www.elsevier.com/locate/tvjl

The Veterinary Journal 173 (2007) 21–30

TheVeterinary Journal

Review

Palmitoylethanolamide, endocannabinoids and relatedcannabimimetic compounds in protection against tissue

inflammation and pain: Potential use in companion animals

G. Re a,*, R. Barbero a, A. Miolo b, V. Di Marzo c

a Department of Animal Pathology, Division of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Turin,

Via Leonardo da Vinci 44, I-10095 Grugliasco (TO), Italyb Scientific Information and Documentation Centre, Innovet Italia Srl, Viale Industria 8, I-35030 Rubano, Italy

c Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34,

I-80078 Pozzuoli, Napoli, Italy

Abstract

Endocannabinoids have analgesic/anti-inflammatory properties. The biology of endocannabinoids, their receptors, signallingmechanisms and role in the regulation of physiological processes have been extensively reviewed. This review focuses on the roleof palmitoylethanolamide (PEA), an endogenous fatty acid amide analogue of the endocannabinoid anandamide, in tissue protec-tive mechanisms. PEA was first identified almost five decades ago in lipid extracts of various natural products, and its anti-inflam-matory and antinociceptive effects were established later. Evidence exists that PEA is synthesised during inflammation and tissuedamage and a number of beneficial effects, including the relief of inflammation and pruritus, have been shown to be useful inthe control of neurogenic and neuropathic pain. The postulated hypotheses as to the mode of action of PEA include a possible localautacoid-like mediator activity regulating mast-cell activity and putative activation of cannabinoids and vanilloid TRPV1 receptorsvia ‘‘entourage’’ effects. The large number of scientific investigations into the effects of PEA and PEA-related compounds has givenrise to new therapeutic opportunities. In spite of the multitude of therapies currently employed to control inflammation, pain, pru-ritus and tissue damage, the possibility of using a natural compound, such as PEA to manipulate endogenous protective mechanismsmay be considered a beneficial novel therapeutic strategy in veterinary medicine.� 2005 Elsevier Ltd. All rights reserved.

Keywords: Fatty acid amides; Palmitoylethanolamide; Inflammation; Pain; Companion animals

1. Introduction

The endogenous fatty acid amide palmitoylethanola-mide (PEA), chemical structure N-(2-hydroxyethyl)esadecanamide (Fig. 1), was initially considered as anautacoid, acting mainly as an anti-inflammatory agentthrough the down-regulation of mediator release frommast-cells, monocytes and macrophages (Aloe et al.,

1090-0233/$ - see front matter � 2005 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tvjl.2005.10.003

* Corresponding author. Tel.: +39 011 6709014; fax: +39 0116709017.

E-mail address: giovanni.re@unito.it (G. Re).

1993; Facci et al., 1995; Mazzari et al., 1996; Berdyshevet al., 1997; Berdyshev, 2000; Ross et al., 2000; Scaram-pella et al., 2001). In addition to the hypothesis thatPEA has potent immunoregulatory properties, recentdata have demonstrated that PEA may also play a keyrole in the regulation of complex systems involved inthe inflammatory response, pruritus, neurogenic andneuropathic pain (Di Marzo et al., 2000).

In general, PEA is thought to be involved in endoge-nous protective mechanisms that are activated in thebody as a result of different types of tissue damage orstimulation of inflammatory responses and nociceptive

Fig. 1. Chemical structure of N-palmitoylethanolamide.

22 G. Re et al. / The Veterinary Journal 173 (2007) 21–30

fibres. The Autacoid Local Inflammation Antagonismacronym (ALIA, Aloe et al., 1993) was modified byLevi-Montalcini and co-workers (1996) to explain themechanism of action of PEA and related fatty acidamides, into Autacoid Local Injury Antagonism. Thischange was made following the observation that thepharmacological effects of PEA appear to reflect theconsequences of supplying the tissue with a sufficientquantity of its physiological regulators of cellularhomeostasis (Levi-Montalcini et al., 1996).

PEA and related fatty acids amides are classified onthe basis of their mode of action as endocannabinoidsand cannabimimetics. Several studies that will be dis-cussed have revealed significant evidence to illustrateimportant pharmacological effects. This review presentsan updated summary of the multifaceted anti-inflamma-tory and anti-nociceptive actions of PEA. The range ofpotential beneficial uses of PEA in small animal medi-cine will be also considered.

