delta-Opioid receptor antagonists inhibit GIRK channel currents in acutely dissociated brainstem neurons of rat.
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.
Shirasaki
Tetsuya
T
Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Abe
Keisuke
K
Soeda
Fumio
F
Takahama
Kazuo
K
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D009761:Nystatin / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011903:Raphe Nuclei / Q000166:cytology*; D051381:Rats; D012701:Serotonin / Q000494:pharmacology; D013820:Thermolysin / Q000494:pharmacology
D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007476:Ionophores; D009292:Narcotic Antagonists; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C068868:naltrindole benzofuran; D009761:Nystatin; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D013820:Thermolysin; C055382:naltrindole; D009638:Norepinephrine