Molecular physiology of enteric opioid receptors.
Molecular physiology of enteric opioid receptors.
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肠受体的分子生理。
DOI：
10.1038/ajgsup.2014.5
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发表时间：
2014-09-10
期刊：
影响因子：
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通讯作者：
Akbarali, Hamid I
中科院分区：
文献类型：
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作者：
Galligan, James J;Akbarali, Hamid I
阿片类药物具有强大的抗便秘作用，许多服用这些药物缓解慢性疼痛的患者会出现慢性便秘，并可能发展为阿片类药物诱导的肠功能障碍。肠神经元表达三类阿片受体：μ-、δ-和κ-阿片受体（莫尔、DOR和KOR）。莫尔和DOR与腺苷酸环化酶和神经末梢Ca 2+通道的抑制和K+通道的激活相耦合。这些作用减少神经元活动和神经递质释放。KOR与抑制Ca 2+通道和抑制神经递质释放偶联。在人胃肠道中，莫尔、DOR和KOR与抑制肠中间神经元的乙酰胆碱释放和抑制性运动神经元的嘌呤/一氧化氮释放有关。这些动作抑制推进运动。莫尔和DOR还与抑制粘膜下分泌运动神经元有关，减少主动Cl−分泌和被动水运动进入结肠腔。这些作用解释了阿片受体激动剂引起的便秘。对阿片受体激动剂的镇痛作用产生耐受性，但对便秘作用不产生耐受性。这可能是由于与小肠和神经元疼痛通路相比，结肠中肠神经中的β-抑制蛋白-2依赖性阿片受体脱敏和内化差异所致。进一步研究肠神经元亚群中的差异阿片受体脱敏和耐受性可能会发现阿片类药物诱导的肠功能障碍的新药或其他治疗策略。
Opioid drugs have powerful antidiarrheal effects and many patients taking these drugs for chronic pain relief experience chronic constipation that can progress to opioid-induced bowel dysfunction. Three classes of opioid receptors are expressed by enteric neurons: μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). MOR and DOR couple to inhibition of adenylate cylase and nerve terminal Ca2+ channels and activation of K+ channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca2+ channels and inhibition of neurotransmitter release. In the human gastrointestinal tract, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and purine/nitric oxide release from inhibitory motorneurons. These actions inhibit propulsive motility. MOR and DOR also link to inhibition of submucosal secretomotor neurons, reducing active Cl− secretion and passive water movement into the colonic lumen. These effects account for the constipation caused by opioid receptor agonists. Tolerance develops to the analgesic effects of opioid receptor agonists but not to the constipating actions. This may be due to differential β-arrestin-2-dependent opioid receptor desensitization and internalization in enteric nerves in the colon compared with the small intestine and in neuronal pain pathways. Further studies of differential opioid receptor desensitization and tolerance in subsets of enteric neurons may identify new drugs or other treatment strategies of opioid-induced bowel dysfunction.