2. Palmitoylethanolamide effects

2.1. Inflammation

Palmitoylethanolamide has been shown to be effectivein several mast-cell mediated experimental models ofinflammation, both of immunogenic (e.g., passive cutane-ous anaphylaxis) and neurogenic origin (e.g., subcutane-ous injection of substance P). Oral administration of PEA(0.1–10 mg/kg bw) led to a dose-dependent reduction ofsubstance P or passive cutaneous anaphylaxis-inducedextravasation of leucocytes, as well as carrageenan ordextran and formalin induced hindpaw oedema in labo-ratory animals (Mazzari et al., 1996; Conti et al., 2002).Moreover, such effects, typically observed followingpre-treatment with PEA, were recently confirmed whenPEA was administered after the induction of inflamma-tion enabling Costa et al. (2002) to conclude that PEAhas a curative as well as a prophylactic effect in certainmodels of acute inflammation.

In veterinary medicine, a recent pilot study was per-formed in fifteen cats with eosinophilic plaques or eosin-ophilic granulomas. Oral administration of palmidrol, asynthetic analogue of PEA (10 mg/kg bw/day for 30days), resulted in resolution of clinical signs (includingerythema) in 65% of the treated patients (Scarampellaet al., 2001).

2.2. Pain

‘‘One of the physiological functions of endocannabinoids

is to suppress pain. . ..’’ (Walker et al., 2002). The Interna-tional Association for the Study of Pain defined pain as‘‘an unpleasant sensory and emotional experience associ-ated with actual or potential tissue damage, or described

in terms of such damage’’ (Bonica, 1990). In domestic ani-mals, the idea of an emotional experience is replaced by‘‘behavioural reaction’’ (Lamont et al., 2000).

One of the first studies on the analgesic effects of can-nabinoids was performed in the dog. In 1899, one of theforefathers of modern pharmacology, W.E. Dixon,designed a device for the delivery of Cannabis sativasmoke to dogs and observed that treated animals didnot react to pin-pricks, concluding that they were underthe classic analgesic effects of cannabinoids (Dixon,1899). Since then, several aspects of the pathophysiologyof pain have been clarified, including the discovery ofendocannabinoids and related cannabimimetic com-pounds, which are endogenous substances actingdirectly or indirectly on cannabinoid receptors (CB),and that these receptors are involved in pain modulation(Hohmann, 2002).

2.2.1. Neurogenic pain

Somatic inflammatory pain. Available evidence sug-gests that PEA is effective against acute pain, especiallypersistent somatic inflammatory pain in laboratory ani-mals. Palmitoylethanolamide pre-treatment (1 h beforestimulation) induced a dose-dependent inhibition ofmechanical and thermal hyperalgesia following the sub-plantar injection of carrageenan (Mazzari et al., 1996;Conti et al., 2002). Furthermore, an antinociceptive effectwas observed as the reduction of pain behaviour elicitedby subcutaneous formalin injection (Calignano et al.,1998; Jaggar et al., 1998; Calignano et al., 2001) and byintraperitoneal injections of acetic acid, kaolin and mag-nesium sulphate (Calignano et al., 2001). Recently, it hasbeen demonstrated that the intraperitoneal administra-tion of PEA immediately after an intra-plantar injectionof nerve growth factor (NGF) reduced the resultingNGF-induced thermal hyperalgesia (Rice, 2000; Farqu-har-Smith and Rice, 2003).

Visceral inflammatory pain. The effects of PEA onhyperalgesia, described above in somatic pain models,have also been confirmed for visceral pain. PEA (2.5mg/kg bw or of 10–30 mg/kg bw), significantly relievedthe viscero-visceral hyper-reflexia following urinary blad-der inflammation induced by NGF or turpentine in a ratmodel (Jaggar et al., 1998; Farquhar-Smith et al., 2002).

2.2.2. Neuropathic pain

Neuropathic pain is a complex phenomenon associ-ated with a heterogeneous group of conditions, which

Fig. 2. The three fields of action of palmitoylethanolamide. The mainclinical signs and symptoms that palmitoylethanolamide has beenproven to reduce.

G. Re et al. / The Veterinary Journal 173 (2007) 21–30 23

differ in both aetiology and location, whose symptomsor signs do not respect cause nor anatomical site andis challenging to treat, both in veterinary and humanmedicine (Jensen et al., 2001; Zimmermann, 2001). Atpresent, controversy remains as to the real effectivenessof opioids in controlling neuropathic pain (Dellemijn,1999), although cannabinoids are still regarded as effec-tive agents (Richardson et al., 1998a). PEA (100 lg/kgbw injected intra-peritoneally) significantly decreasedthe neuropathic mechanical hyperalgesia induced bypartial ligation of the sciatic nerve in rats (Helyeset al., 2003).

