaglandin
E2 (PGE2) causes an episode of acute hyperalgesia (decreased threshold for paw withdrawal from a pressure stimulus) lasting less than 4 h. (b) Injection of the inflammogen,
carrageenan, causes an episode of hyperalgesia that lasts less than 4 days (gray-filled
curve). After carrageenan-induced hyperalgesia is no longer present, the paw remains in a
latent state of hyperalgesic priming. In this state, an injection of PGE2, which would cause
only acute hyperalgesia in the normal (unprimed) paw, now induces an additional chronic
hyperalgesia. In comparison to the unprimed paw, this hyperalgesia is greater in magnitude
and is greatly prolonged, lasting at least 3 weeks (adapted from Reichling and Levine [27]).
Peripheral Nociceptors and Sensitization 47
https://t.me/medicina_free
to the priming. The peripheral activity of PKCε is required for both the
initiation and maintenance of primed hyperalgesia.
Silent nociceptors
One interesting finding related to peripheral sensitization is the silent
nociceptors [25]. In experimental conditions, no physiological stimuli are
found to be able to activate these ‘silent’ receptors. However, after injury,
the silent receptors become active. These silent receptors are mostly
mechanosensitive receptors (or called MIAs, mechanically insensitive
afferents) and have been found in tissues, such as joints, muscles, and
visceral organs. Thus, the recruitment of silent nociceptors provides novel
mechanisms for peripheral sensitization. It is likely that peripheral sensitization can occur via three different mechanisms: (1) enhanced responses
to stimuli, (2) the recruitment of silent nociceptors that are previously
inactive or silent, and (3) sprouting of nociceptors and recruiting new
neuronal networks in the spinal cord (Figure 7). However, due to the poor
access to direct recording from silent fibers, most of the intracellular
molecular mechanisms that lead to re-activation of silent nociceptors
remain unknown. Future advances in single-fiber electrophysiology and
molecular biology interference techniques will facilitate research in this
area.
Figure 7. Silent nociceptors. Spinal dorsal horn neurons receive different types of sensory fibers. Some of these fibers may be ‘silent’ due to the absence of functional postsynaptic receptors to respond to glutamate. These silent receptors may exist in adult synapses,
although they may be difficult to detect by using the electrode placed in the soma of dorsal
horn neurons.
48 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
Mitochondrial contribution to peripheral sensitization
Recent studies showed that the mitochondrion is a downstream element of
the pathway through which PKCε generates mechanical hyperalgesia [26].
Inhibition of two closely related mitochondrial functions — electron transport (complexes I–V) and oxidative stress (reactive oxygen species) —
selectively attenuated the mechanical hyperalgesia (Figure 8). The
Figure 8. Mitochondrial contribution to chronic pain. Joseph and Levine [3] report that
PKCε-induced mechanical hyperalgesia involves mitochondria, including electron transport (complexes I–V) and oxidative stress (reactive oxygen species). Activation of PKCε
by nerve growth factor (NGF) or tumor necrosis factor alpha (TNFα) contributes to priming hyperalgesia, although more upstream receptors are likely also involved. PKCε can
translocate to mitochondria and regulate its functions by phosphorylating signaling molecules, such as respiratory chain proteins. The exact molecular mechanism connecting
mitochondria to mechanical hyperalgesia remains to be studied. Short-lasting hyperalgesia
induced by intradermal injection of PGE2 is likely mediated by a G protein-regulated
cAMP signaling pathway and downstream activation of cAMP-dependent protein kinase
(PKA). This PGE2-induced short-lasting hyperalgesia apparently does not involve a mitochondrial contribution (adapted from Zhuo [27]).
Peripheral Nociceptors and Sensitization 49
https://t.me/medicina_free
PKCε-dependent form of mechanical hyperalgesia induced by PGE2 was
not attenuated by inhibition of mitochondrial function. These studies suggest that at least two downstream signaling pathways mediate the hyperalgesia induced by activating PKCε. Mitochondria apparently contribute
selectively to the long-term hyperalgesia.
Conclusions
Integrative neurobiological approaches have provided us with new information for our understanding of pain biology. Many key proteins and ion channels that are critical for the physiological process of sensory stimuli have
been identified and characterized. While the use of receptor antagonists for
these receptors may cause side effects in patients, it has become clear that
the study of the sensitization, or modification, of these sensory receptors
may reveal new mechanisms for peripheral sensitization of nociceptors.
Selectively inhibiting or preventing sensitization without affecting normal
responses of nociceptors to sensory noxious stimuli will be a challenge for
all sensory neuroscientists who are interested in developing any novel drug
for treating chronic pain that is dependent on peripheral sensitization.
