小胶质细胞对卒中后中枢性疼痛调节机制的研究进展

doi:10.3969/j.issn.1673-5765.2024.08.015

摘要/Abstract

摘要： 卒中后中枢性疼痛（central post-stroke pain，CPSP）是常见的卒中并发的神经病理性疼痛综合征，严重影响卒中患者的后期康复和生活质量。近年来，CPSP的病理机制研究逐渐受到重视，而小胶质细胞作为颅内常驻的巨噬细胞，被认为在CPSP发生发展中起重要调节作用。本篇综述从生物活性因子、细胞受体和信号通路等角度总结了近年来小胶质细胞调节CPSP的研究进展，描述了多个化合物对CPSP的临床前治疗作用，以期促进CPSP靶向治疗策略的发展。

文章导读： 本文总结了近年来小胶质细胞调节卒中后中枢性疼痛的研究进展，以及多种化合物对CPSP的临床前治疗作用。

关键词: 卒中后中枢性疼痛; 小胶质细胞; 神经炎症

Abstract: Central post-stroke pain (CPSP) is a common neuropathic pain syndrome associated with stroke, which severely affects the outcome and life quality of stroke patients. In recent years, more and more attention has been paid to the study of the pathological mechanism of CPSP. Microglia, the resident macrophage within the central nervous system, is considered to play a critical role in the development of CPSP. The present review summarized recent research progress of microglia in mediating CPSP from the perspective of bioactive factors, cellular receptors, and signaling pathways, and described the preclinical therapeutic effects of several compounds on CPSP, hoping to promote the development of targeted therapeutic strategies for CPSP.

Key words: Central post-stroke pain; Microglia; Neuroinflammation

中图分类号:

李月容, 秦秀德, 党朝晖, 陆韵薇, 蔡甜甜, 蔡浩斌, 卜凡.

小胶质细胞对卒中后中枢性疼痛调节机制的研究进展 [J]. 中国卒中杂志, 2024, 19(8): 967-972.

LI Yuerong, QIN Xiude, DANG Zhaohui, LU Yunwei, CAI Tiantian, CAI Haobin, BU Fan.

Research Progress of Microglia on Mediating Central Post-Stroke Pain [J]. Chinese Journal of Stroke, 2024, 19(8): 967-972.

参考文献

[1] YANG F，FU H，LU Y F，et al. Post-stroke pain hypersensitivity induced by experimental thalamic hemorrhage in rats is region-specific and demonstrates limited efficacy of gabapentin[J]. Neurosci Bull，2014，30（6）：887-902.

[2] LIAMPAS A，VELIDAKIS N，GEORGIOU T，et al. Prevalence and management challenges in central post-stroke neuropathic pain：a systematic review and meta-analysis[J]. Adv Ther，2020，37（7）：3278-3291.

[3] KLIT H，FINNERUP N B，JENSEN T S. Central post-stroke pain：clinical characteristics，pathophysiology，and management[J]. Lancet Neurol，2009，8（9）：857-868.

[4] JÖNSSON A C，LINDGREN I，HALLSTRÖM B，et al. Prevalence and intensity of pain after stroke：a population based study focusing on patients’ perspectives[J]. J Neurol Neurosurg Psychiatry，2006，77（5）：590-595.

[5] WIDAR M，AHLSTRÖM G，EK A C. Health-related quality of life in persons with long-term pain after a stroke[J]. J Clin Nurs，2004，13（4）：497-505.

[6] WIDAR M，EK A C，AHLSTRÖM G. Coping with long-term pain after a stroke[J]. J Pain Symptom Manage，2004，27（3）：215-225.

[7] SAIJO K，GLASS C K. Microglial cell origin and phenotypes in health and disease[J]. Nat Rev Immunol，2011，11（11）：775-787.

[8] ELLIS A，BENNETT D L H. Neuroinflammation and the generation of neuropathic pain[J]. Br J Anaesth，2013，111（1）：26-37.

[9] TANG Y，LE W D. Differential roles of M1 and M2 microglia in neurodegenerative diseases[J]. Mol Neurobiol，2016，53（2）：1181-1194.

[10] YENARI M A，KAUPPINEN T M，SWANSON R A. Microglial activation in stroke：therapeutic targets[J]. Neurotherapeutics，2010，7（4）：378-391.

[11] WANG J，XING H Y，WAN L，et al. Treatment targets for M2 microglia polarization in ischemic stroke[J/OL]. Biomed Pharmacother，2018，105：518-525[2023-11-01]. https://doi.org/10.1016/j.biopha.2018.05.143.

[12] PONOMAREV E D，VEREMEYKO T，WEINER H L. MicroRNAs are universal regulators of differentiation，activation，and polarization of microglia and macrophages in normal and diseased CNS[J]. Glia，2013，61（1）：91-103.

