Yang Fei, Jing Jun-Jie, Fu Si-Yin, Su Xiu-Zhu, Zhong Yu-Ling, Chen Dong-Sheng, Wu Xiao-Zhi, Zou Yi-Qing
Department of Anesthesiology and Perioperative Medicine, Fuzong Clinical College/900th Hospital of the Joint Logistic Support Force, Fujian Medical University, Fuzhou, 350025, China.
Department of Anesthesiology and Perioperative Medicine, Dongfang Hospital, Xiamen University, Fuzhou, 350025, China.
Mol Neurobiol. 2023 Apr;60(4):2086-2098. doi: 10.1007/s12035-022-03184-9. Epub 2023 Jan 5.
Central post-stroke pain (CPSP) is a highly refractory form of central neuropathic pain that has been poorly studied mechanistically. Recent observations have emphasized the critical role of the spinal dorsal horn in CPSP. However, the underlying mechanisms remain unclear. In this study, rats were subjected to thalamic hemorrhage to investigate the role of spinal monocyte chemoattractant protein-1 (MCP-1) and C-C motif chemokine receptor 2 (CCR2) in the development of CPSP. Immunohistochemical staining and ELISA were used to assess the expression changes of c-Fos, Iba-1, GFAP, MCP-1, and CCR2 in the dorsal horn of the lumbar spinal cord following thalamic hemorrhage, and the involvement of spinal MCP-1 in CPSP was examined by performing intrathecal anti-MCP-1 mAb injection to neutralize the spinal extracellular MCP-1. We demonstrated that intra-thalamic collagenase microinjection induced persistent bilateral mechanical pain hypersensitivity and facilitated the spontaneous pain behaviors evoked by intraplantar bee venom injection. Accompanying CPSP, the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn was significantly increased up to 28 days post-intra-thalamic collagenase microinjection. Intrathecal injection of minocycline and fluorocitrate dramatically reverses the bilateral mechanical pain hypersensitivity. Moreover, intra-thalamic collagenase microinjection dramatically induced the up-regulation of MCP-1 but had no effect on the expression of CCR2 in the bilateral lumbar spinal dorsal horn, and MCP-1 was primarily localized in the neuron. Intrathecal injection of anti-MCP-1 mAb was also able to reverse CPSP and reduce the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn. These findings indicated that spinal MCP-1 contributes to CPSP by mediating the activation of spinal neurons and glial cells following thalamic hemorrhage stroke, which may provide insights into pharmacologic treatment for CPSP.
中风后中枢性疼痛（CPSP）是一种高度难治的中枢性神经病理性疼痛形式，其发病机制尚未得到充分研究。最近的观察结果强调了脊髓背角在CPSP中的关键作用。然而，其潜在机制仍不清楚。在本研究中，对大鼠进行丘脑出血，以研究脊髓单核细胞趋化蛋白-1（MCP-1）和C-C基序趋化因子受体2（CCR2）在CPSP发生发展中的作用。采用免疫组织化学染色和酶联免疫吸附测定法（ELISA）评估丘脑出血后腰段脊髓背角中c-Fos、离子钙结合衔接分子-1（Iba-1）、胶质纤维酸性蛋白（GFAP）、MCP-1和CCR2的表达变化，并通过鞘内注射抗MCP-1单克隆抗体以中和脊髓细胞外MCP-1，来研究脊髓MCP-1在CPSP中的作用。我们证明，丘脑内胶原酶微量注射可诱导持续的双侧机械性疼痛超敏反应，并促进足底注射蜜蜂毒液诱发的自发疼痛行为。伴随CPSP，在丘脑内胶原酶微量注射后长达28天，腰段脊髓背角中c-Fos、Iba-1和GFAP的表达显著增加。鞘内注射米诺环素和氟柠檬酸可显著逆转双侧机械性疼痛超敏反应。此外，丘脑内胶原酶微量注射可显著诱导双侧腰段脊髓背角中MCP-1的上调，但对CCR2的表达无影响，且MCP-1主要定位于神经元。鞘内注射抗MCP-1单克隆抗体也能够逆转CPSP，并降低腰段脊髓背角中c-Fos、Iba-1和GFAP的表达。这些发现表明，脊髓MCP-1通过介导丘脑出血性中风后脊髓神经元和胶质细胞的激活而导致CPSP，这可能为CPSP的药物治疗提供思路。
