title: Negative regulation of opioid receptor-G protein-Ca2+ channel pathway by the nootropic nefiracetam.
abstract: It has recently been reported that nefiracetam, a nootropic agent, is capable of attenuating the development of morphine dependence and tolerance in mice. The mechanism of this antimorphine action is not clear. The present study was designed to address this issue using Xenopus oocytes expressing delta-opioid receptors, G proteins (G(i3alpha) or G(o1alpha)), and N-type (alpha1B) Ca2+ channels. Membrane currents through Ca2+ channels were recorded from the oocytes under voltage-clamp conditions. The Ca2+ channel currents were reduced reversibly by 40-60% in the presence of 1 microM leucine-enkephalin (Leu-Enk). The Leu-Enk-induced current inhibition was recovered promptly by nefiracetam (1 microM), while control currents in the absence of Leu-Enk were not influenced by nefiracetam. A binding assay revealed that 3H-nefiracetam preferentially bound to the membrane fraction of oocytes expressing G(i3alpha). When delta-opioid receptors were coexpressed, the binding was significantly increased. However, an additional expression of alpha1B Ca2+ channels decreased the binding. The results suggest that nefiracetam preferentially binds to G(i3alpha) associated with delta-opioid receptors, thereby inhibiting the association of G proteins with Ca2+ channels. In conclusion, nefiracetam negatively regulates the inhibitory pathway of opioid receptor-G protein-Ca2+ channel.
authors.affiliation: Department of Neural Plasticity, Tokyo Institute of Psychiatry, Setagaya-ku, Tokyo 156-8585, Japan. yoshii@prit.go.jp
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Yoshii
authors.forename: Taiji
authors.initials: T
authors.lastname: Furukawa
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Ogihara
authors.forename: Shigeo
authors.initials: S
authors.lastname: Watabe
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shiotani
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Masao
authors.initials: M
authors.lastname: Nishimura
authors.forename: Toshihide
authors.initials: T
authors.lastname: Nukada
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011760:Pyrrolidinones / Q000378:metabolism* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D014981:Xenopus
chemical_list: D015220:Calcium Channels; D018697:Nootropic Agents; D011760:Pyrrolidinones; D011957:Receptors, Opioid; C058876:nefiracetam; D019204:GTP-Binding Proteins