Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids.
Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids.
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DOI：
10.1523/jneurosci.2391-10.2010
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发表时间：
2010-11-17
期刊：
影响因子：
--
通讯作者：
Salvemini D
中科院分区：
文献类型：
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作者：
Muscoli C;Doyle T;Dagostino C;Bryant L;Chen Z;Watkins LR;Ryerse J;Bieberich E;Neumman W;Salvemini D
阿片类药物用于疼痛控制的临床疗效受到镇痛耐受和痛觉过敏的严重限制。在此，我们表明，慢性吗啡上调鞘脂神经酰胺在脊髓星形胶质细胞和小胶质细胞，但不是神经元，和脊髓鞘氨醇-1-磷酸（S1 P），神经酰胺代谢的最终产物。共同管理吗啡与鞘内给药的神经酰胺和S1 P的药理学抑制剂阻断脊髓S1 P的形成和发展的痛觉过敏和耐受大鼠。我们的研究结果表明，脊髓形成的S1 P信号至少部分是通过1）调节神经胶质功能，因为抑制S1 P的形成阻断了神经胶质相关的促炎细胞因子，特别是TNF-α、IL-1β α和IL 6的形成增加，这些细胞因子是已知的神经元兴奋性调节剂，过氧亚硝酸盐介导的翻译后硝化和神经胶质相关酶的失活（谷氨酰胺合成酶和谷氨酸转运体，GLT-1）已知在谷氨酸神经传递中起关键作用。神经酰胺代谢途径的抑制剂可能作为阿片类药物的替代品在缓解慢性疼痛方面具有治疗潜力。
The clinical efficacy of opiates for pain control is severely limited by analgesic tolerance and hyperalgesia. Herein we show that chronic morphine upregulates both the sphingolipid ceramide in spinal astrocytes and microglia, but not neurons, and spinal sphingosine-1-phosphate (S1P), the end-product of ceramide metabolism. Co-administering morphine with intrathecal administration of pharmacological inhibitors of ceramide and S1P blocked formation of spinal S1P and development of hyperalgesia and tolerance in rats. Our results show that spinally formed S1P signals at least in part by 1) modulating glial function, since inhibiting S1P formation blocked increased formation of glial-related pro-inflammatory cytokines, in particular TNF-α, IL-1β α, and IL6, which are known modulators of neuronal excitability, and 2) peroxynitrite-mediated post-translational nitration and inactivation of glial-related enzymes (glutamine synthetase and the glutamate transporter, GLT-1) known to play critical roles in glutamate neurotransmission. Inhibitors of the ceramide metabolic pathway may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.