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

1
Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
2
Aether Therapeutics Inc., 4200 Marathon Blvd. Austin, TX 78756, USA
3
Pain and Addiction Research Center, University of California San Francisco, San Francisco, CA 94158, USA
4
Department of Neuroscience, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
5
Departments of Pharmaceutical Sciences and Neurology, University of Illinois at Chicago. Chicago, IL 60612, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Mariana Spetea
Molecules 2020, 25(18), 4163; https://doi.org/10.3390/molecules25184163
Received: 31 July 2020 / Revised: 1 September 2020 / Accepted: 4 September 2020 / Published: 11 September 2020
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. View Full-Text
Keywords: μ opioid receptor; receptor model; biased ligands; dependence; pain therapy; neonatal opioid withdrawal syndrome; naltrexone; 6β-naltrexol; buprenorphine μ opioid receptor; receptor model; biased ligands; dependence; pain therapy; neonatal opioid withdrawal syndrome; naltrexone; 6β-naltrexol; buprenorphine
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MDPI and ACS Style

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. https://doi.org/10.3390/molecules25184163

AMA Style

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(18):4163. https://doi.org/10.3390/molecules25184163

Chicago/Turabian Style

Sadee, Wolfgang; Oberdick, John; Wang, Zaijie. 2020. "Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management" Molecules 25, no. 18: 4163. https://doi.org/10.3390/molecules25184163

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