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
316 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
brainstem. Among them, a major descending pathway consists of the
PAG-RVM and spinal cord connections. Many other central nuclei interact with this so-called endogenous analgesia system and produce antinociceptive/analgesic effects. As the last step of relay nuclei, neurons in
several nuclei in the brainstem play an important role in descending inhibition of spinal sensory transmission. In addition to descending inhibition,
descending facilitatory systems from the brainstem or forebrains have also
been characterized. Biphasic modulation of spinal nociceptive transmission from the RVM offers fine regulation of spinal sensory thresholds and
responses. While descending inhibition is primarily involved in regulating
suprathreshold responses to noxious stimuli, descending facilitation
reduces the neuronal threshold to nociceptive stimulation.
In the spinal cord, serotonin receptors are involved in the facilitation
of synaptic responses as well as behavioral reflexes. One synaptic
mechanism for serotonin-mediated facilitation is the recruitment of functional AMPA receptors at pure NMDA receptor-containing synapses.
Postsynaptic G protein-coupled activation of PKC is important for serotonin-produced facilitation. Furthermore, the interaction between AMPA
receptors and the PDZ protein glutamate receptor-interacting protein
(GRIP) likely contributes to the recruitment of functional AMPA responses.
Descending facilitation can be activated under physiological conditions,
and a possible physiological reason for descending facilitation is to
enhance animals’ ability to detect potential dangerous signals in the environment. Indeed, neurons in the RVM not only respond to noxious stimuli
but also show ‘learning’-type changes during repetitive noxious stimuli.
More importantly, RVM neurons can undergo plastic changes during, and
after, tissue injury and inflammation. Descending facilitation is likely
activated after the injury, contributing to secondary hyperalgesia. Blocking
descending facilitation, by lesion of the RVM, or spinal blockade of serotonin receptors, is antinociceptive. The descending facilitatory system
therefore serves as a double-edged sword in the central nervous system.
On one hand, it allows neurons in different parts of the brain to communicate with each other and enhance sensitivity to potentially dangerous
signals; on the other hand, prolonged facilitation of spinal nociceptive
Current Drug and Novel Drug Target for Treating Chronic Pain 317
https://t.me/medicina_free
transmission after injury speeds up central plastic changes related to
chronic pain.
Alternative treatment of chronic pain
There are several alternative treatments for chronic pain. These include
acupuncture, electrical stimulation, physical therapy, and rehabilitation
[65]. Most of these alternative treatments employ the techniques of
stimulation of the endogenous analgesic systems or shifting the attention
or focus of pain. They are often effective in controlling acute pain.
However, these techniques do not work well for chronic pain in general.
Considering the plastic changes in endogenous descending modulatory
systems, it is expected that electrical stimulation will not produce any
powerful analgesic effects in patients with chronic pain. Future studies
into the molecular mechanisms of alternative medicines for pain control
are needed.
Potential new drugs targeted at central plasticity
and descending facilitation
Based on recent progress in the understanding of central synaptic modulation and plasticity, the following potential drug targets for chronic pain are
suggested:
(1) only or mostly activated during high-frequency neuronal firing or
injury-related pattern of activity but not resting or physiological
activity,
(2) inhibition of the target or function selectively during chronic but not
acute pain or threshold for physiological pain, e.g., AC1 and AC8,
NMDA NR2B,
(3) inhibition will unlikely affect the established memory and with less
effects on the formation of new experiences in animal models.
(4) target proteins showing unique expression in neurons, especially in
areas related to the pain process,
318 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
(5) enhancing the functions of target proteins should selectively enhance
persistent pain with less or no effect on acute pain.
The following is a list of possible candidates suggested based on
recent findings:
Glutamate receptors
NMDA NR2B: Inhibiting NMDA NR2B receptors may affect chronic
pain with fewer side effects.
KA receptors: Blocking function of GluR5 or other KA receptors.
AMPA receptors: Blocking the postsynaptic AMPA traffic triggered by
activity.
Second and third messengers
Adenylyl cyclase AC1 and AC8: Inhibiting calcium-stimulated ACs.
Protein kinases/phosphatases: Blocking calcium-stimulating protein
kinases, such PKA, PKC, and ERK.
Protein–protein interaction: Inhibitors for PDZ93 and PDZ95, AMPA
receptor-related GRIP1/2.
