Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-[kappa]B nuclear signalling in dorsal root ganglia.
D'Agostino, Giuseppe a; La Rana, Giovanna a; Russo, Roberto a; Sasso, Oscar a; Iacono, Anna a; Esposito, Emanuela a,d; Mattace Raso, Giuseppina a; Cuzzocrea, Salvatore c,d; LoVerme, Jesse b; Piomelli, Daniele b; Meli, Rosaria a; Calignano, Antonio a,*
[Miscellaneous Article]
European Journal of Pharmacology.
613(1):54-59, June 24, 2009.
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Despite the clear roles played by peroxisome proliferators-activated receptor [alpha] (PPAR-[alpha]) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-[alpha] agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-[alpha] and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 [mu]g) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 [mu]g), a synthetic PPAR-[alpha] agonist. The obligatory role of PPAR-[alpha] in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-[alpha]. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-[alpha] in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-[alpha] (IkB-[alpha]) degradation and p65 nuclear factor kB (NF-[kappa]B) activation in DRG. PEA prevented IkB-[alpha] degradation and p65 NF-[kappa]B nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-[alpha] agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.
(C) 2009Elsevier, Inc.