Zhang Yue, Wang Kai, Lin Minyan, Li Qi, Hong Yanguo
Provincial Key Laboratory of Developmental Biology and Neuroscience, Fujian Normal University, Fuzhou, Fujian 350117, China.
Provincial Key Laboratory of Developmental Biology and Neuroscience, Fujian Normal University, Fuzhou, Fujian 350117, China.
Eur J Pharmacol. 2017 Nov 15;815:10-17. doi: 10.1016/j.ejphar.2017.10.011. Epub 2017 Oct 6.
Opiate tolerance is a critical issue in pain management. Previous studies show that activation of Mas-related gene (Mrg) C receptor can modulate the development of morphine tolerance. This study was designed to investigate the underlying mechanism(s). Intrathecal (i.t.) administration of morphine (20µg) increased the expression of interleukin-1β (IL-1β) and matrix metalloproteinase-9 (MMP-9) in small- and medium-sized neurons in dorsal root ganglia (DRG). Co-administration of bovine adrenal medulla 8-22 (BAM8-22), a selective MrgC receptor agonist, via i.t. route inhibited the increase of IL-1β and MMP-9 in the DRG. Exposure of DRG cultures to morphine (3.3μM) for 3 or 5 days, but not for 1 day, induced an increase in MMP-9 mRNA expression. The treatment with BAM8-22 (10nM) for 20, 40 or 60min abolished chronic (5 days) morphine-induced increase of MMP-9 mRNA in the cultured DRG. The treatment with BAM8-22 for 1h inhibited chronic morphine-induced increase of MMP-9 and IL-1β mRNA in DRG but these effects were abolished by MrgC receptor antibody. The treatment with BAM8-22 for 24 and 72h respectively inhibited and enhanced morphine-induced expression of MMP-9 and IL-1β mRNA in the cultured DRG. The BAM8-22-induced inhibition and enhancement were abolished by MrgC receptor antibody. The results suggest that the inhibition of IL-1β and MMP-9 expressions in DRG underlain the modulation of morphine tolerance by the acute activation of MrgC receptors. The chronic activation of MrgC receptors can facilitate morphine-induced increase of MMP-9 and IL-1β expressions in DRG.
阿片类药物耐受性是疼痛管理中的一个关键问题。先前的研究表明，Mas相关基因（Mrg）C受体的激活可调节吗啡耐受性的发展。本研究旨在探讨其潜在机制。鞘内注射吗啡（20μg）可增加背根神经节（DRG）中小和中型神经元中白细胞介素-1β（IL-1β）和基质金属蛋白酶-9（MMP-9）的表达。通过鞘内途径共同给予选择性MrgC受体激动剂牛肾上腺髓质8-22（BAM8-22）可抑制DRG中IL-1β和MMP-9的增加。将DRG培养物暴露于吗啡（3.3μM）3天或5天，但不是1天，可诱导MMP-9 mRNA表达增加。用BAM8-22（10nM）处理20、40或60分钟可消除慢性（5天）吗啡诱导的培养DRG中MMP-9 mRNA的增加。用BAM8-22处理1小时可抑制慢性吗啡诱导的DRG中MMP-9和IL-1β mRNA的增加，但这些作用可被MrgC受体抗体消除。分别用BAM8-22处理24小时和72小时可抑制并增强培养DRG中吗啡诱导的MMP-9和IL-1β mRNA的表达。BAM8-22诱导的抑制和增强作用可被MrgC受体抗体消除。结果表明，DRG中IL-1β和MMP-9表达的抑制是MrgC受体急性激活调节吗啡耐受性的基础。MrgC受体的慢性激活可促进吗啡诱导的DRG中MMP-9和IL-1β表达的增加。