[13] QIN C，ZHOU L Q，MA X T，et al. Dual functions of microglia in ischemic stroke[J]. Neurosci Bull，2019，35（5）：921-933.

[14] CALVO M，DAWES J M，BENNETT D L H. The role of the immune system in the generation of neuropathic pain[J]. Lancet Neurol，2012，11（7）：629-642.

[15] HANADA T，KURIHARA T，TOKUDOME M，et al. Development and pharmacological verification of a new mouse model of central post-stroke pain[J/OL]. Neurosci Res，2014，78：72-80[2023-11-01]. https://doi.org/10.1016/j.neures.2013.09.005.

[16] HIRAGA S I，ITOKAZU T，HOSHIKO M，et al. Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting[J/OL]. JCI Insight，2020，5（3）：e131801[2023-11-01]. https://doi.org/10.1172/jci.insight.131801.

[17] ABBRACCHIO M P，BURNSTOCK G. Purinoceptors：are there families of P2X and P2Y purinoceptors？[J]. Pharmacol Ther，1994，64（3）：445-475.

[18] TSUDA M，KUBOYAMA K，INOUE T，et al. Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays[J/OL].
Mol Pain，2009，5：28[2023-11-01]. https://doi.org/10.1186/1744-8069-5-28.

[19] TSUDA M，INOUE K，SALTER M W. Neuropathic pain and spinal microglia：a big problem from molecules in“small”glia[J]. Trends Neurosci，2005，28（2）：101-107.

[20] TSUDA M，SHIGEMOTO-MOGAMI Y，KOIZUMI S，et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury[J]. Nature，2003，424（6950）：778-783.

[21] ULMANN L，HATCHER J P，HUGHES J P，et al. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain[J]. J Neurosci，2008，28（44）：11263-11268.

[22] COULL J A M，BEGGS S，BOUDREAU D，et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain[J]. Nature，2005，438（7070）：1017-1021.

[23] TRANG T，BEGGS S，WAN X，et al. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation[J]. J Neurosci，2009，29（11）：3518-3528.

[24] LU H F，XU C Y，ZHANG L，et al. A new central post-stroke pain rat model：autologous blood injected thalamic hemorrhage involved increased expression of P2X4 receptor[J/OL]. Neurosci Lett，2018，687：124-130
[2023-11-01]. https://doi.org/10.1016/j.neulet.2018.09.023.

[25] BROUGH D，LE FEUVRE R A，IWAKURA Y，et al. Purinergic（P2X7）receptor activation of microglia induces cell death via an interleukin-1-independent mechanism[J]. Mol Cell Neurosci，2002，19（2）：272-280.

[26] MONIF M，BURNSTOCK G，WILLIAMS D A. Microglia：proliferation and activation driven by the P2X7 receptor[J]. Int J Biochem Cell Biol，2010，42（11）：1753-1756.

[27] PELEGRIN P，SURPRENANT A. The P2X7 receptor-pannexin connection to dye uptake and IL-1β release[J]. Purinergic Signal，2009，5（2）：129-137.

[28] KUAN Y H，SHIH H C，TANG S C，et al. Targeting P2X7 receptor for the treatment of central post-stroke pain in a rodent model[J/OL]. Neurobiol Dis，2015，78：134-145[2023-11-01]. https://doi.org/10.1016/j.nbd.
2015.02.028.

[29] BRUZZONE R，HORMUZDI S G，BARBE M T，et al. Pannexins，a family of gap junction proteins expressed in brain[J]. Proc Natl Acad Sci U S A，2003，100（23）：13644-13649.

[30] BURMA N E，BONIN R P，LEDUC-PESSAH H，et al. Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents[J]. Nat Med，2017，23（3）：355-360.

[31] SHESTOPALOV V I，SLEPAK V Z. Molecular pathways of pannexin1-mediated neurotoxicity[J/OL]. Front Physiol，2014，5：23[2023-11-01]. https://doi.org/10.3389/fphys.2014.00023.

[32] BU F，LI Y R，LAN S M，et al. Blocking pannexin-1 channels alleviates thalamic hemorrhage-induced pain and inflammatory depolarization of microglia in mice[J]. ACS Chem Neurosci，2023，14（14）：2548-2559.

[33] RéAUX-LE GOAZIGO A，VAN STEENWINCKEL J，ROSTèNE W，et al. Current status of chemokines in the adult CNS[J/OL]. Prog Neurobiol，2013，104：67-92[2023-11-01]. https://doi.org/10.1016/j.pneurobio.2013.02.001.

[34] REAUX-LE GOAZIGO A，RIVAT C，KITABGI P，et al. Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures：physiological relevance[J]. Eur J Neurosci，2012，36（5）：2619-2631.

