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The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels.
Br J Pharmacol. 2016 Apr; 173(7):1154-62.BJ

Abstract

BACKGROUND AND PURPOSE

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

EXPERIMENTAL APPROACH

Endogenous lipid levels were measured by LC-MS in (i) human keratinocytes incubated with PEA (10-20 μM, 40 min, 6 and 24 h, 37°C); (ii) the blood of spontaneously Ascaris suum hypersensitive beagle dogs given a single oral dose of ultramicronized PEA (30 mg·kg(-1), 1, 2, 4 and 8 h from administration); (iii) the blood of healthy volunteers given a single oral dose of micronized PEA (300 mg, 2, 4 and 6 h from administration). Effects of 2-AG at TRPV1 channels were assessed by measuring intracellular Ca(2+) in HEK-293 cells over-expressing human TRPV1 channels.

KEY RESULTS

PEA elevated 2-AG levels in keratinocytes (∼3-fold) and in human and canine plasma (∼2 and ∼20-fold respectively). 2-AG dose-dependently raised intracellular Ca(2+) in HEK-293-TRPV1 cells in a TRPV1-dependent manner and desensitized the cells to capsaicin. PEA only slightly enhanced 2-AG activation of TRPV1 channels, 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 AND IMPLICATIONS

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

LINKED ARTICLES

This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.

Authors+Show Affiliations

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy. Epitech Group, Saccolongo, Padua, Italy.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy. Epitech Group, Saccolongo, Padua, Italy.Departament de Farmacología, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain.Epitech Group, Saccolongo, Padua, Italy.Departament de Farmacología, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25598150

Citation

Petrosino, Stefania, et al. "The Anti-inflammatory Mediator Palmitoylethanolamide Enhances the Levels of 2-arachidonoyl-glycerol and Potentiates Its Actions at TRPV1 Cation Channels." British Journal of Pharmacology, vol. 173, no. 7, 2016, pp. 1154-62.
Petrosino S, Schiano Moriello A, Cerrato S, et al. The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol. 2016;173(7):1154-62.
Petrosino, S., Schiano Moriello, A., Cerrato, S., Fusco, M., Puigdemont, A., De Petrocellis, L., & Di Marzo, V. (2016). The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. British Journal of Pharmacology, 173(7), 1154-62. https://doi.org/10.1111/bph.13084
Petrosino S, et al. The Anti-inflammatory Mediator Palmitoylethanolamide Enhances the Levels of 2-arachidonoyl-glycerol and Potentiates Its Actions at TRPV1 Cation Channels. Br J Pharmacol. 2016;173(7):1154-62. PubMed PMID: 25598150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. AU - Petrosino,Stefania, AU - Schiano Moriello,Aniello, AU - Cerrato,Santiago, AU - Fusco,Mariella, AU - Puigdemont,Anna, AU - De Petrocellis,Luciano, AU - Di Marzo,Vincenzo, Y1 - 2015/03/26/ PY - 2014/05/23/received PY - 2014/12/16/revised PY - 2015/01/06/accepted PY - 2015/1/20/entrez PY - 2015/1/20/pubmed PY - 2016/12/15/medline SP - 1154 EP - 62 JF - British journal of pharmacology JO - Br J Pharmacol VL - 173 IS - 7 N2 - BACKGROUND AND PURPOSE: Palmitoylethanolamide (PEA) is an endogenous congener of anandamide and potentiates its actions at cannabinoid CB1 and CB2 receptors, and at transient receptor potential vanilloid type-1 (TRPV1) channels. The other endocannabinoid, 2-arachidonoylglycerol (2-AG), was recently suggested to act as a TRPV1 channel agonist. We investigated if PEA enhanced levels of 2-AG in vitro or in vivo and 2-AG activity at TRPV1 channels. EXPERIMENTAL APPROACH: Endogenous lipid levels were measured by LC-MS in (i) human keratinocytes incubated with PEA (10-20 μM, 40 min, 6 and 24 h, 37°C); (ii) the blood of spontaneously Ascaris suum hypersensitive beagle dogs given a single oral dose of ultramicronized PEA (30 mg·kg(-1), 1, 2, 4 and 8 h from administration); (iii) the blood of healthy volunteers given a single oral dose of micronized PEA (300 mg, 2, 4 and 6 h from administration). Effects of 2-AG at TRPV1 channels were assessed by measuring intracellular Ca(2+) in HEK-293 cells over-expressing human TRPV1 channels. KEY RESULTS: PEA elevated 2-AG levels in keratinocytes (∼3-fold) and in human and canine plasma (∼2 and ∼20-fold respectively). 2-AG dose-dependently raised intracellular Ca(2+) in HEK-293-TRPV1 cells in a TRPV1-dependent manner and desensitized the cells to capsaicin. PEA only slightly enhanced 2-AG activation of TRPV1 channels, 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 AND IMPLICATIONS: These observations may explain why several effects of PEA are attenuated by cannabinoid receptor or TRPV1 channel antagonists. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/25598150/The_anti_inflammatory_mediator_palmitoylethanolamide_enhances_the_levels_of_2_arachidonoyl_glycerol_and_potentiates_its_actions_at_TRPV1_cation_channels_ L2 - https://doi.org/10.1111/bph.13084 DB - PRIME DP - Unbound Medicine ER -