2.3. Pruritus

Pruritus is a nociceptive stimulus mediated by fibresthat are anatomically indistinguishable, but functionallydifferent, from those associated with the mediation ofpain (Schmelz, 2001; Twycross et al., 2003). Drugs thatincrease the nociceptive threshold can be considered anovel approach in the treatment of pruritus (Gingoldand Bergasa, 2003). There is evidence that PEA has anantinociceptive effect, which may suggest its possibleefficacy in treating pruritus in domestic animals. Thishypothesis was supported by a pilot study performedin cats affected by eosinophilic plaque and granulomain which 65% of animals treated with palmidrol(10 mg/kg bw for 30 days) exhibited a decrease in clini-cal signs, including pruritus (Scarampella et al., 2001).

3. Mechanism of action of PEA

There is a great deal of evidence showing that PEAmay act both as an anti-inflammatory and anti-nocicep-tive agent (Fig. 2). However, the real mechanism ofaction of this endogenous compound that mediates itsanti-inflammatory, analgesic and anti-pruritic effects isstill debated. There are at least three hypotheses, sup-ported by experimental evidence published in peer-reviewed journals, concerning PEA pharmacodynamics,all seemingly different, but for several aspects they maybe considered complementary and synergistic.

3.1. ALIA hypothesis

The first hypothesis on the mechanism of action ofPEA was formulated when Aloe et al. (1993) introducedthe ALIA acronym (Autacoid Local InflammationAntagonism), to indicate that some endogenous N-acyl-ethanolamines, like PEA, exerted a local antagonism oninflammation. The effect was first attributed to mast-cellactivity control (Jack, 1996). Concomitantly, Mazzariet al. (1996) demonstrated that the in vivo anti-inflam-matory effects of PEA were due to down-regulation ofmast-cell degranulation. Similar results have recently

been obtained in dogs and cats. In fact, densitometricanalysis performed on skin biopsies from cats witheosinophilic granuloma complex and treated with10 mg/kg bw of palmidrol, revealed an increase in thegranular density of cutaneous mast-cells (Fig. 3),thereby suggesting a decrease in mast-cell degranulation(Scarampella et al., 2001).

Using similar techniques, an inhibitory control overmast-cell degranulation has recently been demonstratedin dogs locally exposed to PEA analogues. In particular,the topical application of a gel formulation containingthe fatty acid amide adelmidrol (N,N 0-bis-[2-hydroxy-ethyl] nonandiamide] produced a significant increase inthe densitometric measurement for cutaneous mast-cellslocated in the lips of dogs with experimentally inducedwounds (Fig. 3) (Abramo et al., 2004a). In the dog,the percentage surface re-epithelialisation associatedwith the increase in mast-cell densitometric measure-ment was significantly higher in the lesions exposed toaldemidrol than in those treated with vehicle (Abramoet al., 2004b).

The ALIA mechanism is based on the crucial roleexerted by mast-cells in inflammation and even moreon the protective functions activated in the body duringdisease. Under normal physiological conditions, mast-cells are preferentially localised around nerves andblood vessels in tissues interfacing with the externalenvironment (Maurer et al., 2003), where they performcritical protective and homeostatic functions (Boyce,2003).

The ability of mast-cells to respond to a wide range ofinfectious and chemical stimuli facilitates their key func-tions in immunity and the response to tissue injury,by promoting a rapid release of pro-inflammatory

Fig. 3. Densitometric images of cutaneous mast-cells on toluidine blue-stained sections. (1) Feline skin lesions secondary to eosinophilic granuloma,before (a) and after (b) oral treatment with PLR-120, a synthetic analogue of palmitoylethanolamide (PEA). (2) Canine skin wounds treated for 14days with a topical gel containing vehicle only (a) or a PEA-related compound, adelmidrol (b). Arrows indicate mast-cells. There is a significantincrease in the staining intensity of mast-cells (1b and 2b), supporting reduced degranulation demonstrated by quantitative image analysis.Reproduced courtesy of Francesca Abramo.

24 G. Re et al. / The Veterinary Journal 173 (2007) 21–30

mediators (e.g., cytokines, vasoactive amines), media-tors of hyperalgesia (e.g., proteolytic enzymes, bradyki-nins, neuropeptides) and itch mediators (e.g., histamineand serotonin) (Boyce, 2003). The down-regulationexerted by PEA is an effective tool to naturally controlmast-cell hyperactivity, which occurs not only in inflam-mation, but also in inflammatory hyperalgesia (Levi-Montalcini et al., 1995) and neuropathic hyperalgesia(Theodosiou et al., 1999; Zuo et al., 2003).

3.2. Receptor hypothesis

The hypothesis of a receptor-mediated mode ofaction is compatible and may possibly even be synergis-tic with the ALIA hypothesis. The CB1 receptor, firstidentified by Devane et al. (1988), and later cloned byMatsuda et al. (1990), is expressed in different brainareas (Walker et al., 2002), in neurons of the dorsal rootganglia (Ahluwalia et al., 2002; Ralevic, 2003) and inperipheral tissues (Malan et al., 2002). Munro et al.(1993) later identified the CB2 receptor and defined itas a ‘‘peripheral’’ cannabinoid receptor. CB2 receptormRNA has been detected in inflammatory and immunesystem cells and its expression was 10–100 times higherthan that of CB1 receptor (Malan et al., 2002).

The ‘‘CB2-like receptor’’ hypothesis suggests thatpharmacological effects of PEA may be the result ofdirect or indirect stimulation of CB2 receptors (or of ayet uncharacterised CB2-like receptor). This hypothesisis supported by the results obtained from severalin vivo studies performed using different CB receptoragonist.

The synthetic highly CB2 selective agonists AM 1241and HU-308 decreased experimentally-induced oedema(Hanus et al., 1999; Malan et al., 2002; Quartilho

et al., 2003). In experimental models of nociceptive pain,local or systemic administration of AM 1241, sup-pressed the development of thermal and mechanicalhyperalgesia induced by carrageenan (Malan et al.,2002; Nackley et al., 2003; Quartilho et al., 2003) andby capsaicin (Quartilho et al., 2003), as well as the allo-dynia (a condition characterised by pain from stimuliwhich are not normally painful) produced by carra-geenan (Nackley et al., 2003). In the case of neurophaticallodynia (condition in which opioids are effective onlyat dosages higher than those effective against thermalhyperalgesia), AM 1241 is effective at the same dose thatis effective for the suppression of hyperalgesia (Malanet al., 2002). The effect is dose-dependent and CB1receptor independent.

Topical pre-treatment with HU210, a synthetic non-selective agonist of CB1 and CB2 receptors, significantlyreduced pain perception and the consequent primaryheat hyperalgesia after cutaneous administration ofcapsaicin (Rukwied et al., 2003) and also reduced thehistamine-induced itching perception. The authors pos-tulated that these findings could lead to a new strategyof peripheral treatment for sensitive, itchy and/orinflamed skin unresponsive to conventional therapye.g., anti-histamines (Dvorak et al., 2003).

The hypothesis that PEA may act via a direct or indi-rect interaction with CB2 receptors is confirmed by theresults obtained from different in vivo studies performedusing a selective CB2 receptor antagonist. In fact, theadministration of SR144528, a CB2 specific receptorantagonist, eliminated the antinociceptive effects ofPEA (Calignano et al., 1998, 2001; Conti et al., 2002;Farquhar-Smith and Rice, 2003). In experimental mod-els of visceral pain, the analgesic properties of PEA aresuppressed by the administration of SR144528 (Farqu-

G. Re et al. / The Veterinary Journal 173 (2007) 21–30 25

har-Smith et al., 2002). Moreover, the administration ofSR144528 completely blocked the inhibitory effects ofPEA on carrageenan induced oedema (Conti et al.,2002).

Thus the ‘‘CB2-like receptor’’ hypothesis is based ona plethora of data supporting the existence of a possibleperipheral mode of action of PEA (Malan et al., 2001;Nackley et al., 2003; Quartilho et al., 2003) and involv-ing the activation of CB2 receptors expressed byimmune cells (Malan et al., 2002; Sokal et al., 2003)and perhaps also by primary sensitive neurons in thedorsal horn of the spinal cord (Hohmann, 2002; Nack-ley et al., 2003). CB2 (or CB2-like) receptor activationinhibits the release of substances involved in inflamma-tion and stimulation of afferent nerve fibres (Sokalet al., 2003). It should however be emphasised that, inthe late 1990s, the receptor hypothesis was questionedby some investigators who demonstrated that PEAwas unable to activate either rat or human recombinantCB1 or CB2 receptors even at concentrations as high as10 lM (Sheskin et al., 1997; Lambert et al., 1999).

