Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to μ Opioid Receptors in Analgesia and Addiction

Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the mu opioid receptor (MOR) signals in ligand-free form (MOR-mu*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-mu* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-mu* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-mu) activation to MOR-mu*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-mu*, acting as potent inverse agonists. A neutral antagonist, 6 beta-naltrexol (6BN), binds to but does not block MOR-mu*, preventing MOR-mu activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-mu* reversal to resting-state MOR-mu. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a 'retrograde addiction modulator', 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-mu* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.

Automated summary

Many G-protein-coupled receptors exhibit ligand-free basal signaling and may have physiological functions. The mu opioid receptor signals in a ligand-free form, affecting opioid drug responses. Opioid pain therapy is effective but carries adverse effects and risk of opioid use disorder. Sustained exposure to opioid agonists increases basal receptor activity, which could contribute to opioid use disorder. A neutral antagonist, 6 beta-naltrexol, can prevent opioid dependence in rodents without blocking analgesia or causing withdrawal. It could be a new therapeutic option for opioid use disorder.