Gene expression: Preventing the injury-related gene expression, such as
Egr1 and CREB.
Neurotrophic factors: BDNF and other trophic factors.
Presynaptic regulation
Regulation of sensory transmitter releases: Inhibiting the plasticity-related
enhancement of transmitter release.
Inhibitory mechanism
GABA/Glycine receptors: Drugs to enhance central inhibitory mechanisms or prevention of central disinhibition due to injury.
Descending facilitation
Serotonin subtype receptors: Drugs to block 5-HT receptor mediating
descending facilitation as well as those activate 5-HT subtype receptors
mediating descending inhibition
Current Drug and Novel Drug Target for Treating Chronic Pain 319
https://t.me/medicina_free
Conclusions and future directions
In conclusion, it is clear that we are just beginning to explore the molecular and cellular mechanisms of chronic pain. Due to rapid progress in the
areas of genetics, neuroscience, imaging, and molecular biology, we no
longer need to treat the neuronal circuits involved in the pain as a black
(or gray) box. Instead, future studies will allow us to open the box and
investigate the structures of the boxes at different levels. We will almost
certainly be able to identify new molecular targets for controlling pain in
this exciting exploration.
References
[1] Szallasi, A. et al. (2006) TRPV1: A therapeutic target for novel analgesic
drugs? Trends Mol Med 12, 545–554. 10.1016/j.molmed.2006.09.001.
[2] Gunthorpe, M.J. and Chizh, B.A. (2009) Clinical development of TRPV1
antagonists: Targeting a pivotal point in the pain pathway. Drug Discov
Today 14, 56–67. 10.1016/j.drudis.2008.11.005.
[3] Di Marzo, V. (2008) Targeting the endocannabinoid system: To enhance or
reduce? Nat Rev Drug Discov 7, 438–455. 10.1038/nrd2553.
[4] Wu, L.J. et al. (2007) Kainate receptors and pain: From dorsal root ganglion
to the anterior cingulate cortex. Curr Pharm Des 13, 1597–1605.
10.2174/138161207780765864.
[5] Sandkuhler, J. (2007) Understanding LTP in pain pathways. Mol Pain 3, 9.
10.1186/1744-8069-3-9.
[6] Zhuo, M. (2004) Central plasticity in pathological pain. Novartis Found
Symp 261, 132–145; discussion 145–154.
[7] Zhuo, M. (2007) A synaptic model for pain: Long-term potentiation in the
anterior cingulate cortex. Mol Cells 23, 259–271.
[8] Zhuo, M. (2007) Neuronal mechanism for neuropathic pain. Mol Pain 3, 14.
10.1186/1744-8069-3-14.
[9] Costigan, M. et al. (2009) Neuropathic pain: A maladaptive response of the
nervous system to damage. Annu Rev Neurosci 32, 1–32. 10.1146/annurev.
neuro.051508.135531.
[10] Zhuo, M. (2011) Cortical plasticity as a new endpoint measurement for
chronic pain. Mol Pain 7, 54. 10.1186/1744-8069-7-54.
320 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
[11] Zhuo, M. et al. (2011) Neuronal and microglial mechanisms of neuropathic
pain. Mol Brain 4, 31. 10.1186/1756-6606-4-31.
[12] Ueda, H. (2008) Peripheral mechanisms of neuropathic pain — involve-
ment of lysophosphatidic acid receptor-mediated demyelination. Mol Pain
4, 11. 10.1186/1744-8069-4-11.
[13] 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.
[14] 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.
[15] Ruscheweyh, R. et al. (2011) Long-term potentiation in spinal nociceptive
pathways as a novel target for pain therapy. Mol Pain 7, 20. 10.1186/
1744-8069-7-20.
[16] Zhuo, M. (2008) Cortical excitation and chronic pain. Trends Neurosci 31,
199–207. 10.1016/j.tins.2008.01.003.
[17] Wu, L.J. et al. (2005) Kainate receptor-mediated synaptic transmission in
the adult anterior cingulate cortex. J Neurophysiol 94, 1805–1813. 10.1152/
jn.00091.2005.
[18] Zhao, M.G. et al. (2006) Enhanced presynaptic neurotransmitter release in
the anterior cingulate cortex of mice with chronic pain. J Neurosci 26,
8923–8930. 10.1523/JNEUROSCI.2103-06.2006.
