Acetyl-l-carnitine requires phospholipase C-IP₃ pathway activation to induce antinociception

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• 作者：Galeotti ; Nicoletta ; Bartolini ; Alessandro ; Calvani ; Menotti ; Nicolai ; Raffaella ; Ghelardini ; Carla
• 关键词：Acetyl-l-carnitine ; Analgesia ; Phospholipase Cβ ; ₁ ; Inositol-1 ; 4 ; 5-trisphosphate ; Protein kinase C ; Cholinergic system
• 刊名：Neuropharmacology
• 出版年：2004
• 出版时间：August, 2004
• 年：2004
• 卷：47
• 期：2
• 页码：286-294
• 全文大小：276 K

文摘

The cellular events involved in acetyl-l-carnitine (ALCAR) analgesia were investigated in the mouse hot plate test. I.c.v. pretreatment with aODNs against the α subunit of G_q and G₁₁ proteins prevented the analgesia induced by ALCAR (100 mg kg⁻¹ s.c. twice daily for 7 days). Administration of the phospholipase C (PLC) inhibitors U-73122 and neomycin, as well as the injection of an aODN complementary to the sequence of PLCβ₁, antagonized the increase of the pain threshold induced by ALCAR. Pretreatment with U-73343, an analogue of U-73112 inactive on PLC, did not modify ALCAR analgesic effect. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or pretreatment with TMB-8, a blocker of Ca⁺⁺ release from intracellular stores, the antinociception induced by ALCAR was dose-dependently antagonized. I.c.v. treatment with heparin, an IP₃ receptor antagonist, prevented the increase of pain threshold induced by the investigated compound, analgesia that was restored by co-administration of d-myo-inositol. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitors calphostin C and cheleritryne, resulted in a dose-dependent potentiation of ALCAR antinociception. The administration of PKC activators, such as PMA and PDBu, dose-dependently prevented the ALCAR-induced increase of pain threshold. Neither aODNs nor pharmacological treatments produced any behavioral impairment of mice as revealed by the rota-rod and hole board tests. These results indicate that central ALCAR analgesia in mice requires the activation of the PLC-IP₃ pathway. By contrast, the simultaneous activation of PKC may represent a pathway of negative modulation of ALCAR antinociception.