Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system.
abdominal pain
cell signalling
neurobiology
neurogastroenterology
receptor characterisation
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
23
03
2020
revised:
21
10
2020
accepted:
07
11
2020
pubmed:
5
12
2020
medline:
15
12
2021
entrez:
4
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33272979
pii: gutjnl-2020-321193
doi: 10.1136/gutjnl-2020-321193
pmc: PMC9716638
mid: NIHMS1852083
doi:
Substances chimiques
Analgesics
0
Ligands
0
Receptors, G-Protein-Coupled
0
Sensory System Agents
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
970-981Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE026806
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE029951
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118971
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102722
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: NWB is a founding scientist of Endosome Therapeutics Inc.
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