Disruption of the type 1 inositol 1,4,5-trisphosphate receptor gene suppresses the morphine-induced antinociception in the mouse.

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.