Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia

Giuseppe D'Agostino, Giovanna La Rana, Roberto Russo, Oscar Sasso, Anna Iacono, Emanuela Esposito, Giuseppina Mattace Raso, Salvatore Cuzzocrea, Jesse LoVerme, Daniele Piomelli, Rosaria Meli, Antonio Calignano

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124 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)54-59
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number1-3
Early online date20 Apr 2009
Publication statusPublished - 24 Jun 2009


  • analgesics
  • animals
  • butyrates
  • carrageenan
  • cell nucleus
  • central nervous system
  • cyclooxygenase 2
  • endocannabinoids
  • enzyme induction
  • ethanolamines
  • ganglia, spinal
  • hyperalgesia
  • male
  • mice
  • NF-kappa B
  • nitric oxide synthase type II
  • PPAR alpha
  • palmitic acids
  • phenylurea compounds
  • sciatic nerve
  • signal transduction


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