激活脊髓MrgC受体抑制大鼠痛觉过敏

Activation of spinal Mrg C receptors inhibits hyperalgesia in rats

研究旨在探讨激活脊髓MrgC （Mas-related gene C）受体对痛觉过敏的作用及细胞学机制。在大鼠足底皮下注射（Tyr6）-γ2-MSH-6–12 （MSH）或完全弗氏佐剂（complete Freund’s adjuvant, CFA）形成痛觉过敏或炎性痛模型，通过缩足反射和免疫组织化学等方法观察鞘内给予MrgC受体特异性激动剂MSH或牛肾上腺髓质8-22肽（bovine adrenal medulla 8-22, BAM8-22）对痛觉过敏的影响。结果显示，鞘内给予MSH不影响正常大鼠对热伤害性刺激引起的缩足潜伏期变化，但能抑制足底注射MSH引起的急性痛觉敏感反应，还能降低CFA引起的痛觉过敏，鞘内给予μ阿片受体（μ-opioid receptor, MOR）拮抗剂CTAP （D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2）能阻止鞘内给予MSH的延迟抗痛觉过敏作用。鞘内给予BAM8-22能显著降低CFA引起的脊髓背角L3～L5节段一氧化氮合酶（nitric oxide synthase, NOS）阳性神经元数量和降钙素基因相关肽（calcitonin gene-related peptide, CGRP）样免疫活性物质的表达。以上结果提示，鞘内激活MrgC受体通过抑制NOS阳性神经元活性和下调CGRP阳性产物表达来降低痛觉过敏，并能通过间接机制调制MOR起到延时持续抗痛觉过敏作用。因此，MrgC受体激动剂有望成为一类新型抗炎症痛觉过敏的药物。

This study was aimed to investigate the mechanisms of the modulation effect of activation of spinal Mas-related gene C （MrgC） receptors on hyperalgesia induced by intraplantar （i.pl.） injection of （Tyr6）-γ2-MSH-6–12 （MSH） or complete Freund’s adjuvant （CFA）. Paw withdrawal latency test and immunohistochemistry were used to observe the effect of intrathecal （i.t.） administration of MSH or BAM8-22, two selective agonists of MrgC receptor, in hyperalgesia in rats. The results showed that i.t. administration of MSH inhibited acute hyperalgesic response induced by i.pl. application of MSH, while did not change thermal nociceptive threshold in na？ve rats. The i.t. administration of MSH also attenuated CFA-induced inflammatory hyperalgesia. However, i.t. administration of the μ-opioid receptor （MOR） antagonist CTAP blocked the induction of delayed anti-hyperalgesia by MSH. The i.t. injection of BAM8-22 at a dose of 30 nmol evidently reduced the number of CFA-evoked nitric oxide synthase （NOS）-positive neurons and the expression of calcitonin gene-related peptide （CGRP）-immunoreactivity positive nerve fibers at L3–L5 segments of the spinal cord. These results suggest that the activation of MrgC receptor in CFA-induced inflammation reduces inflammatory hyperalgesia through inactivation of NOS neurons and down-regulation of CGRP expressions, and generates delayed but long-lasting anti-nociception through the endogenous activation of MOR via indirect mechanisms. Agonists for MrgC receptors may, therefore, represent a new class of antihyperalgesics for treating inflammatory pain because of the highly specific expression of their targets.