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.
Aoki
Takeshi
T
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Narita
Minoru
M
Ohnishi
Orie
O
Mizuo
Keisuke
K
Narita
Michiko
M
Yajima
Yoshinori
Y
Suzuki
Tsutomu
T
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000700:Analgesics; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D009020:Morphine