靶向GPCR治疗消化系统慢性疼痛(综述)
  • 损伤组织源介质激活神经元质膜上的GPCR,敏化离子通道,引起急性过度兴奋和痛觉;
  • 激动剂持续释放引起GPCR重分布至核内体,以调控慢性过度兴奋和痛觉相关的通道活性;
  • 核内体靶向的GPCR拮抗剂在临床前有显著止痛效果;
  • 偏向性激动剂可稳定GPCR构象以减少副作用,如μ型阿片受体的偏向性激动剂可减少成瘾、呼吸抑制、恶心及便秘;
  • 变构调节剂可微调内源性配体的作用,如增强内源性阿片的镇痛作用;
  • GPCR二聚体可能作为治疗痛觉的新靶点。
主编推荐语
aluba
慢性疼痛是消化系统功能紊乱、炎症性疾病和癌症的一个常见表现,引发和持续慢性疼痛的机制尚不完全清楚,现有的治疗方法也不足。Gut上发表的一篇最新综述文章,介绍近年来G蛋白偶联受体(GPCR)在介导疼痛和镇痛的结构和功能方面的研究进展,并讨论了多种靶向GPCR的药物设计策略,为研究慢性疼痛的机制和治疗提供了新的思路。
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Gut [IF:19.819]

Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system

靶向G蛋白偶联受体治疗消化系统慢性疼痛

10.1136/gutjnl-2020-321193

2020-12-03, Review

Abstract & Authors:展开

Abstract:收起
Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

First Authors:
Lena Gottesman-Katz

Correspondence Authors:
Nigel W Bunnett

All Authors:
Lena Gottesman-Katz,Rocco Latorre,Stephen Vanner,Brian L Schmidt,Nigel W Bunnett

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