RT Journal Article
SR Electronic
T1 Application of receptor theory to the design and use of fixed-proportion mu-opioid agonist and antagonist mixtures in rhesus monkeys
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.246439
DO 10.1124/jpet.117.246439
A1 Jeremy C Cornelissen
A1 Samuel Obeng
A1 Kenner C Rice
A1 Yan Zhang
A1 S. Stevens Negus
A1 Matthew Banks
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/01/12/jpet.117.246439.abstract
AB 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; MOR) will result in antagonist proportion-dependent decreases in apparent efficacy of the 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, IM) 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 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 (a) efficacy requirements for antinociception at 50 and 54°C and (b) relative efficacy of six MOR agonists that vary in their efficacies to produce agonist-stimuated GTPγS binding in vitro (from lowest to highest efficacy: NAQ, 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.