Provincial Key Laboratory of Developmental Biology and Neuroscience, Fujian Normal University, Fuzhou, Fujian, China.
Provincial Key Laboratory of Developmental Biology and Neuroscience, Fujian Normal University, Fuzhou, Fujian, China
J Pharmacol Exp Ther. 2019 Feb;368(2):237-245. doi: 10.1124/jpet.118.252494. Epub 2018 Nov 28.
Glial activation plays a pivotal role in morphine tolerance. This study investigated effects of Mas-related gene (Mrg) C receptor on morphine-induced activation of microglia and astrocytes in the spinal cord and its underlying mechanisms. Intrathecal administration of morphine (20 g, daily) for 6 days induced a great decline in morphine antinociception and increased expression of glial fibrillary acidic protein and OX-42 in the spinal dorsal horn. These changes were greatly attenuated by the intermittent coinjection of bovine adrenal medulla 8-22 (BAM8-22, 1 nmol), a specific agonist of MrgC receptor. These modulatory effects were accompanied by the reduction of P2X and interleukin-1 expressions in the spinal dorsal horn. Chronic morphine increased the expression of fractalkine in medium- and small-sized neurons of dorsal root ganglia (DRG). Treatment with BAM8-22 inhibited these changes as well as an increase in Toll-like receptor 4 (TLR4) protein in DRG. Chronic treatment of DRG explant cultures with morphine (3.3 M, 5 days) increased the levels of fractalkine mRNA. Application of BAM8-22 (10 nM) for 60 minutes completely blocked the increase of fractalkine mRNA induced by morphine. Our findings indicate that the inhibition of morphine tolerance by MrgC receptor was associated with the modulation of astrocytes and microglia in the spinal dorsal horn and fractalkine and TLR4 expressions in DRG. As MrgC receptor is exclusively located in DRG, intermittent combination of MrgC receptor agonist could be a promising adjunct with limited side effects for chronic use of opiates.
胶质细胞激活在吗啡耐受中起关键作用。本研究探讨了 Mas 相关基因（Mrg）C 受体对吗啡诱导的脊髓小胶质细胞和星形胶质细胞激活的影响及其潜在机制。鞘内给予吗啡（20μg，每日）6 天可导致吗啡镇痛作用明显下降，脊髓背角胶质纤维酸性蛋白和 OX-42 表达增加。MrgC 受体的特异性激动剂牛肾上腺髓质 8-22（BAM8-22，1nmol）间歇性共注射可大大减弱这些变化。这些调节作用伴随着脊髓背角 P2X 和白细胞介素-1 表达的减少。慢性吗啡增加了背根神经节（DRG）中中、小神经元 fractalkine 的表达。BAM8-22 处理抑制了这些变化以及 DRG 中 Toll 样受体 4（TLR4）蛋白的增加。吗啡（3.3M，5 天）对 DRG 外植体培养物的慢性处理增加了 fractalkine mRNA 的水平。BAM8-22（10nM）作用 60 分钟可完全阻断吗啡诱导的 fractalkine mRNA 增加。我们的研究结果表明，MrgC 受体对吗啡耐受的抑制与脊髓背角星形胶质细胞和小胶质细胞以及 DRG 中 fractalkine 和 TLR4 表达的调节有关。由于 MrgC 受体仅位于 DRG 中，间歇性联合 MrgC 受体激动剂可能是一种有前途的辅助治疗方法，用于慢性使用阿片类药物，且副作用有限。