[19] Xu, H. et al. (2008) Presynaptic and postsynaptic amplifications of neuro-
pathic pain in the anterior cingulate cortex. J Neurosci 28, 7445–7453.
10.1523/JNEUROSCI.1812-08.2008.
[20] Metz, A.E. et al. (2009) Morphological and functional reorganization of rat
medial prefrontal cortex in neuropathic pain. Proc Natl Acad Sci U S A 106,
2423–2428. 10.1073/pnas.0809897106.
[21] Bird, G.C. et al. (2005) Protein kinase A-dependent enhanced NMDA
receptor function in pain-related synaptic plasticity in rat amygdala neurones. J Physiol 564, 907–921. 10.1113/jphysiol.2005.084780.
[22] Neugebauer, V. and Li, W. (2003) Differential sensitization of amygdala
neurons to afferent inputs in a model of arthritic pain. J Neurophysiol 89,
716–727. 10.1152/jn.00799.2002.
[23] Calejesan, A.A. et al. (2000) Descending facilitatory modulation of a
behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur J Pain 4, 83–96. 10.1053/eujp.1999.0158.
[24] Zhuo, M. and Gebhart, G.F. (2002) Modulation of noxious and non-noxious
spinal mechanical transmission from the rostral medial medulla in the rat.
J Neurophysiol 88, 2928–2941. 10.1152/jn.00005.2002.
Current Drug and Novel Drug Target for Treating Chronic Pain 321
https://t.me/medicina_free
[25] Zhuo, M. et al. (2002) Biphasic modulation of spinal visceral nociceptive
transmission from the rostroventral medial medulla in the rat. J Neurophysiol
87, 2225–2236. 10.1152/jn.2002.87.5.2225.
[26] Gebhart, G.F. (2004) Descending modulation of pain. Neurosci Biobehav
Rev 27, 729–737. 10.1016/j.neubiorev.2003.11.008.
[27] Bliss, T.V. and Collingridge, G.L. (1993) A synaptic model of memory:
Long-term potentiation in the hippocampus. Nature 361, 31–39. 10.1038/
361031a0.
[28] Collingridge, G.L. and Bliss, T.V. (1995) Memories of NMDA receptors
and LTP. Trends Neurosci 18, 54–56.
[29] Wei, F. et al. (2001) Genetic enhancement of inflammatory pain by fore-
brain NR2B overexpression. Nat Neurosci 4, 164–169. 10.1038/83993.
[30] Zhuo, M. (2002) Glutamate receptors and persistent pain: Targeting
forebrain NR2B subunits. Drug Discov Today 7, 259–267. 10.1016/
s1359-6446(01)02138-9.
[31] Wu, L.J. and Zhuo, M. (2009) Targeting the NMDA receptor subunit NR2B
for the treatment of neuropathic pain. Neurotherapeutics 6, 693–702.
10.1016/j.nurt.2009.07.008.
[32] Zhuo, M. (2009) Plasticity of NMDA receptor NR2B subunit in memory
and chronic pain. Mol Brain 2, 4. 10.1186/1756-6606-2-4.
[33] Wei, F. et al. (2002) Genetic elimination of behavioral sensitization in mice
lacking calmodulin-stimulated adenylyl cyclases. Neuron 36, 713–726.
10.1016/s0896-6273(02)01019-x.
[34] Wong, S.T. et al. (1999) Calcium-stimulated adenylyl cyclase activity is
critical for hippocampus-dependent long-term memory and late phase LTP.
Neuron 23, 787–798. 10.1016/s0896-6273(01)80036-2.
[35] Han, J.S. et al. (2010) Facilitation of synaptic transmission and pain
responses by CGRP in the amygdala of normal rats. Mol Pain 6, 10.
10.1186/1744-8069-6-10.
[36] Sharif-Naeini, R. and Basbaum, A.I. (2011) Targeting pain where it resides
... In the brain. Sci Transl Med 3, 65ps61. 10.1126/scitranslmed.3002077.
[37] Tang, J. et al. (2005) Pavlovian fear memory induced by activation in the
anterior cingulate cortex. Mol Pain 1, 6. 10.1186/1744-8069-1-6.
[38] Zhang, Y. et al. (2011) Induction and requirement of gene expression in the
anterior cingulate cortex and medial prefrontal cortex for the consolidation
of inhibitory avoidance memory. Mol Brain 4, 4. 10.1186/1756-6606-4-4.
