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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 (n = 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 Kd 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 GTPγS binding in vitro (from lowest to highest efficacy: 17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(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.
Footnotes
- Received November 15, 2017.
- Accepted January 9, 2018.
This research was supported by the National Institutes of Health [Grants R01DA037287, R01DA026946, DA024022, and DA044855]. In addition, this research was supported (in part) by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism.
The National Institute on Drug Abuse had no role in the study design, collection, analysis, and interpretation of the data; in the writing; or in the decision to submit the manuscript for publication. The manuscript content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.
- U.S. Government work not protected by U.S. copyright
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