3.3. Entourage hypothesis

A hypothesis termed the ‘‘entourage effect hypothe-sis’’ has been suggested in order to explain some of thediscrepancies between data obtained in vitro (i.e., can-nabinoid receptors binding assays) and those obtainedin vivo (i.e., blockade by a CB2 antagonist) on PEAaction.

Briefly, the hypothesis proposes that PEA may act asan enhancer of the anti-inflammatory and antinocicep-tive activity exerted by other endogenous compoundsthrough an increase in their affinity for receptors orvia inhibition of their metabolic degradation (Ben-Sha-bat et al., 1998; Mechoulam et al., 1998; Lambert andDi Marzo, 1999; Smart et al., 2002). One of these endog-enous compounds, anandamide (AEA), whose activitymay be potentiated by PEA, is particularly interestingfor its powerful anti-inflammatory and antinociceptiveeffects.

Anandamide is an endogenous cannabinoid acting asa natural ligand for the CB1 receptor (Devane et al.,1992). Anandamide, locally synthesized in the brain(Steffens et al., 2003) and other tissues, increases aftertissue damage in macrophages (Pestonjamasp and Bur-stein, 1998; Liu et al., 2003), central (Walker et al.,1999; Hansen et al., 2001) and peripheral neurons(Ahluwalia et al., 2003a). When administered peripher-ally, at very low dosages (0.01 ng/rat), AEA is able toinhibit carrageenan-induced oedema (Richardsonet al., 1998b). AEA reduces formalin-induced pain andcarrageenan-induced thermal hyperalgesia via CB1receptor activation (Calignano et al., 1998; Richardsonet al., 1998b) or through stimulation of CB2 receptorsexpressed in spinal neurons (Sokal et al., 2003). Ananda-

mide is also effective in the same models of visceral painin which PEA antinociceptive effects have beenobserved, but at a dosage (25 mg/kg) higher than thatrequired for PEA (2.5 mg/kg). These effects appear tobe mediated via CB1 receptor stimulation (Farquhar-Smith et al., 2002).

Besides acting as an endocannabinoid, AEA also actsas an endovanilloid. It has been recently demonstratedthat AEA also interacts, in several tissues, with a capsa-icin receptor, named vanilloid receptor type 1 (VR1) ortransient receptor potential vanilloid 1 channel (TRPV1)(Di Marzo et al., 2002; Ross, 2003; van der Stelt and DiMarzo, 2004). Interestingly, TRPV1 has recently beencloned and functionally characterised in the dog (Phelpset al., 2005).

The structure of the vanilloid receptor subunit is illus-trated in Fig. 4. This receptor, unlike CB1, is involved intransducing thermal and inflammatory pain. The emerg-ing antagonism of its actions, endocannabinoid–endova-nilloid, does not facilitate the pharmacologicalclassification of AEA. By acting at the TRPV1 receptor,AEA induces the antidromic release of neuropeptidesclosely involved in neurogenic inflammation, like sub-stance P (SP) and calcitonin gene-related peptide(CGRP), and consequently exerts pro-inflammatoryeffects (Ahluwalia et al., 2003b; Di Marzo et al., 2002;Maccarrone et al., 2002; Ralevic, 2003). However,AEA, like other TRPV1 agonists, can also desensitisethis channel, leading to paradoxical analgesic effects.Furthermore, it is well known that the activation ofTRPV1 reduces itching both in humans (Lysy et al.,2003; Weisshaar et al., 2003) and in dogs (Marsellaet al., 2002). Therefore, the ability of PEA to strengthenthe TRPV1-mediated effects of AEA, probably byincreasing the affinity of AEA and other endovanilloidsfor their receptor, may be considered as a possible strat-egy in the treatment of pruritus and pain (De Petrocelliset al., 2001).

In conclusion, the ‘‘entourage hypothesis’’ proposesthat the anti-inflammatory and antinociceptive effectsof PEA are in part due to the enhancement of the endo-cannabinoid and/or endovanilliod actions exerted byAEA or other endogenous related compounds.

