Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain.

Alessio Ardizzone,Roberta Fusco,Salvatore Cuzzocrea,Daniela Impellizzeri,Emanuela Esposito,Giovanna Casili,Marika Lanza

doi:10.3390/ijms22041967

Abstract

Palmitoylethanolamide (PEA), a fatty acid amide, has been widely investigated for its analgesic and anti-inflammatory properties. The ultra-micronized formulation of PEA (um-PEA), that has an enhanced rate of dissolution, is extensively used. Acetyl-l-carnitine (LAC), employed for the treatment of neuropathic pain in humans, is able to cause analgesia by up-regulating type-2 metabotropic glutamate (mGlu2) receptors. In the present study, we tested different associations of um-PEA, LAC and non-micronized PEA (non-m-PEA) in a rat model of carrageenan (CAR)-induced paw edema. Intraplantar injection of CAR into the hind paw of animals caused edema, thermal hyperalgesia, accumulation of infiltrating inflammatory cells and augmented myeloperoxidase (MPO) activity. All these parameters were decreased in a significantly manner by oral administration of a compound constituted by a mixture of um-PEA and LAC in relation 1:1 (5 mg/kg), but not with the association of single compounds administered one after the other. These findings showed the superior anti-inflammatory and anti-nociceptive action displayed by oral administration of um-PEA and LAC versus LAC plus, separate but consecutive, um-PEA in the rat paw CAR model of inflammatory pain.

Highlights

Inflammation and pain are characterized by elevate levels of interleukins and prostaglandins [1]
The anti-hyperalgesic and antiinflammatory effects of PEA are explained by several mechanisms: the activation on the cell surface of the cannabinoid (CB) 2-like receptor or the orphan G protein-coupled receptor (GPR)-55 receptor, or the nuclear receptor of the peroxisome proliferator-activated receptors (PPAR) family [8], and the down-regulation of mast cells (MC) degranulation Autacoid Local Inflammation Antagonism (ALIA) mechanism [9]
We aim to demonstrate that ultra-micronized formulation of PEA (um-PEA) is able to reduce inflammatory process already at lower dose compared to a higher dose of non-m-PEA

Summary

Introduction

Inflammation and pain are characterized by elevate levels of interleukins and prostaglandins [1]. Current approaches for resolving inflammation consist in targeting ion channels enzymes, epigenetics (for example, histone modification), RNAs (antisense oligonucleotides), and lipid mediators among others These lipid mediators can act restoring homeostasis and moderate pain sensitivity through the regulation of the flow of nociceptive signals to the central nervous system [2]. Palmitoylethanolamide (PEA), a fatty acid amide which belongs to the family of N-acylethanolamines (NAEs), is considered an endogenous molecule that controls tissue reactivity and the related inflammatory antalgic phenomena [3,4] It successfully controls neuropathic pain induced by lesions at the peripheral and at the central nervous system [5,6,7]. A large body of evidence shows the efficacy of acetyl-L-carnitine (LAC) in the treatment of fibromyalgia, neuropathic, and other types of chronic pain, with a good profile of safety and tolerability [10,11]

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