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.
Highlights
The atypical chemokine receptor ACKR3 was suggested as another atypical opioid receptor, based on its unique ability to scavenge a variety of endogenous opioid peptides without inducing canonical downstream G protein-mediated signaling (Meyrath et al, 2020) (Table 1)
The family of classical opioid receptor (OR) is restricted to the μ, δ, κ and nociceptin receptors, or MOP, DOR, KOP and nociceptin/orphanin FQ receptor (NOP)
Atypical ORs are associated with another primary function, which does not relate directly to opioidergic behaviors—e.g. Bradykinin Receptors (BRs) with inflammation, N-Methyl-D-aspartic acid receptors (NMDARs) with excitatory synaptic signals or ACKR3 with maintenance of chemokine homeostasis
Summary
Ancient writings and archeological findings have dated the use of opium (from “opos”, Greek for juice) as far back as antiquity. Its nonselective antagonism was later used as the inclusion criterion in the pursuit of new opioid receptors This rule was bent for the more recently discovered naloxone-insensitive nociceptin/orphanin FQ receptor, NOP (Mollereau et al, 1994), due to its high structural and functional homology to classical opioid receptors (Nothacker et al, 1996). It has been proposed that endogenous opioid peptides have two specific recognition regions, namely the N-terminal “message” containing residues YGGF, and the “address” made up of the C-terminal residues (Mansour, Hoversten, Taylor, Watson, & Akil, 1995) These are key determinants of classical opioid receptor activation and selectivity, respectively. G proteincoupled receptor kinases (GRKs) phosphorylate activated receptors, thereby promoting β-arrestin recruitment, which eventually leads to receptor desensitization and internalization (Al-Hasani & Bruchas, 2011; Connor & Christie, 1999)
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