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

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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 k-opioid receptor mRNAs and the GIRK1 mRNA. 2 (+)-SKF10047 acted as a δ- and k-agonist (EC50 values (μm) = 0.618 and 0.652, respectively) and μ-antagonist (IC50 value (μm) = 8.51). (+)-Cyclazocine acted as a k-agonist and μ-antagonist (IC50 = 33.2). (+)-3PPP acted as a k-agonist (EC50 = 18.08) and a μ-antagonist. DTG acted as a μ- and k-agonist (EC50 = more than 30 and 14.88, respectively). Carbetapentane acted as a k-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 σ 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 k-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 k-opioid receptors in Xenopus oocytes. Our results suggest that the effects of the σ ligands may be partly mediated by the opioid receptors.