远端脊髓节段星形胶质细胞活化介导神经损伤诱发的播散性疼痛

金思璇; 于宁; 孙丰润; 马超

doi:10.16098/j.issn.0529-1356.2024.02.006

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解剖学报 ›› 2024, Vol. 55 ›› Issue (2) : 167-173. DOI: 10.16098/j.issn.0529-1356.2024.02.006

神经生物学

远端脊髓节段星形胶质细胞活化介导神经损伤诱发的播散性疼痛

金思璇^1,2 于宁^1,2 孙丰润^1,2 马超^1,2*

作者信息 +

Activation of astrocytes in distal segments of the spinal cord mediating widespread pain induced by peripheral nerve injury

JIN Si-xuan^1,2 YU Ning^1,2 SUN Feng-run^1,2 MA Chao^1,2*

Author information +

文章历史 +

摘要

目的探讨中枢神经系统中远端脊髓节段胶质细胞活化与播散性疼痛的关系。方法 50只雌性大鼠随机分为假手术(sham)组、眶下神经慢性压迫性损伤(CCI-ION)组、CCI-ION+米诺环素(Mino)组、CCI-ION+L-2-氨基己二酸(LAA)组和CCI-ION+生理盐水(NS)组，每组n=10。建立CCI-ION模型，鞘内注射Mino、LAA和生理盐水，利用免疫荧光染色分别检测延髓、颈段、胸段、腰段脊髓节段中活化的星形胶质细胞标记物自身免疫性胶质纤维酸性蛋白(GFAP)和小胶质细胞标记物离子钙结合衔接分子1(IBA1)；在第7、14、21、28天，使用von Frey 纤维丝评估大鼠触须垫机械痛阈值，并采用电子von Frey仪测量大鼠前足、胸部及后足机械痛阈值，用辐射热痛刺激仪测量大鼠后足热痛阈值。结果结果显示，鞘内注射Mino抑制小胶质细胞后，各脊髓节段活化的小胶质细胞减少，鞘内注射LAA抑制星形胶质细胞后，各脊髓节段活化的星形胶质细胞减少，且注射Mino和LAA后，模型组大鼠触须垫机械痛阈升高，损伤部位的神经病理性疼痛缓解。鞘内注射Mino后，模型组大鼠后足热痛阈和机械痛阈未发现明显变化；鞘内注射LAA后，后足热痛阈和机械痛阈显著升高，播散性疼痛缓解。结论远端脊髓节段星形胶质细胞活化介导外周神经损伤诱发的播散性疼痛。

Abstract

Objective To discuss the relationship between activated glia cells in distal segment of the spinal cord and widespread pain. Methods Fifty female rats were randomly divided into sham group, the chronic constriction injury of the infraorbital nerve (CCI-ION) group, CCI-ION + minocycline (Mino) group, CCI-ION + L-2-aminoadipic acid (LAA) group, and CCI-ION + normal saline (NS) group, n=10 for each group. CCI-ION model was established and Mino, LAA, and normal saline were delivered intrathecally to CCI-ION rats. Immunofluorescence staining was used to detect activated astrocytes and microglia in the medulla oblongata, cervical, thoracic, and lumbar spinal cord segments. On the 7th, 14th, 21st, 28th day, von Frey filaments were used to evaluate the mechanical withdrawal threshold of vibrissa pad, and electronic von Frey tactile pain meter was used to measure the mechanical withdrawal threshold of front paw, chest and hind paw. The radiant thermal stimulator was used to measure the thermal withdrawal threshold of hind paw. Results After intrathecal injection of Mino to inhibit microglia, the activated microglia in each spinal cord segment decreased. Moreover, inhibiting astrocytes by using LAA significantly reduced activated astrocytes in spinal dorsal horn from distal segments. Behavioral assay showed that after intrathecal injection of Mino and LAA, the mechanical allodynia of vibrissa pad in CCI-ION rats was relieved. However, there was no significant difference (P>0.05)in the thermal and mechanical withdrawal thresholds in the hind paw of CCI-ION rats after intrathecal injection of Mino, while intrathecal injection of LAA significantly increased the thermal and mechanical withdrawal thresholds in the hind paw, indicating the relief of widespread pain induced by CCI-ION. Conclusion The activated astrocytes in distal segments of the spinal cord mediated CCI-ION-induced widespread pain.

导出引用

金思璇于宁孙丰润马超. 远端脊髓节段星形胶质细胞活化介导神经损伤诱发的播散性疼痛[J]. 解剖学报. 2024, 55(2): 167-173 https://doi.org/10.16098/j.issn.0529-1356.2024.02.006

JIN Si-xuan YU Ning SUN Feng-run MA Chao. Activation of astrocytes in distal segments of the spinal cord mediating widespread pain induced by peripheral nerve injury[J]. Acta Anatomica Sinica. 2024, 55(2): 167-173 https://doi.org/10.16098/j.issn.0529-1356.2024.02.006

中图分类号： R322.81

参考文献

［1］Raja SN, Carr DB, Cohen M, et al. The revised international association for the study of pain definition of pain: concepts, challenges, and compromises ［J］. Pain, 2020, 161(9): 1976-1982.

