Elsevier

Life Sciences

Volume 77, Issue 14, 19 August 2005, Pages 1685-1698
Life Sciences

The search for the palmitoylethanolamide receptor

https://doi.org/10.1016/j.lfs.2005.05.012Get rights and content

Abstract

Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid that modulates pain and inflammation. Although the anti-inflammatory effects of PEA were first characterized nearly 50 years ago, the identity of the receptor mediating these actions has long remained elusive. We recently identified the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-α), as the receptor mediating the anti-inflammatory actions of this lipid amide. Here we outline the history of PEA, starting with its initial discovery in the 1950s, and discuss the pharmacological properties of this compound, particularly in regards to its ability to activate PPAR-α.

Section snippets

Discovery of PEA

The discovery of naturally occurring fatty acid ethanolamides (FAEs) (Fig. 1) stems from an interesting clinical finding in the early 1940s, when investigators noted that supplementing the diets of underprivileged children with dried chicken egg yolk prevented recurrences of rheumatic fever, despite continued streptococcal infections (Coburn and Moore, 1943). In a continuation of this research, it was demonstrated that lipid fractions purified from egg yolk (Coburn et al., 1954, Long and

PEA in the clinic

The years following the discovery of PEA's anti-inflammatory effects (Benvenuti et al., 1968, Perlik et al., 1971) witnessed a series of interesting clinical studies on this compound, which was tested under the trade name of Impulsin by the Czech pharmaceutical company, SPOFA. It is not clear what prompted these clinical trials; nonetheless, PEA was found to reduce the severity and duration of symptoms caused by the influenza virus in school children and soldiers (Kahlich et al., 1979, Masek et

Cannabinoid receptors

Cannabinoid receptors, the molecular targets of the psychoactive component in marijuana, delta-9-tetrahydrocannabinol (THC), belong to the G-protein-coupled receptor super family (Matsuda et al., 1990, Munro et al., 1993). Activation of either CB1 receptors (which are primarily localized to the brain but are also present in the periphery) or CB2 receptors (which are predominantly found in cells of the immune system) results in Gi-mediated reduction of adenylyl cyclase activity and subsequent

Pharmacological properties of PEA

Since the discovery of anandamide, the properties of PEA have been explored with growing interest (Fig. 3). In addition to its known anti-inflammatory activity, PEA also produces analgesia (Calignano et al., 1998, Calignano et al., 2001, Jaggar et al., 1998), anti-epilepsy, and neuroprotection (Franklin et al., 2003, Lambert et al., 2001, Sheerin et al., 2004, Skaper et al., 1996). PEA also inhibits food intake (Rodríguez de Fonseca et al., 2001), reduces gastrointestinal motility (Capasso et

PEA biosynthesis and inactivation

Unlike classical neurotransmitters and hormones which are stored in and released from intracellular secretory vesicles, the production of FAEs occurs through on-demand synthesis within the lipid bilayer (Cadas et al., 1996, Schmid et al., 1990). In mammalian tissues, two concerted and independent biochemical reactions are responsible (Fig. 4). The first is the transfer of a fatty acid from membrane-bound phospholipids to phosphatidylethanolamine (PE), catalyzed by a calcium ion and cyclic-AMP

Physiological regulation of PEA levels

The physiological stimuli that regulate PEA levels in mammalian tissues are largely unknown; however, multiple studies indicate that this lipid accumulates during cellular stress, particularly following tissue injury. For example, PEA and other FAEs increase postmortem in the pig and mouse brain (Patel et al., 2004, Schmid et al., 1995). In rat testis, PEA levels were elevated nearly 40-fold following CdCl2-induced tissue degeneration (Kondo et al., 1998). Similar elevations of PEA have been

The PEA receptor

Despite its potential clinical significance, the cellular receptor responsible for the actions of PEA has long remained unidentified, and a great deal of controversy has surrounded its identity. The structural and functional similarities between anandamide and PEA first suggested that these two lipid mediators might share the same receptor. In support of this idea, PEA was initially reported to displace the binding of the high-affinity cannabinoid agonist [3H]WIN55,212-2 with a half-maximal

PPAR-α is the anti-inflammatory target of PEA

Prior work in our laboratory has shown that OEA, a lipid amide structurally related to PEA (Fig. 1), regulates feeding behavior and lipid metabolism in rodents by activating the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) (Fu et al., 2003, Gaetani et al., 2003, Guzmán et al., 2004, Rodríguez de Fonseca et al., 2001). A growing body of evidence has implicated PPAR-α in the control of inflammatory responses and these receptors are expressed in various cells of the

Concluding remarks

The discovery that PPAR-α mediates the anti-inflammatory effects of PEA (LoVerme et al., 2005) raises several important questions. Is PPAR-α responsible for all other effects of PEA, including analgesia and neuroprotection? And if so, what is the relationship between PPAR-α and CB2 receptors? How does endogenous PEA interact with PPAR-α to regulate physiological inflammatory processes? Our data suggest that part of this response may involve a reduction in PEA levels in inflamed tissues, which

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