Hutchinson Mark R, Coats Benjamen D, Lewis Susannah S, Zhang Yingning, Sprunger David B, Rezvani Niloofar, Baker Eric M, Jekich Brian M, Wieseler Julie L, Somogyi Andrew A, Martin David, Poole Stephen, Judd Charles M, Maier Steven F, Watkins Linda R
Department of Psychology and The Center for Neuroscience, Campus Box 345, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Brain Behav Immun. 2008 Nov;22(8):1178-89. doi: 10.1016/j.bbi.2008.05.004. Epub 2008 Jul 2.
Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring < or =5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.
脊髓促炎细胞因子是强大的疼痛增强信号，可导致周围神经损伤后疼痛（神经性疼痛）。最近，一种促炎细胞因子白细胞介素-1也被认为与反复暴露于吗啡后镇痛作用丧失（耐受性）有关。与先前的文献不同，我们证明几种脊髓促炎细胞因子的作用与全身和鞘内阿片类药物镇痛作用相反，导致疼痛抑制减弱。体外吗啡暴露于腰段背侧脊髓可导致促炎细胞因子和趋化因子释放显著增加。促炎细胞因子对镇痛作用的拮抗作用迅速，在鞘内（脊髓周围）给予阿片类药物后≤5分钟内发生。我们证明促炎细胞因子对镇痛作用的拮抗作用不能用脊髓吗啡浓度的改变来解释。促炎细胞因子的急性抗镇痛作用以p38丝裂原活化蛋白激酶和一氧化氮依赖的方式发生。慢性鞘内注射吗啡或美沙酮可显著增加脊髓胶质细胞活化（Toll样受体4 mRNA和蛋白）以及多种趋化因子和细胞因子的表达，同时伴有镇痛耐受性和疼痛增强（痛觉过敏、异常性疼痛）的发展。统计分析表明，一组细胞因子和趋化因子与疼痛相关的行为变化有关。此外，在先前与神经元功能改变相关的严格吗啡给药方案期间阻断脊髓促炎细胞因子也可减轻疼痛增强，支持促炎细胞因子在这种方案诱导的耐受性中起重要作用。这些数据表明多种阿片类药物诱导的脊髓促炎细胞因子与急性和慢性阿片类药物镇痛作用相反，并为急性阿片类药物镇痛作用的拮抗提供了一种新机制。
