Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation
Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation
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DOI：
10.1096/fj.201601068r
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Akbarali, Hamid I.
中科院分区：
文献类型：
--
作者：
Bhave, Sukhada;Gade, Aravind;Akbarali, Hamid I.
吗啡是治疗疼痛最广泛使用的药物之一。然而，副作用，包括持续便秘和镇痛耐受性，限制了其临床疗效。长期的吗啡治疗导致肠道“渗漏”，易患结肠炎症，这是由微生物生态失调和相关的细菌易位促进的。在这项研究中，我们研究了肠神经胶质细胞在介导这种继发性炎症反应的作用，长期治疗吗啡。我们发现，嘌呤能P2 X受体的活性显着增强肠神经胶质细胞，从小鼠与长期吗啡治疗（体内），但不直接暴露于吗啡的神经胶质细胞（体外）。LPS（细菌的主要产物）也增加肠神经胶质细胞ATP诱导的电流以及P2 X4、P2 X7、IL-6、IL-1 β mRNA的表达。LPS可增加肠神经胶质细胞连接蛋白43（Cx43）的表达和ATP的释放。Cx43阻断剂Gap 26和甘珀酸可阻断LPS诱导的P2 X电流和促炎细胞因子mRNA表达。同样，甘珀酸（25 mg/kg）显著减轻了与长期暴露于吗啡相关的结肠炎症。甘珀酸还防止肠壁破裂，并显着减少吗啡诱导的便秘。这些发现意味着肠神经胶质细胞活化是吗啡相关炎症和便秘的重要调节剂。
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 (in vivo) but not upon direct exposure of glia to morphine (in vitro). LPS, a major bacterial product, also increased ATP-induced currents, as well as expression of P2X4, P2X7, IL6, IL-1 beta 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 (25mg/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.