Implications of phosphoinositide 3-kinase in the mu- and delta-opioid receptor-mediated supraspinal antinociception in the mouse.

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that activates signalling pathways. The present study was designed to investigate whether PI3K could be involved in supraspinal antinociception induced by intracerebroventricular (i.c.v.) administration of micro- and delta-opioid receptor agonists in the mouse. We demonstrated using the mouse warm-plate assay that the prototype of micro-opioid receptor agonist morphine, selective mu-opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO) and delta-opioid receptor agonists [D-Ala(2)]deltorphin II and [D-Pen(2,5)]enkephalin (DPDPE) when given i.c.v. produced profound antinociceptive responses. Under these conditions, i.c.v. pretreatment with cell-permeable and specific PI3K inhibitors wortmannin (0.7-2.3 nmol) and LY294002 (3-33 nmol), which alone had no effects on the basal warm-plate latencies, caused a dose-dependent inhibition of either morphine-, DAMGO-, DPDPE- or [D-Ala(2)]deltorphin II-induced antinociception. Furthermore, LY294002 at 33 nmol significantly shifted the dose-response curves for DAMGO-, DPDPE- and [D-Ala(2)]deltorphin II-induced antinociception to the right. In the immunoblotting assay, we found that PI3K gamma is dense in the periaqueductal gray and lower medulla regions that include several key sites for the production of opioid-induced antinociception. Our findings provide evidence that central PI3K pathways may, at least in part, contribute to the expression of supraspinal antinociception induced by both mu- and delta-opioid receptor agonists in the mouse.