Palmitoylethanolamide reduces inflammation and itch in a mouse model of contact allergic dermatitis

In mice, 2,4-dinitrofluorobenzene (DNFB) induces contact allergic dermatitis (CAD), which, in a late phase, is characterized by mast cell (MC) infiltration and angiogenesis. Palmitoylethanolamide (PEA), an endogenous anti-inflammatory molecule, acts by down-modulating MCs following activation of the cannabinoid CB₂ receptor and peroxisome proliferator-activated receptor-α (PPAR-α). We have previously reported the anti-inflammatory effect of PEA in the early stage of CAD. Here, we examined whether PEA reduces the features of the late stage of CAD including MC activation, angiogenesis and itching. After sensitization to DNFB, female C57BL/6J mice underwent to three DNFB challenges at days 5, 12 and 19 and treatments were given at each challenge and for two more days. CAD was expressed as Δ increase in ear thickness between challenged and un-challenged mice. PEA (5mg/kg/i.p.) reduced: i) the DNFB-induced Δ increase; ii) the number of MCs per tissue area; iii) the expression of VEGF and its receptor Flk-1. These effects were reversed by co-administration of AM630 (1mg/kg/i.p.), a CB₂ antagonist, but not GW6471 (1mg/kg/i.p.), a PPAR-α antagonist. Finally, PEA reduced the number of ear scratchings 48h after DNFB challenge and this effect was reversed by both CB2 and PPAR-α antagonists, suggesting the involvement of both receptors. PEA, by reducing the features of late stage CAD in mice, may be beneficial in this pathological condition.