The Life Cycle of the Mu-Opioid Receptor. Issue 4 (April 2021)

• Record Type: Journal Article
• Authors: Cuitavi, Javier; Hipólito, Lucía; Canals, Meritxell
• Is Part Of: Trends in biochemical sciences. Volume 46:Issue 4(2021)
• Page Start: 315
• Page End: 328
• Publication Date: 2021-04
• Subjects: G protein-coupled receptor -- OPRM1 -- mu-opioid signalling -- pain -- reward -- addiction; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2020.10.002
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Opioid receptors (ORs) are undisputed targets for the treatment of pain. Unfortunately, targeting these receptors therapeutically poses significant challenges including addiction, dependence, tolerance, and the appearance of side effects, such as respiratory depression and constipation. Moreover, misuse of prescription and illicit narcotics has resulted in the current opioid crisis. The mu-opioid receptor (MOR) is the cellular mediator of the effects of most commonly used opioids, and is a prototypical G protein-coupled receptor (GPCR) where new pharmacological, signalling and cell biology concepts have been coined. This review summarises the knowledge of the life cycle of this therapeutic target, including its biogenesis, trafficking to and from the plasma membrane, and how the regulation of these processes impacts its function and is related to pathophysiological conditions. Highlights: SNPs of OPRM1, resulting in amino acid changes in the protein sequence (e.g., N40D), may have effects in pain and reward processing. Epigenetic changes, as well as positive and negative transcription factors, are key controllers of receptor expression. Alternative splicing generates over 20 different isoforms of mu-opioid receptor (MOR) with distinct pharmacological characteristics; these include isoforms with 7-TM, 6-TM, and 1-TM. MicroRNAs affect OPRM1 mRNA stability upon treatment with opioid drugs. Ligand-dependent regulation of MOR has been the subject of intense research focussed on the development of improved analgesics. Pain might be a risk factor towards drug addiction. The role of MORs in pain and reward processes highlights the role of this receptor in such comorbidity.