Negative regulation of opioid receptor-G protein-Ca2+ channel pathway by the nootropic nefiracetam.
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.
Yoshii
Mitsunobu
M
Department of Neural Plasticity, Tokyo Institute of Psychiatry, Setagaya-ku, Tokyo 156-8585, Japan. yoshii@prit.go.jp
Furukawa
Taiji
T
Ogihara
Yoshiyasu
Y
Watabe
Shigeo
S
Shiotani
Tadashi
T
Ishikawa
Yasuro
Y
Nishimura
Masao
M
Nukada
Toshihide
T
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
D015220:Calcium Channels; D018697:Nootropic Agents; D011760:Pyrrolidinones; D011957:Receptors, Opioid; C058876:nefiracetam; D019204:GTP-Binding Proteins