Atypical opioid receptors: unconventional biology and therapeutic opportunities

Palmer, Christie B.; Meyrath, Max; Canals, Meritxell; Kostenis, Evi; Chevigné, Andy; Szpakowska, Martyna

Abstract

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating four opioid receptors, namely μ (mu, MOP), δ (delta, DOP), κ (kappa, KOP) and the nociceptin/orphanin FQ receptor (NOP). Interestingly, several other receptors are also activated by endogenous opioid peptides and influence opioid-driven signaling and biology. However, they do not meet the criteria to be recognized as classical opioid receptors, as they are phylogenetically distant from them and are insensitive to classical non-selective opioid receptor antagonists (e.g. naloxone). Nevertheless, accumulating reports suggest that these receptors may be interesting alternative targets, especially for the development of safer analgesics. Five of these opioid peptide-binding receptors belong to the family of G protein-coupled receptors (GPCRs)—two are members of the Mas-related G protein-coupled receptor X family (MrgX1, MrgX2), two of the bradykinin receptor family (B1, B2), and one is an atypical chemokine receptor (ACKR3). Additionally, the ion channel N-methyl-D-aspartate receptors (NMDARs) are also activated by opioid peptides. In this review, we recapitulate the implication of these alternative receptors in opioid-related disorders and discuss their unconventional biology, with members displaying signaling to scavenging properties. We provide an overview of their established and emerging roles and pharmacology in the context of pain management, as well as their clinical relevance as alternative targets to overcome the hurdles of chronic opioid use. Given the involvement of these receptors in a wide variety of functions, including inflammation, chemotaxis, anaphylaxis or synaptic transmission and plasticity, we also discuss the challenges associated with the modulation of both their canonical and opioid-driven signaling.

Citation

Palmer, C. B., Meyrath, M., Canals, M., Kostenis, E., Chevigné, A., & Szpakowska, M. (2022). Atypical opioid receptors: unconventional biology and therapeutic opportunities. Pharmacology and Therapeutics, Article 108014. https://doi.org/10.1016/j.pharmthera.2021.108014

• Journal Article Type: Review
• Acceptance Date: Feb 27, 2021
• Online Publication Date: Oct 5, 2021
• Publication Date: May 1, 2022
• Deposit Date: Nov 19, 2021
• Publicly Available Date: Nov 19, 2021
• Journal: Pharmacology and Therapeutics
• Print ISSN: 0163-7258
• Electronic ISSN: 1879-016X
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Article Number: 108014
• DOI: https://doi.org/10.1016/j.pharmthera.2021.108014
• Keywords: Pharmacology (medical); Pharmacology
• Public URL: https://nottingham-repository.worktribe.com/output/6738548
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0163725821002163?via%3Dihub