Abstract
Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.
Highlights
The μ opioid receptor (MOR) is the main target of opioid analgesics, providing strong pain relief and causing multiple adverse effects and addiction
Biased MOR antagonists could serve as modulators of opioid dependence, for improved pain therapy and opioid use management
With the hypothesis that 6BN binds potently to MOR-μ* without suppressing signaling, we propose that 6BN blocks opioid analgesia or causes withdrawal only at much higher doses (Table 1) because it needs to compete with the opioid agonist at MOR-μ (Figure 1)
Summary
The μ opioid receptor (MOR) is the main target of opioid analgesics, providing strong pain relief and causing multiple adverse effects and addiction. Naltrexone suppresses basal MOR-μ* activity and thereby This extraordinary potency against a high agonist dose can be accounted for by non-competitive potently causes withdrawal symptoms in dependent subjects [19,26,27,28,29]. Testing the potency of naltrexone and 6BN in antagonizing the fentanyl-induced suppression of electrically stimulated peristalsis in the guinea pig ileum, Porter et al [26] reported IC50 concentrations of 0.26 and 0.09 nM, respectively, showing that 6BN was highly potent in this assay, and more potent than naltrexone, in contrast to its slightly lower affinity to MOR measured in vitro These results are inconsistent with canonical MOR receptor models, but rather suggests levels (Figure 3).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
