Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain
Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain
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DOI：
10.1073/pnas.1820466116
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发表时间：
2019-05-21
影响因子：
11.1
通讯作者：
Salvemini, Daniela
中科院分区：
文献类型：
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作者：
Chen, Zhoumou;Doyle, Timothy M.;Salvemini, Daniela
神经病理性疼痛困扰着数以百万计的人，是一个主要的健康问题，对此缺乏有效和安全的治疗方法。新出现的文献将鞘磷脂代谢改变与伤害性加工联系起来。然而，在慢性疼痛的背景下，神经鞘脂信号在中枢神经系统中的神经药理学仍在很大程度上未被探索和争议。我们现在提供的证据表明，神经损伤后脊髓背角产生的鞘氨醇-1-磷酸(S1P)通过选择性地激活星形胶质细胞中的S1P受体亚型(S1PR1)来驱动神经病理性疼痛。因此，在两种创伤性神经损伤模型中，使用不同化学类别的多种拮抗剂而不是激动剂的S1PR1的遗传和药理抑制可以减轻甚至逆转啮齿类动物的神经病理性疼痛。这些S1PR1拮抗剂在持续给药过程中保留了抑制神经病理性疼痛的能力，其作用不依赖于内源性阿片环路。此外，星形胶质细胞特异性S1PR1基因敲除的小鼠在神经损伤后没有出现神经病理性疼痛，从而确定星形胶质细胞是S1PR1活动的主要细胞底物。在分子水平上，抑制S1PR1导致的神经病理性疼痛的有益减轻是由白介素10(IL-10)推动的，白介素10是一种强大的神经保护和抗炎细胞因子。总之，我们的结果提供了基本的神经生物学见解，确定了S1PR1轴参与神经病理性疼痛的细胞和分子机制，并建立了S1PR1作为一类非麻醉性镇痛剂的治疗干预靶点。
Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.