References
[1] Nassar, M.A. et al. (2005) Neuropathic pain develops normally in mice
lacking both Na(v)1.7 and Na(v)1.8. Mol Pain 1, 24. 10.1186/1744-
8069-1-24.
[2] Peirs, C. et al. (2021) Mechanical allodynia circuitry in the dorsal horn is
defined by the nature of the Injury. Neuron 109, 73–90 e77. 10.1016/j.
neuron.2020.10.027.
[3] Caterina, M.J. and Julius, D. (2001) The vanilloid receptor: A molecular
gateway to the pain pathway. Annu Rev Neurosci 24, 487–517. 10.1146/
annurev.neuro.24.1.487.
[4] Caterina, M.J. et al. (2000) Impaired nociception and pain sensation in mice
lacking the capsaicin receptor. Science 288, 306–313. 10.1126/
science.288.5464.306.
[5] Colburn, R.W. et al. (2007) Attenuated cold sensitivity in TRPM8 null
mice. Neuron 54, 379–386. 10.1016/j.neuron.2007.04.017.
50 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
[6] Peier, A.M. et al. (2002) A TRP channel that senses cold stimuli and men-
thol. Cell 108, 705–715. 10.1016/s0092-8674(02)00652-9.
[7] Story, G.M. et al. (2003) ANKTM1, a TRP-like channel expressed in noci-
ceptive neurons, is activated by cold temperatures. Cell 112, 819–829.
10.1016/s0092-8674(03)00158-2.
[8] McKemy, D.D. (2005) How cold is it? TRPM8 and TRPA1 in the molecular
logic of cold sensation. Mol Pain 1, 16. 10.1186/1744-8069-1-16.
[9] Bautista, D.M. et al. (2007) The menthol receptor TRPM8 is the principal
detector of environmental cold. Nature 448, 204–208. 10.1038/nature05910.
[10] Abrahamsen, B. et al. (2008) The cell and molecular basis of mechanical,
cold, and inflammatory pain. Science 321, 702–705. 10.1126/
science.1156916.
[11] Chung, M.K. and Caterina, M.J. (2007) TRP channel knockout mice lose
their cool. Neuron 54, 345–347. 10.1016/j.neuron.2007.04.025.
[12] Dhaka, A. et al. (2007) TRPM8 is required for cold sensation in mice.
Neuron 54, 371–378. 10.1016/j.neuron.2007.02.024.
[13] Gold, M.S. and Gebhart, G.F. (2010) Nociceptor sensitization in pain patho-
genesis. Nat Med 16, 1248–1257. 10.1038/nm.2235.
[14] Chen, T. et al. (2010) Spinal microglial motility is independent of neuronal
activity and plasticity in adult mice. Mol Pain 6, 19. 10.1186/1744-8069-6-19.
[15] Cockayne, D.A. et al. (2000) Urinary bladder hyporeflexia and reduced
pain-related behaviour in P2X3-deficient mice. Nature 407, 1011–1015.
10.1038/35039519.
[16] Sun, Y.G. and Chen, Z.F. (2007) A gastrin-releasing peptide receptor medi-
ates the itch sensation in the spinal cord. Nature 448, 700–703. 10.1038/
nature06029.
[17] Sun, Y.G. et al. (2009) Cellular basis of itch sensation. Science 325, 1531–
1534. 10.1126/science.1174868.
[18] Ross, S.E. et al. (2010) Loss of inhibitory interneurons in the dorsal spinal
cord and elevated itch in Bhlhb5 mutant mice. Neuron 65, 886–898.
10.1016/j.neuron.2010.02.025.
[19] Koga, K. et al. (2011) Glutamate acts as a neurotransmitter for gastrin
releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord. Mol Pain 7, 47. 10.1186/1744-8069-7-47.
[20] Bhave, G. and Gereau, R.W.t. (2004) Posttranslational mechanisms of
peripheral sensitization. J Neurobiol 61, 88–106. 10.1002/neu.20083.
[21] Hucho, T. and Levine, J.D. (2007) Signaling pathways in sensitization:
Toward a nociceptor cell biology. Neuron 55, 365–376. 10.1016/j.
neuron.2007.07.008.
Peripheral Nociceptors and Sensitization 51
https://t.me/medicina_free
[22] Moriyama, T. et al. (2005) Sensitization of TRPV1 by EP1 and IP reveals
peripheral nociceptive mechanism of prostaglandins. Mol Pain 1, 3.
10.1186/1744-8069-1-3.
[23] Zhang, X. et al. (2008) Proinflammatory mediators modulate the heat-
activated ion channel TRPV1 via the scaffolding protein AKAP79/150.
Neuron 59, 450–461. 10.1016/j.neuron.2008.05.015.
[24] Bhave, G. et al. (2002) cAMP-dependent protein kinase regulates desensi-
tization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron
35, 721–731. 10.1016/s0896-6273(02)00802-4.
