The phospholipase C-IP3 pathway is involved in muscarinic antinociception

Abstract

The cellular events involved in muscarinic analgesia were investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) pretreatment with antisense oligonucleotides (aODNs) against theasubunit of Gq and G11 proteins prevented the analgesia induced byphysostigmine and oxotremorine. Furthermore, administration of the phospholipase C (PLC) inhibitor U-73122, as wellas the injectionof an aODN complementary to the sequence of PLCß1, antagonized the increase ofthe pain threshold induced by both cholinomimeticdrugs. In mice undergoing treatment with LiCl, which impairs phosphatidylinositolsyn thesis, ortreatment with heparin, an IP3receptorantagonist, the antinociception induced by physostigmine and oxotremorine was dose-dependently antagonized. I.c.v. pretreatment withTMB-8, a blocker of Ca2+ release from intracellular stores, prevented the increase of pain threshold induced by the investigatedcholinomimetic drugs. Coadministration of Ca2+ restored the muscarinic analgesia in LiCl, heparin, and TMB-8-preatreated mice. On theother hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitor calphostinC, resulted in a dose-dependentenhancement of physostigmine- and oxotremorine-induced antinociception. The administration of PKC activators, such as PMA andPDBu, dose dependently prevented the cholinomimetic drug-induced increase of pain threshold. Neither aODNs nor pharmacologicaltreatments employed produced any behavioralimpairment of mice as revealed by the rota-rod and hole-board tests. These resultsindicate a role forthe PLC-IP3 pathway in central muscarinic analgesia in mice. Furthermore, activation of PKC by cholinomimetic drugsmay represent a pathway of negative modulation of muscarinic antinociception. © 2003 American College of Neuropsychopharmacology.