{"title":"肠道阿片受体的分子生理学。","authors":"James J Galligan, Hamid I Akbarali","doi":"10.1038/ajgsup.2014.5","DOIUrl":null,"url":null,"abstract":"<p><p>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 Ca(2+) channels and activation of K(+) channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca(2+) 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. </p>","PeriodicalId":90430,"journal":{"name":"American journal of gastroenterology supplements (Print)","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2014-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/38/b0/nihms686554.PMC4426191.pdf","citationCount":"0","resultStr":"{\"title\":\"Molecular physiology of enteric opioid receptors.\",\"authors\":\"James J Galligan, Hamid I Akbarali\",\"doi\":\"10.1038/ajgsup.2014.5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 Ca(2+) channels and activation of K(+) channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca(2+) 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. </p>\",\"PeriodicalId\":90430,\"journal\":{\"name\":\"American journal of gastroenterology supplements (Print)\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2014-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/38/b0/nihms686554.PMC4426191.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of gastroenterology supplements (Print)\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1038/ajgsup.2014.5\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of gastroenterology supplements (Print)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/ajgsup.2014.5","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
阿片类药物具有强大的止泻作用,许多长期服用此类药物缓解疼痛的患者会出现慢性便秘,并可能发展为阿片类药物引起的肠道功能紊乱。肠道神经元表达三类阿片受体:μ-、δ- 和 κ-阿片受体(MOR、DOR 和 KOR)。MOR 和 DOR 可抑制腺苷酸环化酶和神经末梢 Ca(2+)通道,并激活 K(+)通道。这些作用会降低神经元的活性和神经递质的释放。KOR 可抑制 Ca(2+)通道,抑制神经递质的释放。在人体胃肠道中,MOR、DOR 和 KOR 与抑制肠道中间神经元释放乙酰胆碱和抑制性运动神经元释放嘌呤/一氧化氮有关。这些作用抑制了推进运动。MOR 和 DOR 还可抑制粘膜下分泌运动神经元,减少 Cl(-)的主动分泌和进入结肠腔的被动水运动。这些作用是阿片受体激动剂导致便秘的原因。阿片受体激动剂的镇痛作用会产生耐受性,但便秘作用不会产生耐受性。这可能是由于结肠与小肠的肠道神经以及神经元疼痛通路中不同的β-arrestin-2依赖性阿片受体脱敏和内化所致。进一步研究肠道神经元亚群中阿片受体脱敏和耐受性的差异,可能会发现治疗阿片类药物引起的肠道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 Ca(2+) channels and activation of K(+) channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca(2+) 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.