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Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance

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Gastrointestinal Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 239))

Abstract

Opioid drugs are prescribed extensively for pain treatment but when used chronically they induce constipation that can progress to opioid-induced bowel dysfunction. Opioid drugs interact with three classes of opioid receptors: mu opioid receptors (MORs), delta opioid receptors (DOR), and kappa opioid receptors (KORs), but opioid drugs mostly target the MORs. Upon stimulation, opioid receptors couple to inhibitory Gi/Go proteins that activate or inhibit downstream effector proteins. MOR and DOR couple to inhibition of adenylate cyclase and voltage-gated Ca2+ channels and to activation of K+ channels resulting in reduced neuronal activity and neurotransmitter release. KORs couple to inhibition of Ca2+ channels and neurotransmitter release. In the gastrointestinal tract, opioid receptors are localized to enteric neurons, interstitial cells of Cajal, and immune cells. In humans, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and motor neurons and purine/nitric oxide release from inhibitory motor neurons causing inhibition of propulsive motility patterns. MOR and DOR activation also results in inhibition of submucosal secretomotor neurons reducing active Cl− secretion and passive water movement into the colonic lumen. Together, these effects on motility and secretion account for the constipation caused by opioid receptor agonists. Tolerance develops to the analgesic effects of opioid receptor agonists but not to the constipating actions. This may be due to differences in trafficking and downstream signaling in enteric nerves in the colon compared to the small intestine and in neuronal pain pathways. Further studies of differential opioid receptor desensitization and tolerance in subsets of enteric neurons may identify new drug or other treatment strategies of opioid-induced bowel dysfunction.

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Acknowledgments

This work was supported by NIH DK094932 (JJG), NIH P30 DK41301, Imaging Core (CS).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology and the Neuroscience Program, Michigan State University, 293 Farm Lane, Giltner Hall 108, East Lansing, MI, 48824, USA

    James J. Galligan

  2. CURE/DDRC, Vatche and Tamar Manoukian Division of Digestive Diseases, Departments of Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA

    Catia Sternini

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Correspondence to James J. Galligan .

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  1. Health Sciences Center, The University of Oklahoma, Oklahoma City, Oklahoma, USA

    Beverley Greenwood-Van Meerveld

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Galligan, J.J., Sternini, C. (2016). Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance. In: Greenwood-Van Meerveld, B. (eds) Gastrointestinal Pharmacology . Handbook of Experimental Pharmacology, vol 239. Springer, Cham. https://doi.org/10.1007/164_2016_116

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