[35] LI X Q，ZHANG Z L，TAN W F，et al. Down-regulation of CXCL12/CXCR4 expression alleviates ischemia-reperfusion-induced inflammatory pain via inhibiting glial TLR4 activation in the spinal cord
[J/OL]. PloS One，2016，11（10）：e0163807[2023-11-01].
https://doi.org/10.1371/journal.pone.0163807.

[36] SHEN W，HU X M，LIU Y N，et al. CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord[J/OL]. J Neuroinflammation，2014，11：75[2023-11-01]. https://doi.org/10.1186/1742-2094-11-75.

[37] LUO X，TAI W L，SUN L T，et al. Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain[J/OL]. Mol Pain，2016，12：1744806916636385[2023-11-01]. https://doi.org/10.1177/1744806916636385.

[38] YANG F，LUO W J，SUN W，et al. SDF1-CXCR4 signaling maintains central post-stroke pain through mediation of glial-neuronal interactions[J/OL]. Front Mol Neurosci，2017，10：226[2023-11-01]. https://doi.org/10.3389/fnmol.2017.00226.

[39] LIANG T，CHEN X F，YANG Y，et al. Secondary damage and neuroinflammation in the spinal dorsal horn mediate post-thalamic hemorrhagic stroke pain hypersensitivity：SDF1-CXCR4 signaling mediation
[J/OL]. Front Mol Neurosci，2022，15：911476[2023-11-01]. https://doi.org/10.3389/fnmol.2022.911476.

[40] MUESSEL M J，KLEIN R M，WILSON A M，et al. Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration，attenuates microglial activation，and alters expression of cell death molecules[J]. Brain Res Mol Brain Res，2002，103（1/2）：12-27.

[41] YANG F，JING J J，FU S Y，et al. Spinal MCP-1
contributes to central post-stroke pain by inducing central sensitization in rats[J]. Mol Neurobiol，2023，60（4）：2086-2098.

[42] ZHANG J Y，TAKAHASHI H K，LIU K，et al. Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats[J]. Stroke，2011，42（5）：1420-1428.

[43] MATSUURA W，HARADA S，LIU K Y，et al. Evidence of a role for spinal HMGB1 in ischemic stress-induced mechanical allodynia in mice[J/OL]. Brain Res，2018，1687：1-10[2023-11-01]. https://doi.org/10.1016/j.brainres.2018.02.026.

[44] SHI Z M，JING J J，XUE Z J，et al. Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke[J/OL]. J Neuroinflammation，2023，20（1）：82[2023-11-01]. https://doi.org/10.1186/s12974-023-02765-2.

[45] LI S J，ZHANG Y F，MA S H，et al. The role of NLRP3 inflammasome in stroke and central poststroke pain[J/OL]. Medicine（Baltimore），2018，97（33）：e11861[2023-11-01]. https://doi.org/10.1097/MD.0000000000011861.

[46] LOHMAN A W，WEILINGER N L，SANTOS S M，et al. Regulation of pannexin channels in the central nervous system by Src family kinases[J/OL]. Neurosci Lett，2019，695：65-70[2023-11-01]. https://doi.org/10.1016/j.neulet.2017.09.019.

[47] OKADA M. Regulation of the Src family kinases by Csk[J]. Int J Biol Sci，2012，8（10）：1385-1397.

[48] HUANG T F，FU G L，GAO J，et al. Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways[J/OL]. JCI Insight，2020，5（20）：e139987[2023-11-01]. https://doi.org/10.1172/jci.insight.139987.

[49] KANG O H，LEE G H，CHOI H J，et al. Ethyl acetate extract from angelica dahuricae radix inhibits lipopolysaccharide-induced production of nitric oxide，prostaglandin E2 and tumor necrosis factor-α via mitogen-activated protein kinases and nuclear factor-κB in macrophages[J]. Pharmacol Res，2007，55（4）：263-270.

[50] HUNG A L，LIM M，DOSHI T L. Targeting cytokines for treatment of neuropathic pain[J/OL]. Scand J Pain，2017，17：287-293[2023-11-01]. https://doi.org/10.1016/j.sjpain.2017.08.002.

[51] LIU T T，LI T，CHEN X H，et al. EETs/sEHi alleviates nociception by blocking the crosslink between endoplasmic reticulum stress and neuroinflammation in a central poststroke pain model[J/OL]. J Neuroinflammation，2021，18（1）：211[2023-11-01]. https://doi.org/10.1186/s12974-021-02255-3.

[52] INFANTINO R，SCHIANO C，LUONGO L，et al. MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia[J/OL]. Neurobiol Dis，2022，164：105611
[2023-11-01]. https://doi.org/10.1016/j.nbd.2022.105611.