EFFECTS OF OPIOID AGONISTS SELECTIVE FOR MU-OPIOID, KAPPA-OPIOID AND DELTA-OPIOID RECEPTORS ON SCHEDULE-CONTROLLED RESPONDING IN RHESUS-MONKEYS - ANTAGONISM BY QUADAZOCINE

Rhesus monkeys were trained to respond under a fixed-ratio 30 schedule of food reinforcement. The mu opioid agonists alfentanil and fentanyl , the kappa opioid agonists ethylketocyclazocine (EKC) and U69,593, th e delta opioid agonist BW373U86 {(+/-)-4-((R)-a-((2S*5R*)-4-allyl-2,5 -dimethyl-1 iperazinal)-3-hydroxy-benzyl)-N,N-diethylbenzamide dihydro chloride} and the nonopioid, noncompetitive N-methyl-D-aspartate antag onist ketamine all produced a dose-dependent decrease in rates of resp onding. Quadazocine (0.1-10 mg/kg) antagonized the rate-decreasing eff ects of all the opioid agonists, but not of ketamine. The in vivo appa rent pA2 values (95% CL) for quadazocine in combination with each agon ist were: alfentanil, 7.7 (7.6-7.8); fentanyl, 7.7 (7.6-7.8); EKC, 6.3 (5.9-6.7); U69,593, 6.5 (5.9-7.0); and BW373U86, 5.5 (5.3-5.8). Addit ionally, antagonist effects of individual doses of quadazocine in comb ination with each agonist were evaluated by using in vivo apparent pK( B) analysis, and pK(B) values were found to be similar to the more rig orously determined pA2 values. The relative pA2 and pK(B) values of qu adazocine in antagonizing the rate-decreasing effects of mu, kappa and delta opioid agonists corresponded to the relative potency of quadazo cine in displacing the specific binding of the mu agonist [H-3] Tyr-D- Ala-Gly-(Me)-Phe-Gly-ol (IC50 = 0.080 nM), the kappa agonist [H-3]U69, 593 (IC50 = 0.52 nM) and the delta agonist [D-Pen2,D-Pen5]-[h-3]enkeph alin (IC50 = 4.6 nM) from binding sites in membranes from monkey brain cortex. These results suggest that the rate-decreasing effects of alf entanil and fentanyl in rhesus monkeys are mediated by mu opioid recep tors, whereas kappa receptors mediate the effects of EKC and U69,593 a nd delta receptors mediate the effects of BW373U86.