Opioid thermal antinociception in rhesus monkeys: receptor mechanisms and temperature dependency.
The antinociceptive effects of the opioid agonists etonitazene and alfentanil, as well as the agonist/antagonists nalbuphine, [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan (GPA 1657)] and profadol were studied in the warm water (48 degrees and 55 degrees C) tail-withdrawal assay in rhesus monkeys. Etonitazene and alfentanil produced dose-dependent increases in tail-withdrawal latency up to the maximum possible latency of 20 sec in 48 degrees and 55 degrees C water. Nalbuphine, GPA 1657 and profadol produced the maximum possible effect only at 48 degrees C, and were ineffective at 55 degrees C. The opioid antagonist quadazocine produced a dose-dependent antagonism of all agonists except profadol. In a Schild plot analysis, apparent pA2 values for quadazocine with alfentanil, etonitazene and nalbuphine were homogeneous (7.3-7.7 mol/kg), suggesting their effects were probably mediated by mu opioid receptors. The apparent pA2 value for GPA 1657 was significantly lower (6.2 mol/kg), suggesting GPA 1657 may have produced antinociception by a non mu receptor-mediated mechanism. The selective delta antagonist naltrindole (0.32-1.0 mg/kg) antagonized the antinociceptive effect of GPA 1657. The kappa-selective antagonist nor-binaltorphimine (nor-BNI, 3.2 mg/kg) caused a small rightward shift in the GPA 1657 dose-effect curve. Nalbuphine, GPA 1657 or profadol produced a rightward shift in the alfentanil dose-effect curve in 55 degrees C water, consistent with possible low-efficacy mu agonist effects of these compounds. These studies suggest agonists may be differentiated based on antinociceptive effectiveness, receptor selectivity and intrinsic efficacy in the rhesus monkey tail-withdrawal procedure.
Walker
E A
EA
Department of Pharmacology, University of Michigan, Ann Arbor.
Butelman
E R
ER
DeCosta
B R
BR
Woods
J H
JH
D015760:Alfentanil / Q000494:pharmacology*; D000700:Analgesics; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001575:Benzomorphans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006358:Hot Temperature; D008253:Macaca mulatta; D008297:Male; D009266:Nalbuphine / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*; D013623:Tail
D000700:Analgesics; D001392:Azocines; D001562:Benzimidazoles; D001575:Benzomorphans; D011759:Pyrrolidines; D011957:Receptors, Opioid; C003100:GPA 1657; D015760:Alfentanil; C051844:norbinaltorphimine; C073329:profadol; D009271:Naltrexone; C055382:naltrindole; D009266:Nalbuphine; C035969:quadazocine