Aoki Takeshi, Narita Minoru, Ohnishi Orie, Mizuo Keisuke, Narita Michiko, Yajima Yoshinori, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Neurosci Lett. 2003 Oct 23;350(2):69-72. doi: 10.1016/s0304-3940(03)00829-2.
The present study was designed to investigate whether endoplasmic inositol 1,4,5-trisphosphate (IP3) receptor-mediated intracellular signaling pathway could be involved in the morphine-induced antinociception in the mouse. An intracerebroventricular (i.c.v.) pretreatment with xestospongin C (10-100 pmol per mouse, i.c.v.), a membrane permeable and selective antagonist for IP3 receptor, produced a dose-dependent reduction in the supraspinal antinociceptive effect produced by i.c.v. administration of morphine (0.3-10 nmol). In addition, the dose-response curve for morphine-induced antinociception was significantly shifted to the right by i.c.v. pretreatment with xestospongin C at 100 pmol. In the present study, we confirmed that the IP3R1 mRNA in opisthonos (opt) heterozygote mice was approximately 50% reduced as compared to that in wild-type mice. Under these conditions, a significant antinociception produced by subcutaneous (s.c.) injection of morphine (5 mg/kg) observed in wild-type mice was markedly reduced in opt heterozygote mice. These findings suggest that IP3 receptor-, especially type 1 IP3 receptor-mediated intracellular signaling pathway may be implicated in the expression of antinociceptive effect induced by morphine in mice.
本研究旨在探究内质网肌醇1,4,5 -三磷酸（IP3）受体介导的细胞内信号通路是否参与吗啡诱导的小鼠镇痛作用。用西司他汀C（每只小鼠脑室内注射10 - 100 pmol）进行脑室内预处理，西司他汀C是一种膜通透性且选择性的IP3受体拮抗剂，可使脑室内注射吗啡（0.3 - 10 nmol）产生的脊髓上镇痛作用呈剂量依赖性降低。此外，100 pmol的西司他汀C脑室内预处理可使吗啡诱导的镇痛作用剂量 - 反应曲线显著右移。在本研究中，我们证实与野生型小鼠相比，角弓反张（opt）杂合子小鼠中的IP3R1 mRNA减少了约50%。在这些条件下，野生型小鼠皮下注射吗啡（5 mg/kg）产生的显著镇痛作用在opt杂合子小鼠中明显减弱。这些发现表明，IP3受体，尤其是1型IP3受体介导的细胞内信号通路可能参与了吗啡诱导的小鼠镇痛作用的表达。
