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

Despite the clear roles played by peroxisome proliferators-activated receptor α (PPAR-α) 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-α agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-α 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 μg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 μg), a synthetic PPAR-α agonist. The obligatory role of PPAR-α in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-α. 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-α in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-α (IkB-α) degradation and p65 nuclear factor kB (NF-κB) activation in DRG. PEA prevented IkB-α degradation and p65 NF-κB 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-α agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.