nystatin-a1 and naltrindole

In this study, we investigated the effects of delta-opioid receptor antagonists on the G protein-coupled inwardly rectifying potassium (GIRK) channel currents induced by serotonin (5-HT) and noradrenaline (NAd) in the dorsal raphe and the locus coeruleus neurons, respectively. Perforated patch and conventional whole-cell patch clamp recording techniques were used for the study. Neurons were acutely dissociated from neonatal rats. Both naltrindole (NTI) and naltriben (NTB), which are selective delta-antagonists possessing antitussive activity in in vivo animal studies, reversibly inhibited the 5-HT-induced GIRK channel currents (I(5-HT)) in dorsal raphe neurons. This inhibition was concentration-dependent and voltage-independent. The half-maximum inhibitory concentration (IC(50)) on I(5-HT) was 9.84x10(-5) M for NTI and 1.28x10(-5) M for NTB. The inhibition was not reversed by 10(-5) M DPDPE, a selective delta-opioid receptor agonist. NTI did not affect 50% effective concentration (EC(50)) on the concentration-response relationship for 5-HT but inhibited the maximum response. In neurons internally perfused with GTPgammaS, both NTI and NTB also inhibited the GIRK channel currents irreversibly activated by 5-HT. Furthermore, these antagonists concentration dependently inhibited 10(-6) M NAd-induced currents (I(NAd)) in locus coeruleus neurons. The IC(50) of NTI on I(NAd) was 8.44x10(-5) M, which was close to that on I(5-HT). The results suggest that NTI and NTB, which are delta-opioid receptor antagonists possessing antitussive activity, may inhibit GIRK channel currents through a non-opioid action, and give further support to our idea previously proposed that centrally acting non-narcotic antitussives have a common characteristic of the inhibitory action on GIRK channels.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Guanosine 5'-O-(3-Thiotriphosphate); Ionophores; Locus Coeruleus; Naltrexone; Narcotic Antagonists; Neurons; Norepinephrine; Nystatin; Patch-Clamp Techniques; Potassium Channels; Potassium Channels, Inwardly Rectifying; Raphe Nuclei; Rats; Serotonin; Thermolysin