δ-Opioid receptor antagonists inhibit GIRK channel currents in acutely dissociated brainstem neurons of rat

• Published in: Brain research 2004-05, Vol.1006 (2), p.190-197
• Main Authors: Shirasaki, Tetsuya, Abe, Keisuke, Soeda, Fumio, Takahama, Kazuo
• Format: Article
• Language: English
• Subjects: 5-HT 1A receptor; Acutely dissociated brain neuron; Analgesics, Opioid - pharmacology; Animals; Animals, Newborn; Biological and medical sciences; Cells, Cultured; Central nervous system; Centrally acting antitussive; Cough; Dorsal raphe; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology; Enkephalin, D-Penicillamine (2,5)- - pharmacology; Fundamental and applied biological sciences. Psychology; G Protein-Coupled Inwardly-Rectifying Potassium Channels; GIRK; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology; Ionophores - pharmacology; Locus coeruleus; Locus Coeruleus - cytology; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Neurons - drug effects; Neurons - physiology; Norepinephrine - pharmacology; Nystatin - pharmacology; Patch clamp; Patch-Clamp Techniques - methods; Potassium Channels - drug effects; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Raphe Nuclei - cytology; Rats; Serotonin - pharmacology; Thermolysin - pharmacology; Vertebrates: nervous system and sense organs; α 2 Adrenoceptor; δ-Antagonist
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.02.004

In this study, we investigated the effects of δ-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 δ-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 9.84×10 −5 M for NTI and 1.28×10 −5 M for NTB. The inhibition was not reversed by 10 −5 M DPDPE, a selective δ-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 GTPγS, 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 8.44×10 −5 M, which was close to that on I 5-HT. The results suggest that NTI and NTB, which are δ-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.