[39] Wu, L.J. et al. (2005) Upregulation of forebrain NMDA NR2B receptors
contributes to behavioral sensitization after inflammation. J Neurosci 25,
11107–11116. 10.1523/JNEUROSCI.1678-05.2005.
322 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
[40] Wei, F. et al. (1999) Loss of synaptic depression in mammalian anterior
cingulate cortex after amputation. J Neurosci 19, 9346–9354.
[41] Zhao, M.G. et al. (2005) Roles of NMDA NR2B subtype receptor in pre-
frontal long-term potentiation and contextual fear memory. Neuron 47,
859–872. 10.1016/j.neuron.2005.08.014.
[42] Wei, F. et al. (2002) Calcium calmodulin-dependent protein kinase IV is
required for fear memory. Nat Neurosci 5, 573–579. 10.1038/nn0602-855.
[43] Frey, U. et al. (1993) Effects of cAMP simulate a late stage of LTP in hip-
pocampal CA1 neurons. Science 260, 1661–1664. 10.1126/science.
8389057.
[44] Nguyen, P.V. et al. (1994) Requirement of a critical period of transcription
for induction of a late phase of LTP. Science 265, 1104–1107. 10.1126/
science.8066450.
[45] Huang, Y.Y. et al. (1996) Mice lacking the gene encoding tissue-type plas-
minogen activator show a selective interference with late-phase long-term
potentiation in both Schaffer collateral and mossy fiber pathways. Proc Natl
Acad Sci USA 93, 8699–8704. 10.1073/pnas.93.16.8699.
[46] Kandel, E.R. (2001) The molecular biology of memory storage: A dialogue
between genes and synapses. Science 294, 1030–1038. 10.1126/science.
1067020.
[47] Li, X.Y. et al. (2010) Alleviating neuropathic pain hypersensitivity by
inhibiting PKMzeta in the anterior cingulate cortex. Science 330, 1400–
1404. 10.1126/science.1191792.
[48] Chen, T. et al. (2014) Adenylyl cyclase subtype 1 is essential for late-phase
long term potentiation and spatial propagation of synaptic responses in the
anterior cingulate cortex of adult mice. Mol Pain 10, 65. 10.1186/
1744-8069-10-65.
[49] Gurwitz, D. and Weizman, A. (2002) The NR2B subunit of glutamate
receptors as a potential target for relieving chronic pain: Prospects and
concerns. Drug Discov Today 7, 403–406. 10.1016/s1359-6446(02)
02242-0.
[50] Xia, Z. and Storm, D.R. (1997) Calmodulin-regulated adenylyl
cyclases and neuromodulation. Curr Opin Neurobiol 7, 391–396. 10.1016/
s0959-4388(97)80068-2.
[51] Liauw, J. et al. (2005) Calcium-stimulated adenylyl cyclases required for
long-term potentiation in the anterior cingulate cortex. J Neurophysiol 94,
878–882. 10.1152/jn.01205.2004.
Current Drug and Novel Drug Target for Treating Chronic Pain 323
https://t.me/medicina_free
[52] Wang, H. et al. (2011) Identification of an adenylyl cyclase inhibitor for
treating neuropathic and inflammatory pain. Sci Transl Med 3, 65ra63.
10.1126/scitranslmed.3001269.
[53] Vadakkan, K.I. et al. (2006) Genetic reduction of chronic muscle pain in
mice lacking calcium/calmodulin-stimulated adenylyl cyclases. Mol Pain 2,
7. 10.1186/1744-8069-2-7.
[54] Wang, G.D. and Zhuo, M. (2002) Synergistic enhancement of glutamate-
mediated responses by serotonin and forskolin in adult mouse spinal dorsal
horn neurons. J Neurophysiol 87, 732–739. 10.1152/jn.00423.2001.
[55] Wei, F. et al. (2006) Calcium calmodulin-stimulated adenylyl cyclases con-
tribute to activation of extracellular signal-regulated kinase in spinal dorsal
horn neurons in adult rats and mice. J Neurosci 26, 851–861. 10.1523/
JNEUROSCI.3292-05.2006.
[56] Koga, K. et al. (2010) In vivo whole-cell patch-clamp recording of sensory
synaptic responses of cingulate pyramidal neurons to noxious mechanical
stimuli in adult mice. Mol Pain 6, 62. 10.1186/1744-8069-6-62.