［2］Türp JC, Kowalski CJ, O’leary N, et al. Pain maps from facial pain patients indicate a broad pain geography ［J］. J Dent Res, 1998, 77(6): 1465-1472.

［3］Chen H, Slade G, Lim PF, et al. Relationship between temporomandibular disorders, widespread palpation tenderness, and multiple pain conditions: a case-control study ［J］. J Pain, 2012, 13(10): 1016-1027.

［4］Hu TT, Wang RR, Tang YY, et al. TLR4 deficiency abrogated widespread tactile allodynia, but not widespread thermal hyperalgesia and trigeminal neuropathic pain after partial infraorbital nerve transection ［J］. Pain, 2018, 159(2): 273-283.

［5］Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances ［J］. The Lancet, 2021, 397(10289): 2082-2097.

［6］Ji RR, Nackley A, Huh Y, et al. Neuroinflammation and central sensitization in chronic and widespread pain ［J］. Anesthesiology, 2018, 129(2): 343-366.

［7］Loeser JD, Melzack R. Pain: an overview ［J］. The Lancet, 1999, 353(9164): 1607-1609.

［8］Gundersen V, Storm-mathisen J, Bergersen LH. Neuroglial transmission ［J］. Physiol Rev, 2015, 95(3): 695-726.

［9］Donnelly CR, Andriessen AS, Chen G, et al. Central nervous system targets: glial cell mechanisms in chronic pain ［J］. Neurotherapeutics, 2020, 17(3): 846-860.

［10］Zhang SH, Yu J, Lou GD, et al. Widespread pain sensitization after partial infraorbital nerve transection in MRL/MPJ mice ［J］. Pain, 2016, 157(3): 740-749.

［11］John MT, Miglioretti DL, Leresche L, et al. Widespread pain as a risk factor for dysfunctional temporomandibular disorder pain ［J］. Pain, 2003, 102(3): 257-263.

［12］Dominguez CA, Kouya PF, Wu WP, et al. Sex differences in the development of localized and spread mechanical hypersensitivity in rats after injury to the infraorbital or sciatic nerves to create a model for neuropathic pain ［J］. Gender Medicine, 2009, 6: 225-234.

［13］Castro A, Li Y, Raver C, et al. Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons ［J］. Pain, 2017, 158(7): 1366-1372.

［14］Zhou YQ, Liu DQ, Chen SP, et al. Minocycline as a promising therapeutic strategy for chronic pain ［J］. Pharmacol Res, 2018, 134: 305-310.

［15］Khurgel M, Koo AC, Ivy GO. Selective ablation of astrocytes by intracerebral injections of alpha-aminoadipate ［J］. Glia, 1996, 16(4): 351-58.

［16］Vos BP, Strassman AM, Maciewicz RJ. Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve ［J］. J Neurosci, 1994, 14(5 Pt 1): 2708-2723.

［17］Zhu A, Shen L, Xu L, et al. Wnt5a mediates chronic post-thoracotomy pain by regulating non-canonical pathways, nerve regeneration, and inflammation in rats ［J］. Cell Signal, 2018, 44: 51-61.

［18］Yuan H, Duan L, Rao ZhR. The response of astrocytes in the caudal trigeminal nucleus of rats to pain stimuli and their relationship with neurons ［J］. Acta Anatomicala Sinica, 2003，34 (6): 563-567. (in Chinese)

袁华, 段丽, 饶志仁.大鼠三叉神经尾侧亚核内星形胶质细胞对疼痛刺激的反应及与神经元的关系［J］.解剖学报, 2003，34(6): 563-567.

［19］Fu KY, Light AR, Matsushima GK, et al. Microglial reactions after subcutaneous formalin injection into the rat hind paw ［J］. Brain Res, 1999, 825(1-2): 59-67.

［20］Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation ［J］. Science, 2016, 354(6312): 572-577.

［21］Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain ［J］. Nat Rev Drug Discov, 2014, 13(7): 533-548.

［22］Ji RR, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch ［J］. Nat Rev Neurosci, 2019, 20(11): 667-685.

［23］Jiang BC, Cao DL, Zhang X, et al. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5 ［J］. J Clin Invest, 2016, 126(2): 745-761.

［24］Mah W, Lee SM, Lee J, et al. A role for the purinergic receptor P2X(3) in astrocytes in the mechanism of craniofacial neuropathic pain ［J］. Sci Rep, 2017, 7(1): 13627.

［25］Xie YF, Zhang S, Chiang CY, et al. Involvement of glia in central sensitization in trigeminal subnucleus caudalis (medullary dorsal horn) ［J］. Brain Behav Immun, 2007, 21(5): 634-641.