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

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.

Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model

“…Alternatively, 6BN may interact in novel ways with the opioid receptor, possibly binding with high affinity to a distinct receptor conformation involved in the development of dependence. For example, Jeske (Jeske 2019) has proposed a receptor model with distinct peripheral and central mu opioid receptor forms that could in part account for the observed peripheral selectivity of 6BN, even in rhesus monkeys where it readily penetrates the adult's brain (J. Oberdick, unpublished results; see also (Sadee et al, 2020)). It appears that our current understanding of the molecular pharmacology of opioid receptors is incomplete-requiring a new approach to account for the high potency of 6BN in selectively preventing opioid withdrawal behavior in dependent animals, as observed here and in mice (Oberdick et al, 2016;Sadee et al, 2020).…”

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

“…Referred to as shape-shifters [16], GPCRs exist in multiple silent and active conformations signaling along diverse pathways. Ligands can interact preferentially with each of these states, leading to design of biased agonists and antagonists with favorable pharmacological properties [6,7,29]. Receptor states are stabilized by allosteric interactions with other membrane components such as cholesterol and proteins, generating receptor ensembles poised for ligand activation or already basally active in a ligand-free form.…”

Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology

“…While the rewarding, addictive and consequent withdrawal effects associated with opioid use are major side effects, their complex and multi-faceted nature as well as the myriad of approaches used to investigate them are outside the scope of this review. The mechanisms underlying these behaviours, as well as the methods used to study them in preclinical models are elegantly reviewed elsewhere (Banks & Negus, 2017;Charbogne, Kieffer, & Befort, 2014;Kreek, et al, 2012;Negus & Moerke, 2019;Rodríguez-Arias, Aguilar, Manzanedo, & Miñarro, 2010;Sadee, Oberdick, & Wang, 2020;Swain, Gewirtz, & Harris, 2021)…”