New Technologies for Elucidating Opioid Receptor Function

Abstract

Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an unparalleled pallette of tools for deconstructing opioid receptor actions in vitro and in vivo. Here we provide a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives, as well as their role in neural circuits in vivo. We then show how insights into the molecular details of opioid actions can facilitate the creation of functionally-selective (biased) and photoswitchable opioid ligands. Finally, we describe how newly engineered opioid receptor-based chemo- and optogenetic tools, and new mouse lines are expanding and transforming our understanding of opioid function and, perhaps, paving the way for new therapeutics.

Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor

“…Opioid receptors (ORs) are members of the class A (rhodop-sin-like) subfamily of GPCRs, which includes three subtypes, µ, δ and κ, and are important targets for analgesia [6] . Many studies have shown that the analgesic effect of μ-OR occurs through activation of the Gi signal, whereas the downstream β-arrestin pathway of the receptor can lead to constipation, respiratory depression, addiction and other adverse effects [7,8] .…”

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

“…including adenylyl cyclase inhibition and early ERK1/2 phosphorylation. Conversely, KOPr-mediated p38MAPK activation contributes to dysphoria and aversion Ehrich et al, 2015) as well as to sedation and motor incoordination (Bruchas and Roth, 2016). Furthermore, activation of this latter signaling pathway promotes partial sciatic nerve ligation (pSNL)-induced astrocyte proliferation and subsequent hyperalgesia and thermal allodynia (Clayton et al, 2009), and contributes to the modulation of potassium channel heterologous desensitization, possibly leading to antinociceptive tolerance .…”

“…Notably, functional selectivity at opioid receptors has been intensely investigated in the last decade aiming at identifying more effective and safer analgesics, as many of the unwanted effects determined by MOPr or KOPr agonists are reduced or absent in b-arrestin-2 knock-out mice (Bohn et al, 2000;Raehal et al, 2005;Li et al, 2009;Bruchas and Roth, 2016). Therefore, increasing efforts have been devoted to developing functionally selective opioid agonists displaying a limited activation of arrestin-dependent signaling pathways.…”

“…KOPr activation by agonists induces antinociception and may also prevent hyperalgesia produced by chronic use of MOPr targeting therapeutics (Kivell and Prisinzano, 2010;Vanderah, 2010). However, the clinical use of currently available KOPr agonists is limited by their relevant side effects, such as severe dysphoria, neuropathy-induced astrocyte proliferation and subsequent hyperalgesia, sedation, coordination impairment, and anhedonia (Bruchas and Chavkin, 2010;Bruchas and Roth, 2016). Indeed, no KOPr agonist is presently used to treat pain in humans (Bedini and Spampinato, 2018).…”

“…Thus, functionally selective KOPr agonists biased toward G protein-coupled intracellular signaling over b-arrestin-2mediated pathways may be considered candidate therapeutics possibly devoid of the above-described adverse effects (Bruchas and Roth, 2016).…”