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Negative Regulation of Opioid Receptor‐G Protein‐Ca 2+ Channel Pathway by the Nootropic Nefiracetam
Author(s) -
YOSHII MITSUNOBU,
FURUKAWA TAIJI,
OGIHARA YOSHIYASU,
WATABE SHIGEO,
SHIOTANI TADASHI,
ISHIKAWA YASURO,
NISHIMURA MASAO,
NUKADA TOSHIHIDE
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1316.048
Subject(s) - chemistry , opioid receptor , opioid , biophysics , inhibitory postsynaptic potential , receptor , voltage clamp , pharmacology , membrane potential , biochemistry , endocrinology , biology
A bstract : 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 δ‐opioid receptors, G proteins (G i3α or G o1α ), and N‐type (α 1B ) Ca 2+ channels. Membrane currents through Ca 2+ channels were recorded from the oocytes under voltage‐clamp conditions. The Ca 2+ channel currents were reduced reversibly by 40‐60% in the presence of 1 μM leucine‐enkephalin (Leu‐Enk). The Leu‐Enk‐induced current inhibition was recovered promptly by nefiracetam (1 μM), while control currents in the absence of Leu‐Enk were not influenced by nefiracetam. A binding assay revealed that 3 H‐nefiracetam preferentially bound to the membrane fraction of oocytes expressing G i3α . When δ‐opioid receptors were coexpressed, the binding was significantly increased. However, an additional expression of α 1B Ca 2+ channels decreased the binding. The results suggest that nefiracetam preferentially binds to G i3α associated with δ‐opioid receptors, thereby inhibiting the association of G proteins with Ca 2+ channels. In conclusion, nefiracetam negatively regulates the inhibitory pathway of opioid receptor‐G protein‐Ca 2+ channel.