3.4. Is a unified hypothesis plausible?

In our opinion, all three hypotheses could be consid-ered as potentially possible and complementary. Thereceptor ALIA and entourage hypotheses may simplybe molecular completions (Fig. 4). Mast-cells, the targetof the ALIA mechanism, may provide a ‘‘trait d�union’’between the different hypotheses, and express CB2receptors (Facci et al., 1995).

Although originally challenged (Maccarrone et al.,2000; Lau and Chow, 2003), the presence of CB2 recep-tors has recently been confirmed by in vitro studies

Fig. 4. Structure of a vanilloid receptor (TRPV1) channel subunit. The architecture of a TRPV1 channel subunit model consisting of an N-terminaldomain containing three ankirin domains and a phosphorylation site for protein kinase A (PKA), six trans-membrane segments (S1–S6) (pinkcylinders) with a pore region between S5 and S6 segments, a capsaicin binding site, a large connection between S5 and S6 trans-membrane segmentsholding a short amphipathic fragment (yellow loop) and a cytosolic C-terminal domain in which calmodulin (CaM) and phosphatydylinositol-4,5-diphosphate (PIP2) binding sites are located. The subunits assemble as tetramers around a central aqueous pore, producing non-selective cationchannels to form the TRPV1 (from Ferrer-Montiel et al., 2004; modified).

26 G. Re et al. / The Veterinary Journal 173 (2007) 21–30

performed in RBL2H3 cells, where mRNA and proteinof both CB1 and CB2 receptors were identified (Samsonet al., 2003; V. Di Marzo, unpublished data). Bothreceptors are functional (Small-Howard et al., 2005)and are involved in modulation of mast-cell degranula-tion (Samson et al., 2003). Mast-cells have also beenreported to express TRPV1 vanilloid receptors (Biroet al., 1998; Stander et al., 2004), which are the target,together with CB2 receptors, of the ‘‘entourage hypoth-esis’’ and are involved in the control of pruritus (seeFig. 5).

Another point of confluence between the differenthypotheses emerged from experiments performed onNGF-induced hyperalgesia (Farquhar-Smith and Rice,2003). The effect of PEA against hyperalgesia may bemediated by the inhibition of neutrophil accumulationafter the down-regulation of mast-cell degranulation(Rice et al., 2002; Farquhar-Smith and Rice, 2003). Fur-ther results were obtained in other experiments using aselective synthetic CB2 receptor agonist, which inhibitedpain possibly via a mast-cell receptor, but not via anafferent neuron receptor. The activation of mast-cellCB2 receptor reduced the release of peripheral nocicep-

tor mediators (e.g., NGF, prostanoids, cytokines, sero-tonin, histamine) (Malan et al., 2002). NGF is knownto activate and enhance the expression of TRPV1, andthis receptor mediates in part the NGF-induced hyperal-gesia. Indeed, TRPV1-expressing neurons can be tar-geted with TRPV1 antagonists or with desensitisingTRPV1 agonists to reduce neuropathic pain (Rashidet al., 2003; Walker et al., 2003).

How can the ‘‘receptor hypothesis’’ be applied wheninflammatory pain is not present, e.g., thermal nocicep-tion? In this case the mechanism could be indirect andrelated to the activation of mast-cell CB2 and TRPV1receptors, with a consequent decrease in the release ofmolecules which sensitise non-inflamed tissues. In thisscenario, a crucial role is attributed to the control of basalrelease of NGF from mast-cells (Malan et al., 2002).

4. PEA and basal threshold of endogenous protective

systems: homeostatic roles

The surprising capacity of PEA to modulate the pro-tective responses of animals during inflammation and

Fig. 5. Proposed pharmacodynamic pathways for palmitoylethanolamide: a unified view. Palmitoylethanolamide (PEA) may act by an autacoidlocal injury antagonism through the down-regulation of mast-cell degranulation (ALIA hypothesis – grey arrow) that may be mediated throughactivation of CB2-like (denoted here as CB2) receptors expressed by mast-cells and sensory neurons. The latter also express CB1 and TRPV1receptors. The net result is inhibition of the release of inflammatory, pruritic and pain-inducing substances (Receptor hypothesis – blue arrows).Furthermore, PEA may act indirectly by increasing the affinity for the receptors (i.e., CB1 or TRPV1) or by inhibiting the metabolic degradation ofsome other endogenous compounds endowed with anti-inflammatory and antinociceptive activity, such as anandamide (Entourage hypothesis – pinkarrows).

