The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia
The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia
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DOI：
10.1111/bph.12895
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发表时间：
2015-01-01
影响因子：
7.3
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Fan, Hui;Gong, Nian;Wang, Yong-Xiang
背景和目的胰高血糖素样肽-1（GLP-1）受体的两种肽激动剂艾塞那肽和GLP-1本身在神经性疼痛、癌症和糖尿病疼痛中发挥抗过敏作用。在这项研究中，我们已经评估了非肽激动剂WB 4 -24在炎症性伤害感受和可能参与的小胶质细胞内啡肽和促炎cytokines.Experimental ApproachWe使用大鼠模型的福尔马林，角叉菜胶或完全弗氏佐剂（CFA）诱导的炎症性伤害感受，测试机械异常性疼痛和热痛觉过敏的抗异常性疼痛和抗痛觉过敏的效果。内啡肽和促炎细胞因子的表达进行了测量，使用实时定量PCR和荧光immunoassays.Key ResultsWB 4 -24取代exendin（9-39）在小胶质细胞的特异性结合。单次鞘内注射WB 4 -24（0.3、1、3、10、30和100 g）对福尔马林、角叉菜胶和CFA诱导的急性和慢性炎性伤害性反应具有剂量依赖性、特异性和抗过敏作用，最大抑制率为60- 80%。脊柱WB 4 -24在改变伤害性疼痛方面无效。皮下注射WB 4 -24在CFA处理的大鼠中也具有抗伤害感受性。WB 4 -24诱发内啡肽释放，但不抑制CFA处理的大鼠脊髓或LPS刺激的培养的小胶质细胞中促炎细胞因子的表达。WB 4 -24抗异常性疼痛被小胶质细胞抑制剂、β-内啡肽抗血清和α-阿片受体拮抗剂所阻止。结论和启示我们的结果表明，WB 4 -24通过释放镇痛-内啡肽而不是抑制脊髓小胶质细胞中促痛促炎细胞因子的表达来抑制炎性伤害感受，并且脊髓GLP-1受体是用于治疗疼痛超敏反应（包括炎性伤害感受）的潜在靶分子。
Background and PurposeTwo peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor, exenatide and GLP-1 itself, exert anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we have assessed the anti-allodynic and anti-hyperalgesic effects of the non-peptide agonist WB4-24 in inflammatory nociception and the possible involvement of microglial -endorphin and pro-inflammatory cytokines.Experimental ApproachWe used rat models of inflammatory nociception induced by formalin, carrageenan or complete Freund's adjuvant (CFA), to test mechanical allodynia and thermal hyperalgesia. Expression of -endorphin and pro-inflammatory cytokines was measured using real-time quantitative PCR and fluorescent immunoassays.Key ResultsWB4-24 displaced the specific binding of exendin (9-39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100g) exerted dose-dependent, specific, anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60-80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 was also antinociceptive in CFA-treated rats. WB4-24 evoked -endorphin release but did not inhibit expression of pro-inflammatory cytokines in either the spinal cord of CFA-treated rats or cultured microglia stimulated by LPS. WB4-24 anti-allodynia was prevented by a microglial inhibitor, -endorphin antiserum and a -opioid receptor antagonist.Conclusions and ImplicationsOur results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic -endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1 receptor is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception.