Bhave Sukhada, Gade Aravind, Kang Minho, Hauser Kurt F, Dewey William L, Akbarali Hamid I
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
FASEB J. 2017 Jun;31(6):2649-2660. doi: 10.1096/fj.201601068R. Epub 2017 Mar 9.
Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance, limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut, predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment () but not upon direct exposure of glia to morphine (). LPS, a major bacterial product, also increased ATP-induced currents, as well as expression of P2X4, P2X7, IL6, IL-1β mRNA in enteric glia. LPS increased connexin43 (Cx43) expression and enhanced ATP release from enteric glia cells. LPS-induced P2X currents and proinflammatory cytokine mRNA expression were blocked by the Cx43 blockers Gap26 and carbenoxolone. Likewise, colonic inflammation related to prolonged exposure to morphine was significantly attenuated by carbenoxolone (25 mg/kg). Carbenoxolone also prevented gut wall disruption and significantly reduced morphine-induced constipation. These findings imply that enteric glia activation is a significant modulator of morphine-related inflammation and constipation.-Bhave, S., Gade, A., Kang, M., Hauser, K. F., Dewey, W. L., Akbarali, H. I. Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.
吗啡是治疗疼痛最常用的药物之一。然而，包括持续性便秘和抗伤害感受性耐受在内的副作用限制了其临床疗效。长期使用吗啡治疗会导致肠道“渗漏”，易引发结肠炎症，微生物群落失调和相关细菌易位会加剧这种炎症。在本研究中，我们研究了肠神经胶质细胞在介导对长期吗啡治疗的这种继发性炎症反应中的作用。我们发现，从长期接受吗啡治疗的小鼠分离出的肠神经胶质细胞中，嘌呤能P2X受体活性显著增强（），但神经胶质细胞直接暴露于吗啡时则未增强（）。脂多糖（LPS）是一种主要的细菌产物，它还增加了ATP诱导的电流，以及肠神经胶质细胞中P2X4、P2X7、IL6、IL-1β mRNA的表达。LPS增加了连接蛋白43（Cx43）的表达，并增强了肠神经胶质细胞的ATP释放。Cx43阻滞剂Gap26和甘珀酸可阻断LPS诱导的P2X电流和促炎细胞因子mRNA表达。同样，甘珀酸（25 mg/kg）可显著减轻与长期接触吗啡相关的结肠炎症。甘珀酸还可防止肠壁破坏，并显著减轻吗啡引起的便秘。这些发现表明，肠神经胶质细胞激活是吗啡相关炎症和便秘的重要调节因子。-巴韦，S.，加德，A.，康，M.，豪泽，K.F.，杜威，W.L.，阿克巴利，H.I.肠神经胶质细胞中的连接蛋白-嘌呤能信号传导介导吗啡对便秘的长期影响。
