Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes

1 Taking advantage of the functional coupling of the opioid receptors with the G-protein-activated K+ (GIRK) channel, we investigated the effects of sigma (sigma) ligands of various structural and pharmacological classes, (+)-N-allylnormetazocine ((+)-SKF10047) and (+)-cyclazocine, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), 1,3-di-(2-tolyl)guanidine (DTG), carbetapentane and haloperidol, on the inward K+ current responses in Xenopus oocytes co-injected with each of the cloned mu-, delta- and kappa-opioid receptor mRNAs and the GIRK1 mRNA. 2 (+)-SKF10047 acted as a delta- and kappa-agonist (EC(50) values (mu M)=0.618 and 0.652, respectively) and mu-antagonist (IC50 value (mu M)=8.51). (+)-Cyclazocine acted as a kappa-agonist and mu-antagonist (IC50=33.2). (+)-3PPP acted as a kappa-agonist (EC(50)=18.08) and a mu-antagonist. DTG acted as a mu- and kappa-agonist (EC(50)=more than 30 and 14.88, respectively). Carbetapentane acted as a kappa-agonist and mu-antagonist (IC50=11.2). Haloperidol acted as a mu- and delta-agonist (EC(50)=5.683 and 7.389, respectively). 3 All currents induced by a ligands were reduced by 1 mu M naloxone, an opioid receptor antagonist, and blocked by 300 mu M Ba2+, a GIRK channel blocker. It was also indicated that the antagonism by naloxone at the delta- and kappa-opioid receptors was weaker than that of naloxone at the mu-opioid receptor. The sigma ligands tested had no effect on the current responses in the oocytes injected with each of the opioid receptor mRNAs alone or with the GIRK1 mRNA alone. 4 We conclude that various sigma ligands directly interact with the cloned mu-, delta- and kappa-opioid receptors in Xenopus oocytes. Our results suggest that the effects of the sigma ligands may be partly mediated by the opioid receptors.