[57] Vadakkan, K.I. et al. (2005) A behavioral model of neuropathic pain
induced by ligation of the common peroneal nerve in mice. J Pain 6,
747–756. 10.1016/j.jpain.2005.07.005.
[58] Descalzi, G. et al. (2009) Presynaptic and postsynaptic cortical mechanisms
of chronic pain. Mol Neurobiol 40, 253–259. 10.1007/s12035-009-8085-9.
[59] Esteban, J.A. et al. (2003) PKA phosphorylation of AMPA receptor subu-
nits controls synaptic trafficking underlying plasticity. Nat Neurosci 6,
136–143. 10.1038/nn997.
[60] Wu, L.J. et al. (2008) Enhancement of presynaptic glutamate release and
persistent inflammatory pain by increasing neuronal cAMP in the anterior
cingulate cortex. Mol Pain 4, 40. 10.1186/1744-8069-4-40.
[61] Sacktor, T.C. (2008) PKMzeta, LTP maintenance, and the dynamic
molecular biology of memory storage. Prog Brain Res 169, 27–40. 10.1016/
S0079-6123(07)00002-7.
[62] Naik, M.U. et al. (2000) Distribution of protein kinase Mzeta and the com-
plete protein kinase C isoform family in rat brain. J Comp Neurol 426,
243–258. 10.1002/1096-9861(20001016)426:2<243::aid-cne6>3.0.co;2-8.
[63] Pierre, S. et al. (2009) Capturing adenylyl cyclases as potential drug targets.
Nat Rev Drug Discov 8, 321–335. 10.1038/nrd2827.
[64] Pavan, B. et al. (2009) Adenylyl cyclases as innovative therapeutic goals.
Drug Discov Today 14, 982–991. 10.1016/j.drudis.2009.07.007.
324 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
[65] Han, J.S. (2011) Acupuncture analgesia: Areas of consensus and contro-
versy. Pain 152, S41–S48. 10.1016/j.pain.2010.10.012.
[66] Liu, M.G. and Zhuo, M. (2014) No requirement of TRPV1 in long-term
potentiation or long-term depression in the anterior cingulate cortex. Mol
Brain 7, 27. 10.1186/1756-6606-7-27.
[67] Koga, K. et al. (2015) Coexistence of two forms of LTP in ACC provides a
synaptic mechanism for the interactions between anxiety and chronic pain.
Neuron 86, 1109. 10.1016/j.neuron.2015.05.016.
[68] Liu, S.B. et al. (2020) Cyclic AMP-dependent positive feedback signaling
pathways in the cortex contributes to visceral pain. J Neurochem 153,
252–263. 10.1111/jnc.14903.
[69] Xia, Z. and Storm, D.R. (2005) The role of calmodulin as a signal integrator
for synaptic plasticity. Nat Rev Neurosci 6(4), 267–276.
Index
https://t.me/medicina_free
AC1, 128, 169, 170, 187, 199, 300,
305
adenylyl cyclase (AC), 13
AMPA receptor, 106, 118
amputation, 156
amygdala, 211, 243
analgesia, 292
anterior cingulate cortex (ACC), xiii,
6, 23, 112, 117, 143, 150, 162,
164, 165, 185, 186, 245, 247, 267
anxiety, 240
basolateral amygdala (BLA), 212
Ca2+/calmodulin-dependent protein
kinase type IV (CaMKIV), 123
CaMKIV, 220
cAMP, 101, 105
central amygdala (CeA), 212
central nervous system (CNS), 3, 4, 6
chronic pain, 113, 115, 116, 184,
237, 239, 286, 288, 299
cold, 39
cortical reorganization, 163, 164
CREB, 123, 220
CREB binding protein (CBP), 124
descending facilitation, 267, 268
descending inhibition, 267, 271
descending modulation, 25
DRG, 36, 41
fear memory, 212
5-HT, 274
gate control, 54
gene, 12
GluN2B, 186
glutamate, 56, 74, 89, 95, 101
heat, 35, 37
hippocampus, 210, 211
hyperalgesia, 44, 46
IC, 113, 190, 191, 197
inflammatory pain, 286, 298
insular cortex, 132
itch, 41
kainate (KA), 54, 240, 246, 251
325
Соседние файлы в папке Библиотека им академика М.И. Перельмана