The supraspinal cellular events involved in H(1)-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 H(1) 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 IP(3)-receptor antagonist, the
hyperalgesia induced by the H(1)-receptor agonist remained unchanged. Similarly, pretreatment with D-myo
inositol did not alter the H(1)-induced hypernociceptive response. Neither i.c.v. pretreatment with
TMB-8, a blocker of Ca(2+) release from intracellular stores, nor pretreatment with
thapsigargin, a depletor of Ca(2+) 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 H(1)-receptor agonist-induced
hyperalgesia. The administration of PKC activators, such as 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 H(1)-induced
hyperalgesia in mice. Furthermore, activation of PLC-IP(3) did not appear to play a major role in the modulation of pain perception by H(1)-receptor agonists.