[The involvement of phosphoinositide 3-kinase (PI3-Kinase) and phospholipase C gamma (PLC gamma) pathway in the morphine-induced supraspinal antinociception in the mouse].
The present study was designed to investigate whether the phospholipase C gamma (PLC gamma)/phosphoinositide 3-kinase (PI3-Kinase) pathway could participate in the expression of the supraspinal antinociception induced by intracerebroventricular (i.c.v.) administration of mu-opioid receptor agonist in the mouse. The i.c.v. pretreatment with PI3-Kinase inhibitors, wortmannin and LY294002, and a specific antibody to PLC gamma 1 significantly attenuated the antinociception produced by either i.c.v. or systemic (s.c.) injection of a prototype of mu-agonist morphine. The s.c. injection of morphine produced a marked increase in the level of membrane-bound PLC gamma 1 isoform as compared to that from the saline-treated mice. This up-regulation of PLC gamma 1 by morphine was significantly inhibited by i.c.v. pretreatment with LY294002, indicating that morphine can activate PLC gamma 1 through the stimulation of PI3-Kinase. Pretreatment with a specific IP3 receptor inhibitor xestospongin C suppressed the morphine-induced antinociception in a dose-dependent manner. Recent studies have demonstrated that PI3-Kinase can be activated by G beta gamma, but not by G alpha subunit. In the present study, i.c.v. pretreatment with specific antibodies to G12 alpha and G beta gamma significantly suppressed the antinociception induced by morphine, whereas the specific antibody to Gq/11 alpha did not affect the antinociception induced by morphine. The present findings suggest that the supraspinal antinociception induced by mu-opioid receptor agonist may be mediated, at least in part, by the activation of PLC gamma through the stimulation of PI3-Kinase modulated by G beta gamma subunit.
Narita
M
M
Department of Toxicology, School of Pharmacy, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Ohnishi
O
O
Nemoto
M
M
Aoki
T
T
Suzuki
T
T
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D047028:Macrocyclic Compounds; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D011957:Receptors, Opioid / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D000077191:Wortmannin
D000701:Analgesics, Opioid; D000730:Androstadienes; D002867:Chromones; D007527:Isoenzymes; D047028:Macrocyclic Compounds; D009020:Morphine; D009025:Morpholines; D010080:Oxazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D011957:Receptors, Opioid; D010738:Type C Phospholipases; D000077191:Wortmannin; C108644:xestospongin A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one