H1-receptor stimulation induces hyperalgesia through activation of the phospholipase C-PKC pathway.

The supraspinal cellular events involved in H1-mediated hyperalgesia were investigated in a condition of acute thermal pain by means of the mouse hot-plate test. I.c.v. administration of the phospholipase C (PLC) inhibitors U-73122 and neomycin antagonized the hyperalgesia induced by the selective H1 agonist FMPH. By contrast, U-73343, an analogue of U-73122 used as negative control, was unable to modify the reduction of the pain threshold induced by FMPH. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or treatment with heparin, an IP3-receptor antagonist, the hyperalgesia induced by the H1-receptor agonist remained unchanged. Similarly, pretreatment with D-myo inositol did not alter the H1-induced hypernociceptive response. Neither i.c.v. pretreatment with TMB-8, a blocker of Ca2+ release from intracellular stores, nor pretreatment with thapsigargin, a depletor of Ca2+ intracellular stores, prevented the decrease of pain threshold induced by FMPH. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitors calphostin C and chelerytrine resulted in a dose-dependent prevention of the H1-receptor agonist-induced hyperalgesia. The administration of PKC activators, suchas PMA and PDBu, did not produce any effect on FMPH effect. The pharmacological treatments employed did not produce any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate a role for the PLC–PKC pathway in central H1-induced hyperalgesia in mice. Furthermore, activation of PLC–IP3 did not appear to play a major role in the modulation of pain perception by H1-receptor agonists.