DIFFERENTIATION OF KAPPA-OPIOID AGONIST-INDUCED ANTINOCICEPTION BY NALTREXONE APPARENT PA(2) ANALYSIS IN RHESUS-MONKEYS

Naltrexone (NTX) exhibited approximately 3-fold higher affinity for si tes labeled by [H-3]U69,593 (putative kappa(1)-selective ligand) than [H-3]bremazocine (non-selective ligand) in the presence of mu and delt a receptor blockade in monkey brain membranes. This led us to test an hypothesis that NTX could display in vivo antagonist selectivity for k appa(1)- versus non-kappa(1)-mediated effects. Six opioid agonists wer e characterized by NTX apparent pA(2), analysis in a 50 degrees C wate r tail-withdrawal assay in rhesus monkeys. Constrained NTX pA(2) value s (95% confidence limits) were: alfentanil, 8.66 (8.47-8.85); ethylket ocyclazocine, 7.97 (7.93-8.01); U69,593, 7.64 (7.49-7.79); U50,488, 7. 55 (7.42-7.67); bremazocine, 6.92 (6.73-7.12); enadoline, 6.87 (6.69-7 .05). Pretreatment with clocinnamox, an irreversible mu antagonist, co nfirmed that mu receptors were not involved in the antinociception pro duced by the kappa agonists, U69,593, U50,488, bremazocine and enadoli ne; however, both mu and kappa receptors mediated the antinociceptive effects of ethylketocyclazocine. The apparent NTX pA(2) profile of opi oid agonists correlated highly with the radioligand binding studies, w hich indicates that U69,593 and U50,488 produced antinociception by ac ting on kappa-1 receptors, whereas bremazocine and enadoline probably acted via non-kappa-1 receptors. This study provides further functiona l evidence of kappa opioid receptor multiplicity in primates and sugge sts that NTX may be a useful tool to study this phenomenon in vivo.