title: The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors.
abstract: 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.
authors.affiliation: Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy Department of Pharmacology, University of Milano, via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Francesca
authors.initials: F
authors.lastname: Comelli
authors.forename: Isabella
authors.initials: I
authors.lastname: Bettoni
authors.forename: Mariapia
authors.initials: M
authors.lastname: Colleoni
authors.forename: Gabriella
authors.initials: G
authors.lastname: Giagnoni
mesh_terms: D000577:Amides; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003594:Cytoplasmic Granules / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids; D004983:Ethanolamines; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008026:Ligation; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism*; D047493:PPAR alpha / Q000037:antagonists & inhibitors; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D010169:Palmitic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D010812:Physical Stimulation / Q000009:adverse effects; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries; D012585:Sciatica / Q000188:drug therapy* / Q000503:physiopathology; D013116:Spinal Cord / Q000737:chemistry; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D014110:Touch; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000577:Amides; D018712:Analgesics, Non-Narcotic; D063388:Endocannabinoids; D004983:Ethanolamines; D016328:NF-kappa B; D009414:Nerve Growth Factors; D047493:PPAR alpha; D047495:PPAR gamma; D010169:Palmitic Acids; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C005958:palmidrol