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: 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
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 613 Issue 1-3 Pg. 54-9 (Jun 24 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19386271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Analgesics
• Butyrates
• Endocannabinoids
• Ethanolamines
• GW 7647
• NF-kappa B
• PPAR alpha
• Palmitic Acids
• Phenylurea Compounds
• palmidrol
• Carrageenan
• Nitric Oxide Synthase Type II
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Amides
• Analgesics (administration & dosage, pharmacology, therapeutic use)
• Animals
• Butyrates (administration & dosage, pharmacology)
• Carrageenan (toxicity)
• Cell Nucleus (drug effects, metabolism)
• Central Nervous System (metabolism)
• Cyclooxygenase 2 (biosynthesis)
• Endocannabinoids
• Enzyme Induction (drug effects)
• Ethanolamines
• Ganglia, Spinal (drug effects, metabolism, pathology)
• Hyperalgesia (chemically induced, drug therapy, metabolism, pathology)
• Male
• Mice
• NF-kappa B (metabolism)
• Nitric Oxide Synthase Type II (biosynthesis)
• PPAR alpha (agonists, metabolism)
• Palmitic Acids (administration & dosage, pharmacology, therapeutic use)
• Phenylurea Compounds (administration & dosage, pharmacology)
• Sciatic Nerve (drug effects, metabolism)
• Signal Transduction (drug effects)