The gastrointestinal epithelium is critical for maintaining a symbiotic relationship with commensal microbiota. Chronic morphine exposure can compromise the gut epithelial barrier in mice and lead to dysbiosis. Recently, studies have implicated morphine-induced dysbiosis in the mechanism of antinociceptive tolerance and reward, suggesting the presence of a gut-brain axis in the pharmacological effects of morphine. However, the mechanism(s) underlying morphine-induced changes in the gut microbiome remains unclear. The pro-inflammatory cytokine, Interleukin-18 (IL-18), released by enteric neurons can modulate gut barrier function. Therefore, in the present study we investigated the effect of morphine on IL-18 expression in the mouse ileum. We observed that chronic morphine exposure in vivo induces IL-18 expression in the ileum myenteric plexus that is attenuated by naloxone. Given that mu-opioid receptors (MORs) are mainly expressed in enteric neurons, we also characterized morphine effects on the excitability of cholinergic (excitatory) and vasoactive intestinal peptide (VIP)-expressing (inhibitory) myenteric neurons. We found fundamental differences in the electrical properties of cholinergic and VIP neurons such that VIP neurons are more excitable than cholinergic neurons. Furthermore, MORs were primarily expressed in cholinergic neurons, although a subset of VIP neurons also expressed MORs and responded to morphine in electrophysiology experiments. In conclusion, these data show that morphine increases IL-18 in ileum myenteric plexus neurons via activation of MORs in a subset of cholinergic and VIP neurons. Thus, understanding the neurochemistry and electrophysiology of MOR-expressing enteric neurons can help to delineate mechanisms by which morphine perturbs the gut barrier.

Graphic Abstract

中文翻译：

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慢性吗啡通过胆碱能和 VIPergic 神经元中的 Mu-阿片受体激活在回肠肌间神经丛神经元中诱导 IL-18

胃肠道上皮细胞对于维持与共生微生物群的共生关系至关重要。慢性吗啡暴露会损害小鼠的肠道上皮屏障并导致生态失调。最近，研究表明吗啡诱导的生态失调与抗伤害耐受和奖励机制有关，表明吗啡的药理作用中存在肠-脑轴。然而，吗啡引起肠道微生物组变化的潜在机制仍不清楚。肠神经元释放的促炎细胞因子白细胞介素 18 (IL-18) 可以调节肠道屏障功能。因此，在本研究中，我们研究了吗啡对小鼠回肠中 IL-18 表达的影响。我们观察到体内慢性吗啡暴露会诱导回肠肌间神经丛中的 IL-18 表达，而纳洛酮会减弱这种表达。鉴于 mu-阿片受体 (MOR) 主要在肠神经元中表达，我们还描述了吗啡对胆碱能（兴奋性）和血管活性肠肽 (VIP) 表达（抑制性）肌间神经元兴奋性的影响。我们发现胆碱能神经元和 VIP 神经元的电学特性存在根本差异，因此 VIP 神经元比胆碱能神经元更容易兴奋。此外，MORs 主要在胆碱能神经元中表达，尽管 VIP 神经元的一个子集也表达 MORs 并且在电生理学实验中对吗啡有反应。综上所述，这些数据表明，吗啡通过激活一部分胆碱能神经元和 VIP 神经元中的 MOR，增加回肠肌间神经丛神经元中的 IL-18。因此，了解表达 MOR 的肠神经元的神经化学和电生理学有助于阐明吗啡扰乱肠道屏障的机制。

图形摘要