Fu X, Zhu Z-H, Wang Y-Q, Wu G-C
Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, Shanghai Medical College, Fudan University, P.O. Box 291, 138 Yi Xue Yuan Road, Shanghai 200032, China.
Neuroscience. 2007 Jan 5;144(1):275-85. doi: 10.1016/j.neuroscience.2006.09.016. Epub 2006 Oct 25.
Peripheral inflammation induces central sensitization characterized by the development of allodynia and hyperalgesia to thermal stimuli. Recent evidence suggests that activation of glial cells and a subsequent increase in proinflammatory cytokines contribute to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous agonist of the N/OFQ peptide receptor (ORL1 receptor), has been demonstrated to play an important role in modulation of nociceptive signals. In the present study, we investigated: (1) astrocyte activation and proinflammatory cytokine expression at the lumbar spinal cord following intraplantar administration of complete Freund's adjuvant (CFA) in rats; (2) the mechanism of N/OFQ on nociception modulation, the relationship between N/OFQ and cytokines in the rat CNS in vivo and in vitro. The results showed: (1) CFA-induced peripheral inflammation evoked robust astrocyte activation and proinflammatory cytokines spinally; (2) down-regulation of cytokine mRNA transcripts by intrathecal administration of N/OFQ, the effects produced by N/OFQ were abolished by combination with ORL1 receptor-specific antagonist [Nphe(1)]N/OFQ(1-13)NH2; (3) ORL1 receptor was expressed on astrocytes of rat spinal cord; (4) cytokine gene expression was inhibited in astrocyte cultures exposed to N/OFQ, the inhibiting effects of N/OFQ were significantly blocked by [Nphe(1)]N/OFQ(1-13)NH2. The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway.
外周炎症会诱发中枢敏化，其特征为对热刺激出现痛觉过敏和痛觉超敏。最近的证据表明，神经胶质细胞的激活以及随后促炎细胞因子的增加，有助于神经损伤或外周炎症后行为超敏反应的发展。神经肽孤啡肽/孤啡肽FQ（N/OFQ），即N/OFQ肽受体（ORL1受体）的内源性激动剂，已被证明在伤害性信号的调制中起重要作用。在本研究中，我们调查了：（1）在大鼠足底注射完全弗氏佐剂（CFA）后，腰脊髓中星形胶质细胞的激活和促炎细胞因子的表达；（2）N/OFQ对伤害感受调制的机制，以及在体内和体外大鼠中枢神经系统中N/OFQ与细胞因子之间的关系。结果显示：（1）CFA诱导的外周炎症在脊髓中引起强烈的星形胶质细胞激活和促炎细胞因子表达；（2）鞘内注射N/OFQ可下调细胞因子mRNA转录本，与ORL1受体特异性拮抗剂[Nphe(1)]N/OFQ(1-13)NH2联合使用可消除N/OFQ产生的效应；（3）ORL1受体在大鼠脊髓的星形胶质细胞上表达；（4）在暴露于N/OFQ的星形胶质细胞培养物中，细胞因子基因表达受到抑制，[Nphe(1)]N/OFQ(1-13)NH2可显著阻断N/OFQ的抑制作用。目前的数据表明，中枢神经系统中星形胶质细胞的激活和细胞因子表达增强在引发行为超敏反应中起作用；N/OFQ的抗伤害感受功能可能依赖于星形胶质细胞衍生的细胞因子，其效应归因于ORL1受体途径。
