Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

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Abstract

Opioid receptors are widely distributed in the human body and are crucially involved in numerous physiological processes. These include pain signaling in the central and the peripheral nervous system, reproduction, growth, respiration, and immunological response. Opioid receptors additionally play a major role in the gastrointestinal (GI) tract in physiological and pathophysiological conditions. This review discusses the physiology and pharmacology of the opioid system in the GI tract. We additionally focus on GI disorders and malfunctions, where pathophysiology involves the endogenous opioid system, such as opioid-induced bowel dysfunction, opioid-induced constipation or abdominal pain. Based on recent reports in the field of pharmacology and medicinal chemistry, we will also discuss the opportunities of targeting the opioid system, suggesting future treatment options for functional disorders and inflammatory states of the GI tract.

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Most cited references 179

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Transduction of receptor signals by beta-arrestins.

Robert Lefkowitz, Sudha Shenoy (2005)

The transmission of extracellular signals to the interior of the cell is a function of plasma membrane receptors, of which the seven transmembrane receptor family is by far the largest and most versatile. Classically, these receptors stimulate heterotrimeric G proteins, which control rates of generation of diffusible second messengers and entry of ions at the plasma membrane. Recent evidence, however, indicates another previously unappreciated strategy used by the receptors to regulate intracellular signaling pathways. They direct the recruitment, activation, and scaffolding of cytoplasmic signaling complexes via two multifunctional adaptor and transducer molecules, beta-arrestins 1 and 2. This mechanism regulates aspects of cell motility, chemotaxis, apoptosis, and likely other cellular functions through a rapidly expanding list of signaling pathways.

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Molecular mechanisms of opioid receptor-dependent signaling and behavior.

Ream Al-Hasani, Michael Bruchas (2011)

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.

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Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.

L. M. Bohn, R R Gainetdinov, F Lin … (2000)

Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness. In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicates that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta-arrestins. Using a knockout mouse lacking beta-arrestin-2 (beta arr2-/-), we have assessed the contribution of desensitization of the mu-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.

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Author and article information

Contributors

: ++48-42-2725707 , ++48-42-2725694 , jakub.fichna@umed.lodz.pl

Journal

Journal ID (nlm-ta): J Gastroenterol

Journal ID (iso-abbrev): J. Gastroenterol

Title: Journal of Gastroenterology

Publisher: Springer Japan (Tokyo )

ISSN (Print): 0944-1174

ISSN (Electronic): 1435-5922

Publication date (Electronic): 9 February 2013

Publication date PMC-release: 9 February 2013

Publication date (Print): 2014

Volume: 49

Pages: 24-45

Affiliations

[ ]Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland

[ ]Division of Gastroenterology, Department of Medicine, Ludwig Maximilians University of Munich, Munich, Germany

Article

Publisher ID: 753

DOI: 10.1007/s00535-013-0753-x

PMC ID: 3895212

PubMed ID: 23397116

SO-VID: 26cb9e8a-54e2-4869-a1a3-0cf4216785ff

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

History

Date received : 28 November 2012

Date accepted : 10 January 2013

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: abdominal pain,inflammatory bowel diseases,opioid receptors and their ligands,functional gastrointestinal disorders,opioid-induced bowel dysfunction

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: abdominal pain, inflammatory bowel diseases, opioid receptors and their ligands, functional gastrointestinal disorders, opioid-induced bowel dysfunction

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

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Karger: Gastroenterology

Most cited references 179

Transduction of receptor signals by beta-arrestins.

Molecular mechanisms of opioid receptor-dependent signaling and behavior.

Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.

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