OPIOID THERMAL ANTINOCICEPTION IN RHESUS-MONKEYS - RECEPTOR MECHANISMS AND TEMPERATURE DEPENDENCY

The antinociceptive effects of the opioid agonists etonitazene and alf entanil, as well as the agonist/antagonists nalbuphine, -2'-hydroxy-2, 9-dimethyl-5-phenyl-6,7-benzomorphan (GPA 1657)] and profadol were stu died in the warm water (48-degrees and 55-degrees-C) tail-withdrawal a ssay in rhesus monkeys. Etonitazene and alfentanil produced dose-depen dent increases in tail-withdrawal latency up to the maximum possible l atency of 20 sec in 48-degrees- and 55-degrees-C water. Nalbuphine, GP A 1657 and profadol produced the maximum possible effect only at 48-de grees-C, and were ineffective at 55-degrees-C. The opioid antagonist q uadazocine produced a dose-dependent antagonism of all agonists except profadol. In a Schild plot analysis, apparent pA2 values for quadazoc ine with alfentanil, etonitazene and nalbuphine were homogeneous (7.3- 7.7 mol/kg), suggesting their effects were probably mediated by mu opi oid receptors. The apparent pA2 value for GPA 1657 was significantly l ower (6.2 mol/kg), suggesting GPA 1657 may have produced antinocicepti on by a non mu receptor-mediated mechanism. The selective delta antago nist naltrindole (0.32-1.0 mg/kg) antagonized the antinociceptive effe ct of GPA 1657. The kappa-selective antagonist nor-binaltorphimine (no r-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 sh ift in the alfentanil dose-effect curve in 55-degrees-C water, consist ent with possible low-efficacy mu agonist effects of these compounds. These studies suggest agonists may be differentiated based on antinoci ceptive effectiveness, receptor selectivity and intrinsic efficacy in the rhesus monkey tail-withdrawal procedure.