Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: Review of the available pre-clinical data, and first human studies

Abstract

The endogenous cannabimimetic compound, and anandamide analogue, N-palmitoyl-ethanolamine (PEA), was shown to exert potent anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic and inflammatory pain by acting via several possible mechanisms. However, only scant data have been reported on the regulation of PEA levels during pathological conditions in animals or, particularly, humans. We review the current literature on PEA and report the results of three separate studies indicating that its concentrations are significantly increased during three different inflammatory and neuropathic conditions, two of which have been assessed in humans, and one in a mouse model. In patients affected with chronic low back pain, blood PEA levels were not significantly different from those of healthy volunteers, but were significantly and differentially increased (1.6-fold, P<0.01, N = 10 per group) 30 min following an osteopathic manipulative treatment. In the second study, the paw skin levels of PEA in mice with streptozotocin-induced diabetic neuropathic pain were found to be significantly higher (1.5-fold, P<0.005, N = 5) than those of control mice. In the third study, colonic PEA levels in biopsies from patients with ulcerative colitis were found to be 1.8-fold higher (P<0.05, N = 8–10) than those in healthy subjects. These heterogeneous data, together with previous findings reviewed here, substantiate the hypothesis that PEA is an endogenous mediator whose levels are increased following neuroinflammatory or neuropathic conditions in both animals and humans, possibly to exert a local anti-inflammatory and analgesic action.

Introduction

The N-acyl-ethanolamines (NAEs) represent a class of endogenous bioactive amides sharing common biosynthetic and metabolic pathways. One of the members of this family, the anti-inflammatory compound, N-palmitoyl-ethanolamine (PEA), has been known since the late 1950s (see Schmid et al., 1990 for review). However, it was not until the discovery of the endocannabinoid N-arachidonoyl-ethanolamine (AEA, anandamide) (Devane et al., 1992) that interest in these fatty acid amides was revived. Since it was soon clear that only long chain polyunsaturated NAEs are capable of binding to cannabinoid receptors (Di Marzo, 1998), different molecular targets were looked for: (1) N-stearoyl-ethanolamine (SEA), to explain its pro-apoptotic effects in vitro and central cannabimimetic actions in vivo (Maccarrone et al., 2002a); (2) N-oleoyl-ethanolamine (OEA), to provide a mechanism for its anorexic actions (Rodriguez de Fonseca et al., 2001); and (3) PEA, to explain its anti-inflammatory, neuroprotective and analgesic properties (see Lambert et al., 2002 for review). It has been recently suggested that while SEA has its own binding sites in the brain (Maccarrone et al., 2002a), OEA binds with high affinity to the peroxisome proliferator receptor-α (PPAR-α) (Fu et al., 2003). Regarding PEA, at least part of its neuroprotective or anti-inflammatory effects that are insensitive to cannabinoid receptor antagonists (Lambert et al., 2002) might be due to the interaction with a possibly new G-protein coupled receptor in microglial cells (Franklin et al., 2003) or to PPAR-α (Lo Verme et al., 2005), respectively. However, it had also been proposed that PEA could act as an agonist for the cannabinoid receptor type 2 (Facci et al., 1995), since some of its analgesic effects are antagonized by SR144528, a selective CB₂ receptor blocker (Jaggar et al., 1998a; Calignano et al., 1998). Yet, PEA, like OEA and SEA, exhibits very little, if any, affinity for the cloned CB₁ and CB₂ cannabinoid receptors from the rat, mouse or man (Sheskin et al., 1997, Lambert et al., 1999). Several possibilities were proposed to explain the SR144528-sensitive analgesic effects of PEA, including the activation of a “CBn” receptor, very similar to the CB₂ receptor, and an action as “entourage” compound, i.e. by enhancing the activity and/or by inhibiting the degradation of endogenous agonists of CB₂ receptors (Mechoulam et al., 1998). Indeed, apart from being synthesized from different precursors through the action of the same enzyme, the recently cloned N-arachidonoyl-phosphatidyl-ethanolamine-selective phospholipase D (Okamoto et al., 2004), PEA and AEA are hydrolyzed by the same amidase enzymes. There are two examples of such enzymes identified so far: (i) the “fatty acid amide hydrolase” (FAAH) (see Fowler et al., 2001 for review), and (ii) a lysosomal hydrolase with tissue distribution different from that of FAAH (Ueda et al., 2001). In the latter case, the catalytic efficacy of the enzyme is higher with PEA than with AEA, and, in principle, it allows PEA to efficiently inhibit AEA degradation by substrate competition. In the case of FAAH, instead, chronic PEA was shown to down-regulate its expression, thereby enhancing some pharmacological actions of AEA (Di Marzo et al., 2001a).

By acting independently of FAAH, PEA also enhances those effects of AEA that are mediated by the vanilloid TRPV1 receptor (De Petrocellis et al., 2001). This is a non-selective cation channel expressed in C-fibers and acting as a molecular transducer of nociceptive stimuli, gated by protons, heat and plant toxins such as capsaicin and resiniferatoxin (Caterina et al., 1997). AEA also can gate TRPV1, particularly when certain regulatory events occur (see Di Marzo et al., 2002 for review). It was shown recently that PEA can enhance the TRPV1-mediated actions on intracellular Ca²⁺ of AEA, in part by increasing its affinity for the channel in specific binding assays (De Petrocellis et al., 2001). Furthermore, PEA was found to enhance the anti-proliferative effects on cancer cells of vanilloid compounds in vitro (De Petrocellis et al., 2002).

Although the metabolic pathways of PEA have been extensively investigated, very few studies have examined the regulation of PEA levels under physiological or pathological conditions (Lambert et al., 2002, for a review). Furthermore, no such study has ever been carried out in humans during conditions of inflammation and pain. Here, we report the results of three studies, two of which have been carried out in humans, and one in an animal model, showing that PEA levels may increase during inflammatory or neuropathic pain.