Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Version 1 : Received: 31 July 2020 / Approved: 2 August 2020 / Online: 2 August 2020 (11:27:40 CEST)

A peer-reviewed article of this Preprint also exists.

Sadee, W.; Oberdick, J.; Wang, Z. Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management. Molecules 2020, 25, 4163. Sadee, W.; Oberdick, J.; Wang, Z. Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management. Molecules 2020, 25, 4163.

Journal reference: Molecules 2020, 25, 4163
DOI: 10.3390/molecules25184163

Abstract

Opioid analgesics are effective pain therapeutics but cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct m opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-m) to a ligand-free active form (MOR-m*), which mediates MOR signaling. Moreover, MOR-m converts spontaneously to MOR-m* (basal signaling). Persistent upregulation of MOR-m* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-m and MOR-m* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6b-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-m*, naltrexone but not 6b-naltrexol suppresses MOR-m*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-m*with high potency, whereas 6BN must compete with agonists at MOR-m, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose-response curve may also result from opposing effects on MOR-m and MOR-m*. In contrast, we find that 6b-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6b-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

Subject Areas

μ opioid receptor; receptor model; biased ligands; dependence; pain therapy; neonatal opioid withdrawal syndrome; naltrexone; 6β-naltrexol; buprenorphine

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.