TY - JOUR T1 - Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-α Agonist, Modulates Carrageenan-Induced Paw Edema in Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1137 LP - 1143 DO - 10.1124/jpet.107.123265 VL - 322 IS - 3 AU - Giuseppe D'Agostino AU - Giovanna La Rana AU - Roberto Russo AU - Oscar Sasso AU - Anna Iacono AU - Emanuela Esposito AU - Giuseppina Mattace Raso AU - Salvatore Cuzzocrea AU - Jesse Lo Verme AU - Daniele Piomelli AU - Rosaria Meli AU - Antonio Calignano Y1 - 2007/09/01 UR - http://jpet.aspetjournals.org/content/322/3/1137.abstract N2 - Peroxisome proliferator-activated receptor (PPAR)-α is a nuclear transcription factor. Although the presence of this receptor in different areas of central nervous system (CNS) has been reported, its role remains unclear. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-α ligand, exerting analgesic and anti-inflammatory effects. High levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Using carrageenan-induced paw edema in mice, we show that i.c.v. administration of PEA may control peripheral inflammation through central PPAR-α activation. A single i.c.v. administration of 0.01 to 1 μg of PEA, 30 min before carrageenan injection, reduced edema formation in the mouse carrageenan test. This effect was mimicked by 0.01 to 1 μg of GW7647 [2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid], a synthetic PPAR-α agonist. Moreover, central PEA administration significantly reduced the expression of the proinflammatory enzymes cyclooxygenase-2 and inducible nitric-oxide synthase, and it significantly restored carrageenan-induced PPAR-α reduction in the spinal cord. To investigate the mechanism by which i.c.v. PEA attenuated the development of carrageenan-induced paw edema, we evaluated inhibitor κB-α (IκB-α) degradation and nuclear factor-κB (NF-κB) p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB-α degradation and NF-κB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral inflammation. The obligatory role of PPAR-α in mediating the effects of PEA was confirmed by the lack of the compounds anti-inflammatory effects in mutant mice lacking PPAR-α. In conclusion, our data show for the first time that PPAR-α activation in the CNS can control peripheral inflammation. ER -