Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys

Abstract

Receptor theory predicts that fixed-proportion mixtures of a competitive, reversible agonist (e.g., fentanyl) and antagonist (e.g., naltrexone) at a common receptor [e.g., mu-opioid receptors (MORs)] will result in antagonist proportion-dependent decreases in apparent efficacy of the agonist/antagonist mixtures and downward shifts in mixture dose-effect functions. The present study tested this hypothesis by evaluating behavioral effects of fixed-proportion fentanyl/naltrexone mixtures in a warm-water tail-withdrawal procedure in rhesus monkeys ( = 4). Fentanyl (0.001-0.056 mg/kg) alone, naltrexone (0.032-1.0 mg/kg, i.m.) alone, and fixed-proportion mixtures of fentanyl/naltrexone (1:0.025, 1:0.074, and 1:0.22) were administered in a cumulative-dosing procedure, and the proportions were based on published fentanyl and naltrexone values at MOR in monkey brain. Fentanyl alone produced dose-dependent antinociception at both 50 and 54°C thermal intensities. Up to the largest dose tested, naltrexone alone did not alter nociception. Consistent with receptor theory predictions, naltrexone produced a proportion-dependent decrease in the effectiveness of fentanyl/naltrexone mixtures to produce antinociception. The maximum effects of fentanyl, naltrexone, and each mixture were also used to generate an efficacy-effect scale for antinociception at each temperature, and this scale was evaluated for its utility in quantifying 1) efficacy requirements for antinociception at 50 and 54°C and 2) relative efficacy of six MOR agonists that vary in their efficacies to produce agonist-stimuated GTPS binding in vitro (from lowest to highest efficacy: 17-cyclopropylmethyl-3,14-dihyroxy-4,5-epoxy-6-[(3'-isoquinolyl)acetamindo]morphine, nalbuphine, buprenorphine, oxycodone, morphine, and methadone). These results suggest that fixed-proportion agonist/antagonist mixtures may offer a useful strategy to manipulate apparent drug efficacy for basic research or therapeutic purposes.

In vitro and in vivo functional profile characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ) as a low efficacy mu opioid receptor modulator

“…NAQ showed an affinity of 0.55 nM to MOR with over 200-fold selectivity for the MOR over the DOR and 50-fold selectivity over the KOR (Yuan et al, 2011). NAQ acted as a low-efficacy MOR partial agonist in the [ 35 S]GTPγS binding assay, but antagonized the effects of DAMGO (a MOR full agonist) and morphine in the [ 35 S]GTPγS binding assay and warm-water tail immersion assay (Cornelissen et al, 2018; Li et al, 2009; Siemian et al, 2016; Yuan et al, 2011, 2013, 2015). Further pharmacological characterization showed that NAQ significantly reversed morphine withdrawal-associated depression of intracranial self-stimulation (ICSS) in rats (Altarifi et al, 2015).…”

Vaccine blunts fentanyl potency in male rhesus monkeys

“…For comparison to subsequent vaccine effects, 0.032 mg/kg, IM naltrexone was administered as an acute pretreatment before a single cumulative fentanyl dose-effect test session. This naltrexone has previously shown to produce an approximate 10-fold shift in fentanyl antinociceptive potency in rhesus monkeys (Cornelissen et al, 2018). Human laboratory studies have suggested an approximate 8 to 10-fold potency shift is the minimum clinically effective necessary for naltrexone .…”

“…ED50 values were determined for fentanyl and oxycodone in each monkey for each assay as a function of fentanyl vaccine administration. ED50 values were calculated by linear regression when at least three data points on the linear portion of the dose-effect function were available or log-linear interpolation (one below and one above 50% effect) as described previously Cornelissen et al, 2018;Cornelissen et al, 2019). Individual ED50 values were averaged to yield mean ED50s and 95% confidence limits.…”

Manipulating Pharmacodynamic Efficacy with Agonist + Antagonist Mixtures: In Vitro and In Vivo Studies with Opioids and Cannabinoids

“…agonists is often serendipitous despite their therapeutic potential. An alternative approach to controlling efficacy of a pharmacological treatment at a receptor target has been suggested by principles of receptor theory (Cornelissen et al, 2018). Specifically, receptor theory predicts that proportions of a competitive agonist and antagonist in an agonist/antagonist mixture can be manipulated to precisely control the net efficacy of the mixture, such that increasing agonist proportions increase mixture efficacy.…”