Palmitoylethanolamide (PEA) is an endogenous lipid that is thought to be involved in endogenous protective mechanisms activated as a result of stimulation of inflammatory response. In spite of the well demonstrated anti-inflammatory properties of PEA, its involvement in controlling pain pathways still remains poorly characterized. On this basis, we tested the efficacy of PEA in vivo against a peculiar persistent pain, such as neuropathic one. PEA was administered i.p. to mice with chronic constriction injury of sciatic nerve (CCI) once a day for one week starting the day after the lesion. This therapeutic regimen evoked a relief of both thermal hyperalgesia and mechanical allodynia in neuropathic mice. Various selective receptor antagonists were used in order to clarify the relative contribution of cannabinoid, vanilloid and peroxisome proliferator-activated receptor to PEA-induced effects. The results indicated that CB(1), PPARgamma and TRPV1 receptors mediated the antinociception induced by PEA, suggesting that the most likely mechanism might be the so-called "entourage effect" due to the PEA-induced inhibition of the enzyme catalyzing the endocannabinoid anandamide (AEA) degradation that leads to an enhancement of its tissue levels thus increasing its analgesic action. In addition, the hypothesis that PEA might act through the modulation of local mast cells degranulation is sustained by our findings showing that PEA significantly reduced the production of many mediators such as TNFalpha and neurotrophic factors, like NGF. The findings presented here, in addition to prove the beneficial effects of PEA in chronic pain, identify new potential targets for analgesic medicine.

The anti‐inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo‐oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan‐induced acute paw inflammation and compared with the nonsteroidal anti‐inflammatory drug (NSAID) indomethacin. Palmitoylethanolamide (1, 3, 5, 10 mg kg⁻¹; p.o.) and indomethacin (5 mg kg⁻¹; p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO₂⁻/NO₃⁻), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan‐induced oedema in a dose‐ and time‐dependent manner. This effect was not reversed by the selective CB₂ receptor antagonist (N‐[(1S)‐endo‐1,3,3‐trimethylbicyclo[2.2.1]heptan‐2yl]‐5‐(4‐chloro‐3‐methylphenyl)‐1‐(4‐methylbenzyl)pyrazole‐3 carboxamide) (SR144528), 3 mg kg⁻¹ p.o. On the fourth day after carrageenan injection, COX activity and the level of NO₂⁻/NO₃⁻, eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg⁻¹) and indomethacin markedly reduced these increases. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity. British Journal of Pharmacology (2002) 137, 413–420. doi:10.1038/sj.bjp.0704900