Aims and background Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways. Methods Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+ imaging techniques. Results Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits. Conclusions Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.

中文翻译：

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在慢性结肠炎期间，压力激活 DRG 神经元中的伤害性内源性阿片样物质信号

目的和背景心理压力伴随着慢性炎症性疾病，如 IBD，压力荷尔蒙会加剧疼痛信号。相反，内源性阿片系统在慢性炎症期间具有重要的镇痛作用。本研究检查了这些途径的相互作用。方法 将小鼠伤害性背根神经节 (DRG) 神经元与从慢性 UC 患者和葡聚糖硫酸钠 (cDSS) 诱导的慢性结肠炎小鼠中收集的发炎结肠节段的上清液一起孵育。通过向分离的神经元添加应激激素（肾上腺素和皮质酮）或通过将 cDSS 小鼠暴露于避水应激来研究应激效应。使用膜片钳和 Ca2+ 成像技术测量结肠 DRG 伤害感受器的兴奋性变化。结果 慢性 UC 患者和慢性结肠炎小鼠结肠的上清液引起神经元兴奋性和辣椒素诱发的 Ca2+ 反应的纳洛酮敏感抑制。应激激素减少了人和小鼠上清液诱导的信号传导。这种效应是由于应激激素直接向 DRG 神经元发出信号，并通过向免疫系统发出信号而间接发出信号，从而导致阿片类药物水平降低和急性炎症增加。压力的净效应是将 DRG 神经元中的内源性阿片类信号转导从抑制作用变为兴奋作用。这种转换与 G 蛋白偶联受体兴奋性信号转导至对蛋白激酶 A 蛋白、磷脂酶 C 蛋白和 G 蛋白 βϒ 亚基抑制剂敏感的通路的变化有关。结论 应激激素阻断了内源性阿片类药物的抑制作用，可以改变背根神经节神经元阿片类信号传导对兴奋的影响。针对这些途径可能会阻止 IBD 患者大量使用阿片类药物。