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Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system
  1. Lena Gottesman-Katz1,2,
  2. Rocco Latorre1,
  3. Stephen Vanner3,
  4. Brian L Schmidt4,
  5. Nigel W Bunnett1
  1. 1Molecular Pathobiology, New York University, New York, New York, USA
  2. 2Division of Pediatric Gastroenterology, Columbia University Medical Center/New York Presbyterian, New York, New York, USA
  3. 3Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queens University, Kingston, Ontario, Canada
  4. 4Bluestone Center, New York University, New York, New York, USA
  1. Correspondence to Professor Nigel W Bunnett, Molecular Pathobiology, New York University, New York, NY 10010, USA; nwb2{at}nyu.edu

Abstract

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.

  • abdominal pain
  • cell signalling
  • neurobiology
  • neurogastroenterology
  • receptor characterisation

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Footnotes

  • Contributors LGK, RL, SV, BS and NB researched field and wrote the manuscript.

  • Funding Supported by grants from National Institutes of Health (NS102722, DE026806, DE029951, DK118971; NWB and BLS) and Department of Defense (W81XWH1810431, NWB and BLS).

  • Competing interests NWB is a founding scientist of Endosome Therapeutics Inc.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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