Acetyl-L-carnitine requires phospholipase C-IP3 pathway activation to induce antinociception.
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 alpha subunit of G(q) and G(11) 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 PLCbeta(1), 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 IP(3) 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-IP(3) pathway. By contrast, the simultaneous activation of PKC may represent a pathway of negative modulation of ALCAR antinociception.
Galeotti
Nicoletta
N
Department of Pharmacology, University of Florence, Viale G. Pieraccini 6, I-50139 Florence, Italy. nicoletta.galeotti@unifi.it
Bartolini
Alessandro
A
Calvani
Menotti
M
Nicolai
Raffaella
R
Ghelardini
Carla
C
D000108:Acetylcarnitine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000700:Analgesics / Q000037:antagonists & inhibitors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004075:Diglycerides / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006358:Hot Temperature; D007276:Injections, Intraventricular; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D051379:Mice; D018697:Nootropic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance; D011493:Protein Kinase C / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000502:physiology*
D000700:Analgesics; D004075:Diglycerides; D018697:Nootropic Agents; D016376:Oligonucleotides, Antisense; D000108:Acetylcarnitine; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases; D018021:Lithium Chloride