Li Tang, Wang Haiyun, Wang Jinxin, Chen Yimeng, Yang Chenyi, Zhao Mingshu, Wang Guolin, Yang Zhuo
Department of Anesthesiology, The Third Central Clinical College of Tianjin Medical University, Tianjin the Third Central Hospital, Key labouratory of Artificial Cell, Institute of Hepatobiliary Disease, Engineering Research Centre of Artificial Cell of the Ministry of Health, Tianjin 300170, China.
Department of Anesthesiology, The Third Central Clinical College of Tianjin Medical University, Tianjin the Third Central Hospital, Key labouratory of Artificial Cell, Institute of Hepatobiliary Disease, Engineering Research Centre of Artificial Cell of the Ministry of Health, Tianjin 300170, China.
Neurosci Res. 2019 Jul;144:48-55. doi: 10.1016/j.neures.2018.07.007. Epub 2018 Aug 16.
Chemokines related neuroinflammation and N-methyl-d-aspartate receptor (NMDAR) mediated nociceptive transmission are pivotal determinants in the pathogenesis of opioid-induced hyperalgesia (OIH), but little is known about specific mechanism and treatment. Chemokine CXCL12 with its receptor CXCR4 is implicated in different pathological pain, moreover, neurotoxicity of CXCL12 is associated with NMDAR activation. Recent studies recapitulate the anti-nociception of Annexin 1 (ANXA1) in inflammatory pain. This study examined whether ANXA1 prevented remifentanil-caused OIH through modulating CXCL12 and NMDAR pathway in rats. Acute exposure to remifentanil induced mechanical allodynia and thermal hyperalgesia, which was accompanied by the increase of spinal ANXA1 and CXCL12/CXCR4 expression. Central injection of Anxa1 attenuated behavioral OIH in a dose-dependent manner, facilitated ANXA1 production, and inhibited up-regulation of CXCL12/CXCR4 level and NR2B-containing NMDAR phosphorylation. Moreover, pretreatment with AMD3100 reduced hyperalgesia and NR2B-containing NMDAR phosphorylation. Also, exogenous CXCL12 elicited pain hypersensitivity and NMDAR activation in naïve rats, which was reversed by the supplemental delivery of Anxa1. These current findings indicate the participation of spinal CXCL12/CXCR4 and NR2B-containing NMDAR pathway in anti-hyperalgesic action of ANXA1 in OIH.
趋化因子相关的神经炎症和N-甲基-D-天冬氨酸受体（NMDAR）介导的伤害性感受传递是阿片类药物诱导的痛觉过敏（OIH）发病机制中的关键决定因素，但具体机制和治疗方法尚不清楚。趋化因子CXCL12及其受体CXCR4与不同的病理性疼痛有关，此外，CXCL12的神经毒性与NMDAR激活有关。最近的研究概括了膜联蛋白1（ANXA1）在炎性疼痛中的抗伤害感受作用。本研究探讨了ANXA1是否通过调节大鼠CXCL12和NMDAR途径来预防瑞芬太尼引起的OIH。急性暴露于瑞芬太尼会诱发机械性异常性疼痛和热痛觉过敏，同时伴有脊髓ANXA1和CXCL12/CXCR4表达增加。中枢注射Anxa1以剂量依赖性方式减轻行为性OIH，促进ANXA1产生，并抑制CXCL12/CXCR4水平上调和含NR2B的NMDAR磷酸化。此外，用AMD3100预处理可减轻痛觉过敏和含NR2B的NMDAR磷酸化。同样，外源性CXCL12在未处理的大鼠中引起疼痛超敏反应和NMDAR激活，而补充Anxa1可逆转这种情况。这些当前发现表明脊髓CXCL12/CXCR4和含NR2B的NMDAR途径参与了ANXA1在OIH中的抗痛觉过敏作用。
