Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1445 Budapest, Hungary.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Molecules. 2023 Nov 24;28(23):7766. doi: 10.3390/molecules28237766.
Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.
阿片受体激动剂，特别是那些激活μ-阿片受体（MOR）的激动剂，是治疗急性或慢性轻至重度疼痛的重要镇痛剂。然而，它们的使用引起了人们的关注，包括肠道菌群失调等。此外，越来越多的关于便秘引起的肠道菌群失调的数据也有报道。阿片类药物引起的便秘（OIC）给继续使用阿片类镇痛药治疗带来了障碍。当非阿片类疗法无法克服 OIC 时，具有外周、快速首过代谢和胃肠道局部作用的阿片受体拮抗剂仍然是 OIC 的首选药物，本文将对此进行讨论。乍一看，它们的使用似乎仅限于便秘，但最近关于 OIC 相关的菌群失调及其对几种阿片类药物副作用出现的贡献的研究数据引起了研究人员的极大关注。外周 MOR 也被认为是一种具有有限中枢副作用的阿片类镇痛药的未来靶点。本文将重点介绍对抗 OIC 的 MOR 拮抗剂的特性，以及对中枢和可能的外周 MOR 介导的镇痛作用的影响有限。还提出了一个新概念，即开发肠道选择性 MOR 拮抗剂来治疗或恢复 OIC，同时保持外周镇痛作用不受影响。还包括了阿片受体拮抗剂对肠道微生物组变化与 OIC 之间关系的影响。
