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

Abstract

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 (σ) 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 μ-, δ- and κ-opioid receptor mRNAs and the GIRK1 mRNA. 2. (+)-SKF10047 acted as a δ- and κ-agonist (EC50 values (μM) = 0.618 and 0.652, respectively) and μ-antagonist (IC50 value (μM) = 8.51). (+)-Cyclazocine acted as a κ-agonist and μ-antagonist (IC50 = 33.2). (+)-3PPP acted as a κ-agonist (EC50 = 18.08) and a μ-antagonist. DTG acted as a μ- and κ-agonist (EC50 = more than 30 and 14.88, respectively). Carbetapentane acted as a κ-agonist and μ-antagonist (IC50 = 11.2). Haloperidol acted as a μ- and δ-agonist (EC50 = 5.683 and 7.389, respectively). 3. All currents induced by a ligands were reduced by 1 μM naloxone, an opioid receptor antagonist, and blocked by 300 μM Ba2+, a GIRK channel blocker. It was also indicated that the antagonism by naloxone at the δ- and κ-opioid receptors was weaker than that of naloxone at the μ-opioid receptor. The σ 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 σ ligands directly interact with the cloned μ-, δ- and κ-opioid receptors in Xenopus oocytes. Our results suggest that the effects of the σ ligands may be partly mediated by the opioid receptors.