Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats
Introduction.
Mast cells (MCs) are well recognized as a "body guard" in host defense reactions, as inducers of innate and acquired immunity and tissue remodelling, because of their pivotal role in initiating allergic reactions. Moreover, in recent years, MCs have also been acknowledged to modulate the inflammatory process [1].
Their contribution to neuro-immune processes remains, however, less clear. There are many independent lines of evidence that indicate massive, bidirectional cross-talk between MCs and sensory nerves (SNs) suggesting that MCs and SNs may be functionally [2] and anatomically assembled within certain tissues [3,4].
In the skin, for instance, MCs are frequently co-localized with nerve fibres expressing substance P (SP) and calcitonin gene-related peptide (CGRP) and/or other peptidergic mediators [5]; moreover, activated MCs produce and release histamine, serotonin, and tryptase leading to SNs activation thus contributing to neurogenic inflammatory reactions [6]. Above all, MCs by releasing NGF and TNF-α, are thought to regulate SNs development, degeneration, and regeneration [7,8]. Therefore, MCs and SNs have been suggested to co-orchestrate a variety of physiological and pathological processes, such as hair follicle cycling, wound healing, stress responses and to contribute to the pathogenesis of inflammatory and autoimmune diseases [9,10].
In several animal models of inflammatory pain, including complete Freund's adjuvant-induced arthritis [11], carrageenin-induced paw oedema [12] and a rat model of cystitis [13,14], NGF expression was found to be increased. Moreover, it has been shown that over-expression of NGF results in a marked nerve fibre hyperplasia in the urinary bladder submucosa [15]. Recently, the administration of a new molecule sequestrating endogenous NGF has shown to reduce acute and chronic inflammatory processes and associated pain [16]. These studies suggest that peripherally produced NGF is involved in the development and maintenance of nociceptive sensory neuron sensitivity and that an up-regulation of NGF is responsible for alterations in pain-related behaviour [17]. Therefore, blockade of NGF production and/or its action has been proposed as a novel strategy to avoid nerve hypersensitivity induced by inflammation, and possibly as a novel non-canonical anti-inflammatory analgesic drug [18].
A class of molecules potentially able to control NGF synthesis and release is represented by ALIA compounds (from the acronym Autacoid Local Injury Antagonist), naturally-occurring lipid amides deriving from membrane fatty acids and structurally related to endocannabinoids. Palmitoylethanolamide (PEA) is considered the most important of the ALIAmides because of its ability to negatively modulate MC activation [19,20].
Although considerably more abundant than the endocannabinoid anandamide (arachidonoyl ethanol amide: AEA) or 2-arachidonoylglycerol (2-AG) in many tissues, the effects of PEA are less well know than those of AEA or 2-AG, probably due to its puzzling mechanism of action. In fact, PEA, although structurally related to AEA is inactive at the cannabinoid CB1/CB2 receptor site, but it exhibits several important pharmacological effects shared with endocannabinoid compounds, such as marked anti-inflammatory, anti-oedema and analgesic properties in a wide range of experimental models of inflammation [21]. There are several pieces of evidence indicating that PEA might represent part of a "parallel" endocannabinoid signalling system, with its own putative receptors.
To date, peroxisome proliferator-activated receptor-α (PPAR-α) and G protein-coupled receptor 55 (GPR55) have been suggested as endogenous putative receptors for PEA, since their stimulation contributes to some of PEA-induced anti-inflammatory and analgesic effects.
Moreover, it has been demonstrated that PEA significantly reduces peripheral pain through a mechanism that is enhanced by AEA and blocked by CB2 receptor antagonists [16]. The mechanism through which PEA exerts its anti-nociceptive effects remains unclear since it does not interact with the CB2 receptor. Therefore, it has been postulated that this compound might evoke analgesia through a still uncharacterized CB2-like receptor [16], probably expressed specifically on MCs [19]. Alternatively, several important actions of PEA seem to be mediated by none of these receptors, but independently of any receptor activation [22].
The effect of PEA on NGF release leads to a reduction in the number of nerve fibres in λ-carrageenin-induced granulomatous tissue. These results are consistent with the well known role of NGF, able to produce nerve sprouting within and close to injured tissue [34], an effect due to the neurotrophic ability of NGF to affect neuronal growth, neuronal survival and axonal outgrowth [8]. The decrease in the number of nerve fibres observed in the histological analysis of PEA-treated animals was also seen to occur in parallel with a concentration-dependent decrease in PGP 9.5 protein expression, a cytoplasmic protein present in neurons and neuroendocrine cells, useful to visualize several different populations and subtypes of nerves, which confirmed our previously discussed results.
Therefore, it seems possible to justify the lower pain sensitivity exhibited by rats treated with PEA considering the reduced number of nerve fibres obtained with PEA treatment which is associated with a decrease in NGF. In fact, NGF is considered to be not only a promoter of neuronal sprouting, but it is also involved in neural sensitization since it increases the excitability and the firing of sensory neurons [35-37]. Our results are in agreement with previous data showing that administration of PEA produces antinociception in the formalin test [38], reduces inflammatory hyperalgesia and oedema by inhibiting MC degranulation [39] and inhibits mechanical hyperalgesia after intraplantar carrageenin challenge in animals [40].
Moreover, the results reported in the present study are consistent with a recent study demonstrating that the anti-hyperalgesic action of PEA in a model of neuropathic pain depends, at least in part, on the reduction in NGF up-regulation [32].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034677/
Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again