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

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• 作者：Galeotti ; Nicoletta ; Malmberg-Aiello ; Petra ; Bartolini ; Alessandro ; Schunack ; Walter ; Ghelardini ; Carla
• 关键词：Histamine H1-receptor ; Hyperalgesia ; Phospholipase C ; Inositol-1 ; 4 ; 5-trisphosphate ; Protein kinase C ; Ca²⁺
• 刊名：Neuropharmacology
• 出版年：2004
• 出版时间：August, 2004
• 年：2004
• 卷：47
• 期：2
• 页码：295-303
• 全文大小：313 K

文摘

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, 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 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.