[25] Wall, P.D. (1988) Recruitment of ineffective synapses after injury. Adv
Neurol 47, 387–400.
[26] Zhuo, M. (2010) Mitochondrial connection in chronic pain. Pain 150, 1–2.
10.1016/j.pain.2010.04.019.
[27] Reichling, D.B. and Levine, J.D. (2009) Critical role of nociceptor plastic-
ity in chronic pain. Trends Neurosci 32, 611–618. 10.1016/j.tins.2009.07
.007.
This page intentionally left blankThis page intentionally left blankThis page intentionally left blankThis page intentionally left blank
https://t.me/medicina_free
Chapter 3
https://t.me/medicina_free
Spinal Dorsal Horn Synaptic
Transmission and Gate Theory
News and Views
53
54 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
The gate control theory of pain describes how non-painful sensations can
override, and even reduce, painful sensations. A painful, nociceptive
stimulus stimulates primary afferent fibers and travels to the brain via
transmission cells. Increasing the activity of the transmission cells
results in increased perceived pain. Conversely, decreasing the activity
of transmission cells reduces perceived pain. In the gate control theory,
a closed “gate” describes when input to transmission cells is blocked,
therefore reducing the sensation of pain. An open “gate” describes when
input to transmission cells is permitted, therefore allowing the sensation
of pain.
First proposed in 1965 by Ronald Melzack and Patrick Wall, the gate
theory offers a physiological explanation for the previously observed
effect of psychology on pain perception. Combining early concepts
derived from the specificity theory, and the peripheral pattern theory, the
gate control theory is considered to be one of the most influential theories
of pain. This theory provided a neural basis which reconciled the specificity and pattern theories and ultimately revolutionized pain research.
Summary
Whole-cell patch-clamp recordings reveal that sensory synaptic currents
in the spinal cord are mainly mediated by glutamate. Postsynaptic glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)
receptor mediated most of the synaptic responses, while kainate (KA)
receptors contributed to synaptic responses receiving nociceptive inputs.
Repetitive stimulation of high-threshold nociceptive fibers also triggers
neuropeptide-mediated synaptic currents. These neuropeptides include SP
and NKA. There is no evidence of the existence of other sensory neurotransmitters. Synaptic excitatory transmission is biphasically modulated
by G protein-coupled receptors; both presynaptic and postsynaptic mechanisms are likely involved. For postsynaptic regulation, G protein-coupled
receptors — cholinergic, serotonergic, and adrenergic — are involved.
Presynaptic regulation can be mediated by different receptors, including
ATP P2X and KA receptors. Activation of KA receptor regulates spinal
inhibitory transmission as well; both GABA and glycine had mediated
responses. Inhibition or the reduction of these modulations can produce
Spinal Dorsal Horn Synaptic Transmission and Gate Theory 55
https://t.me/medicina_free
either analgesic or facilitation of behavioral nociceptive responses in
freely moving animals.
Keywords: Kainate receptor; glutamate; SP; NKA; gate control;
presynaptic regulation; mGluRs; spinal dorsal horn; nociception; wholecell patch-clamp
Introduction
Spinal cord dorsal horn is the first synapse of the CNS. It has received
much attention because it is functionally simpler than the synapses in the
brain. It is believed that the spinal cord circuit is simple and the understanding of it will help us to develop analgesics for the treatment of
chronic pain. However, the reality is that it is not as simple as we think.
The neuronal information travels through the spinal cord in a complicated
manner, and the subsequent neuronal activities quickly “leak” into the
supraspinal structures, inducing long-term plastic changes. Even at the
spinal cord level, synaptic transmission and modulation are very sophisticated, and the roles of “pain” transmitters are often biphasic. This chapter
will review recent progress made in this area.
Glutamate is the major excitatory transmitter
Neurons in the spinal cord dorsal horn, and related areas, receive sensory
inputs, including noxious information, and convey them to supraspinal
structures. Studies using pharmacological and behavioral approaches
show that glutamate and neuropeptides, including SP, are excitatory transmitters for pain [1–5]. Electrophysiological investigation of sensory synaptic responses between primary afferent fibers and dorsal horn neurons
provides evidence that glutamate is the principal fast excitatory transmitter, and synaptic responses are mediated by postsynaptic glutamate receptors [6–9]. While AMPA receptors mediate the largest component of
postsynaptic currents (Figure 1), KA receptors preferentially contribute to
synaptic responses induced by higher (noxious) stimulation intensities
(Figure 1). Consistent with this, antagonism of both KA and AMPA receptors yields greater analgesic effects in adult animals than AMPA receptor
Соседние файлы в папке Библиотека им академика М.И. Перельмана