title: Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-kappaB nuclear signalling in dorsal root ganglia.
abstract: 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 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), 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-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB 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.
authors.affiliation: Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.forename: Giovanna
authors.initials: G
authors.lastname: La Rana
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.forename: Anna
authors.initials: A
authors.lastname: Iacono
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mattace Raso
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Jesse
authors.initials: J
authors.lastname: Loverme
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
mesh_terms: D000577:Amides; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002087:Butyrates / Q000008:administration & dosage / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D063388:Endocannabinoids; D004790:Enzyme Induction / Q000187:drug effects; D004983:Ethanolamines; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D010169:Palmitic Acids / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000577:Amides; D000700:Analgesics; D002087:Butyrates; D063388:Endocannabinoids; D004983:Ethanolamines; C453899:GW 7647; D016328:NF-kappa B; D047493:PPAR alpha; D010169:Palmitic Acids; D010671:Phenylurea Compounds; C005958:palmidrol; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2