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

G蛋白偶联受体 慢性疼痛 医学 伤害 伤害感受器 类阿片 受体 神经科学 内脏痛 变构调节剂 生物信息学 药理学 内科学 兴奋剂 生物
作者
Lena Gottesman-Katz,Rocco Latorre,Stephen Vanner,Brian L. Schmidt,Nigel W. Bunnett
出处
期刊:Gut [BMJ]
卷期号:70 (5): 970-981 被引量:26
标识
DOI:10.1136/gutjnl-2020-321193
摘要

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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Dr空瓶氧气完成签到 ,获得积分10
刚刚
刚刚
自由山槐发布了新的文献求助10
刚刚
小马哥爱学习完成签到,获得积分10
1秒前
幸福大白发布了新的文献求助10
2秒前
一路向南发布了新的文献求助10
2秒前
3秒前
SYLH应助Lynn采纳,获得10
4秒前
bbbbb26完成签到 ,获得积分10
4秒前
深情安青应助喵喵采纳,获得10
4秒前
sunflower完成签到,获得积分10
4秒前
1024完成签到,获得积分10
5秒前
HEIKU应助自由山槐采纳,获得10
6秒前
6秒前
7秒前
绝尘发布了新的文献求助20
7秒前
tdtk发布了新的文献求助10
7秒前
小宇完成签到,获得积分10
8秒前
8秒前
8秒前
善学以致用应助满意若烟采纳,获得10
9秒前
非要起名完成签到 ,获得积分10
10秒前
100发布了新的文献求助10
10秒前
Leon发布了新的文献求助10
10秒前
乐乐应助Licyan采纳,获得10
11秒前
LU发布了新的文献求助10
12秒前
高兴电脑发布了新的文献求助10
13秒前
NeXt_best完成签到,获得积分10
14秒前
共享精神应助怕黑嘉懿采纳,获得10
14秒前
口腔溃杨79完成签到,获得积分10
15秒前
16秒前
19秒前
20秒前
LINDA完成签到,获得积分10
20秒前
一只医学dog完成签到 ,获得积分10
20秒前
丽丽发布了新的文献求助10
21秒前
小巴德发布了新的文献求助10
22秒前
丘比特应助从容诗云采纳,获得10
22秒前
24秒前
大婷子发布了新的文献求助10
24秒前
高分求助中
Les Mantodea de Guyane Insecta, Polyneoptera 2500
One Man Talking: Selected Essays of Shao Xunmei, 1929–1939 (PDF!) 1000
Technologies supporting mass customization of apparel: A pilot project 450
A Field Guide to the Amphibians and Reptiles of Madagascar - Frank Glaw and Miguel Vences - 3rd Edition 400
China Gadabouts: New Frontiers of Humanitarian Nursing, 1941–51 400
The Healthy Socialist Life in Maoist China, 1949–1980 400
Walking a Tightrope: Memories of Wu Jieping, Personal Physician to China's Leaders 400
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 物理 生物化学 纳米技术 计算机科学 化学工程 内科学 复合材料 物理化学 电极 遗传学 量子力学 基因 冶金 催化作用
热门帖子
关注 科研通微信公众号,转发送积分 3787714
求助须知:如何正确求助?哪些是违规求助? 3333335
关于积分的说明 10261246
捐赠科研通 3049024
什么是DOI,文献DOI怎么找? 1673399
邀请新用户注册赠送积分活动 801874
科研通“疑难数据库(出版商)”最低求助积分说明 760385