The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at transient receptor potential vanilloid type-1 channels.

BACKGROUND AND AIMS:

Palmitoylethanolamide (PEA) is an endogenous congener of anandamide and an enhancer of its actions at cannabinoid receptors, CB1 and CB2, and transient receptor potential vanilloid type-1 (TRPV1) channels. The other endocannabinoid, 2-arachidonoylglycerol (2-AG), was recently suggested to act as a TRPV1 agonist. We investigated if PEA enhances the levels of 2-AG in vitro or in vivo and 2-AG activity at TRPV1.

METHODS:

Endogenous lipid levels were measured by liquid chromatography-mass spectrometry in: 1) human keratinocytes treated with PEA (10-20 μM, 40 min, 6h and 24 h, 37°C); 2) in the blood of spontaneously Ascaris suum hypersensitive Beagle dogs given a single oral dose of ultramicronized PEA (30 mg/kg, 1, 2, 4 and 8 h from administration); 3) the blood of healthy volunteers given a single oral dose of micronized PEA (300 mg, 2, 4 and 6 h from administration). The effect of 2-AG at TRPV1 was assessed by measuring intracellular Ca2+ in HEK-293 cells over-expressing human TRPV1.

RESULTS:

PEA significantly elevated the amounts of 2-AG in keratinocytes (∼3-fold) and its plasma levels in humans and dogs (∼2 and ∼20-fold, respectively). 2-AG dose-dependently elevated intracellular Ca2+ in HEK-293-TRPV1 cells in a TRPV1-dependent manner, and desensitized the cells to the effect of capsaicin. PEA only slightly enhanced 2-AG activation of TRPV1, but significantly increased 2-AG-induced TRPV1 desensitization to capsaicin (IC50 from 0.75±0.04 to 0.45±0.02 μM, with PEA 2 μM).

CONCLUSIONS:

These observations may explain why several effects of PEA can be attenuated by cannabinoid receptor or TRPV1 channel antagonists.
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