Abstract

Naltrexone (NTX) exhibited approximately 3-fold higher affinity for sites labeled by [³H]U69,593 (putative κ₁-selective ligand) than [³H]bremazocine (non-selective ligand) in the presence of mu anddelta receptor blockade in monkey brain membranes. This led us to test an hypothesis that NTX could display in vivo antagonist selectivity for κ₁-versus non-κ₁-mediated effects. Six opioid agonists were characterized by NTX apparent pA₂ analysis in a 50°C water tail-withdrawal assay in rhesus monkeys. Constrained NTX pA₂ values (95% confidence limits) were: alfentanil, 8.66 (8.47–8.85); ethylketocyclazocine, 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, confirmed that mu receptors were not involved in the antinociception produced by the kappa agonists, U69,593, U50,488, bremazocine and enadoline; however, both mu andkappa receptors mediated the antinociceptive effects of ethylketocyclazocine. The apparent NTX pA₂ profile of opioid agonists correlated highly with the radioligand binding studies, which indicates that U69,593 and U50,488 produced antinociception by acting on kappa-1 receptors, whereas bremazocine and enadoline probably acted via non-kappa-1 receptors. This study provides further functional evidence ofkappa opioid receptor multiplicity in primates and suggests that NTX may be a useful tool to study this phenomenonin vivo.