G. Re et al. / The Veterinary Journal 173 (2007) 21–30 27

pain led to the hypothesis that endogenous PEA may bea component of the complex homeostatic system control-ling the basal threshold of both inflammation and pain/itching (Calignano et al., 2001; Malan et al., 2002; Hoh-mann, 2002). This hypothesis is supported by the factthat PEA is synthesised during the early stages of inflam-mation and pain, and is locally and rapidly increasedduring tissue damage by leucocytes (Bisogno et al.,1997), mast-cells (Di Marzo et al., 1996), epidermal cells(Berdyshev, 2000) and inflamed skin (Calignano et al.,1998; Hohmann, 2002). Increased PEA synthesis hasalso been demonstrated in diabetic cutaneous neuropa-thy, inflammatory bowel disorders (Darmani et al.,2005), in response to an experimentally induced increasein intracellular calcium concentrations by cortical neu-rons (Cadas et al., 1996) and in rat cerebral cortex afterfocal ischaemia (Franklin et al., 2003).

There is no direct evidence to support the involvementof PEA in the control of pain and inflammation (i.e.,selective inhibition of PEA biosynthesis or degradation),however, the pharmacological data presented in thisreview as well as the production of PEA during inflam-matory conditions strongly support this role. Datastrongly supporting the hypothesis of an endogenoussystem controlling the basal pain threshold that is mod-ulated by endocannabinoids/cannabimimetics, werereported in experiments on the down-regulation anddesensitisation of CB receptors (Calignano et al., 1998).

It has been demonstrated that intrathecal administra-tion of a specific CB1 receptor antagonist causesNMDA-dependent like hyperalgesia (Richardsonet al., 1997, 1998a) and an experimentally inducedCB1 receptor number reduction produced a significantthermal hyperalgesia (Richardson et al., 1998a). Thus,tonic spinal cannabinoid receptor activation probablyresults in modulation of basal thermal nociceptivethreshold. These results support the hypothesis that can-nabinoid system hypoactivity may be involved in theaetiology of certain chronic pain states. Since opioidsare not thought to be involved in the modulation ofbasal nociceptive thresholds, these findings demonstratea major difference between these two endogenous anal-gesic systems (Richardson et al., 1998a).

5. Conclusions

ALIA well describes the effects of PEA. The autacoidorigin of PEA, its capacity to act locally and to protect tis-sues against actual or potential damage are the premiseson which the therapeutic applications are based: firstly,as an endogenous compound, PEA has basically noadverse effects; secondly, the presence of a double thera-peutic effect (i.e., anti-inflammatory and antinociceptive);thirdly, the down-regulation of mast-cells that providesthe most likely basis for preventing tissue damage.

28 G. Re et al. / The Veterinary Journal 173 (2007) 21–30

Based on the efficacy of PEA against several damag-ing conditions, this compound and its congeners mayprove to be useful in different fields of veterinary andhuman medicine, such as dermatology, odontostomatol-ogy, neurology, orthopaedics, nephrology and cardiol-ogy. In all of these fields there are several inflammatoryand/or nociceptive conditions where mast-cells play apivotal role in disease pathogenesis. In some disorders,such as hypersensitivity dermatoses of dogs and cats,cutaneous wounds in dogs and gingivitis of dogs andcats, the positive effects of PEA and its analogues havealready been reported (Scarampella et al., 2001; Abramoet al., 2004a,b).

A large number of scientific investigations on theeffects of PEA and PEA-related compounds are nowavailable, and give rise to new therapeutic opportunities.In the multitude of disease-oriented therapies employedthe opportunity to use natural compounds aimed at thecontrol of endogenous protective mechanisms mayprove to be beneficial.

The local mechanism of PEA action presents remark-able therapeutic advantages, not only against inflamma-tion and pruritus, but also in the treatment of chronicpain such as neuropathic pain (Richardson et al.,1998a). In fact, CB2 receptor-selective agonistic medica-tions will probably lack the CNS side effects which limitthe efficacy of many currently available medications(Ibrahim et al., 2003). Furthermore, cannabinoidligands, especially peripherally acting selective CB2receptor agonists, free of CNS side effects, could openfuture perspectives for neuropathic pain management(Helyes et al., 2003).

On this occasion, veterinary medicine may be the firstto enjoy the advantages offered by the large number ofscientific investigations performed on the palmitoyle-thanolamide family.

Acknowledgement

Special thanks to Dr. Linda Massari for the compe-tent revision of English style and grammar.

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