Palmitoylethanolamide and Related ALIAmides for Small Animal Health: State of the Art

Abstract

ALIAmides are a family of fatty acid amides whose name comes from their mechanism of action, i.e., the Autacoid Local Injury Antagonism (ALIA). Actually, the ALIAmide parent molecule, palmitoylethanolamide (PEA), is locally produced on demand from a cell membrane precursor in order to control immune-inflammatory cell responses, avert chronic non-resolving inflammation, and limit the resulting clinical signs. ALIAmide sister compounds, such as Adelmidrol and palmitoylglucosamine, share mechanisms of action with PEA and may also increase endogenous levels of PEA. Provided that their respective bioavailability is properly addressed (e.g., through decreasing the particle size through micronization), exogenously administered ALIAmides thus mimic or sustain the prohomeostatic functions of endogenous PEA. The aim of the present paper is to review the main findings on the use of ALIAmides in small animals as a tribute to the man of vision who first believed in this “according-to-nature” approach, namely Francesco della Valle. After briefly presenting some key issues on the molecular targets, metabolism, and pharmacokinetics of PEA and related ALIAmides, here we will focus on the preclinical and clinical studies performed in dogs and cats. Although more data are still needed, ALIAmides may represent a novel and promising approach to small animal health.

1. Introduction

ALIAmides are a family of fatty acid amides sharing a common mechanism of action, i.e., the autacoid local injury antagonism (ALIA), originally proposed in the mid-1990s by the late Nobel prize winner Rita Levi Montalcini [1]. The term “autacoid” comes from the Greek “autos” (self) and “acos” (healing or remedy) and refers to cell-produced factors that act locally near their site of synthesis [2]. In particular, the autacoid mechanism of ALIAmides serves auto-protective purposes through the down-modulation of cell hyperactivity (mainly immune cells), thus controlling inflammatory responses and limiting tissue damage [3]. It was originally observed that the ALIAmide parent molecule, palmitoylethanolamide (PEA), down-modulates rat mast cell behavior after challenge [1,4], as later confirmed in companion animals [5,6,7]. Different cell populations were also shown to be targets of PEA, with macrophages, keratinocytes, T and B cells, and glial cells being negatively controlled by PEA once overactivated [8,9,10,11,12,13,14,15,16,17,18].

Palmitoylethanolamide is a body’s own (endogenous) N-acylethanolamine, produced “on demand” by several cell types, including mast cells, astrocytes, and microglia [19,20,21]. Interestingly, the autoprotective function of PEA was first suggested in dogs. It was indeed found that (i) the canine myocardium produces PEA in response to ischemic injury [22,23], and (ii) the canine brain possesses the biosynthetic and degradative machinery for PEA [24]. Since the 1980s, knowledge has advanced considerably in the field of ALIAmides, mainly due to the renewed interest in these molecules driven by the discovery of the PEA congener and the endocannabinoid mediator anandamide arachidonoylethanolamide (AEA) [25].

In those days, an enlightened man, Francesco della Valle (to whom the present special issue is dedicated), was launching his own science-driven entrepreneurial activity in the field of human and animal health, focused on innovation and networking [26]. During his previous experience in managing a pharmaceutical firm, he had been actively cooperating with two eminent scientists, Rita Levi Montalcini [27] and Erminio Costa [28,29] (Figure 1).

Both of them repeatedly invited della Valle to orientate the focus and efforts toward biological modulation mechanisms while learning from nature how to design a strategy of modulation [30,31]. Accordingly, della Valle based his strategic business plan on a “hypothetical-deductive” approach to inflammation and pain, according to regulatory pathways laid down by nature and intended to maintain a homeostatic balance in the body when challenged by stress or injury. This was the ALIAmide project. Although the historical view of ALIAmides is beyond the scope of the present review, it must be acknowledged that the ALIAmide story began in this particular framework, and most of the research data that will be reviewed here were born within it.

Besides PEA, ALIAmides currently comprise several lipid compounds, ranging from Adelmidrol (the diethanolamide derivative of azelaic acid) to palmitoylglucosamine (PGA), oleoylethanolamide, and many others (Figure 2).

Their respective mechanisms of action have been (and still are being) investigated and appear to be profoundly interconnected to the parent compound PEA, which is by far the most studied ALIAmide [3,32,33]. A brief overview of their molecular mechanisms will be given in the following paragraphs.

A large body of evidence has been accumulating on the prohomeostatic functions of ALIAmides in several diseases sustained by non-resolving inflammatory and neuroinflammatory responses. The findings have been reviewed by several excellent papers, to which the reader is encouraged to refer [3,32,33,34,35,36,37]. After addressing a few general key points on ALIAmides, here we will focus exclusively on the main studies performed on small animals.

2. Mimicking and Supporting the Healing Power of Nature

Palmitoylethanolamide is produced starting from a glycerophospholipid precursor in the cell membrane and degraded by two amidases located in the cell membrane and lysosome, respectively, i.e., the fatty acid amide amidase (FAAH) and N-acylethanolamine acid amidase (NAAA) [38,39,40,41]. Although the endogenous levels of PEA are strictly regulated by these biosynthetic and degradative metabolic pathways [38], great deals of evidence suggest that PEA metabolism may be disturbed under certain conditions, such as chronic inflammatory disorders [42]. Indeed, the local levels of PEA change during disease states, and decreased levels are considered to contribute to disease development [8,43,44]. For example, a significant decrease in the local level of PEA has been found in different chronic pain models [45,46,47] as well as in human patients affected by visceral and somatic pain [48,49,50]. Interestingly, it was also shown that normalizing PEA levels through the inhibition of PEA degradative pathways resulted in reduced inflammation and pain relief in a rat model of osteoarthritis pain [47].

On the other side, PEA levels may increase in response to cell damage, as shown in epidermal cells subjected to UV irradiation [51] and the lesional skin of privately-owned dogs affected with atopic dermatitis [52] as well as the colons of dogs with chronic enteropathy [53].

It is currently accepted that changes in PEA levels are either suggestive of a loss of protection against inflammation/pain (i.e., decreased levels) or a compensatory synthesis in the attempt to limit disease severity (i.e., increased levels). Accordingly, the exogenous administration of PEA to effectively ‘top up’ the body’s own supply is regarded as a promising approach [54]. Interestingly, other ALIAmides, such as Adelmidrol and PGA, have recently been found to increase the endogenous levels of PEA [55,56,57].

3. A Brief Insight into PEA Metabolism and Molecular Targets

As mentioned above, the biosynthesis of PEA occurs “on demand” in the cell membrane through the enzymatic hydrolysis of its glycerophospholipid precursor N-acyl-phosphatidylethanolamine [39,40]. Although early studies suggested the existence of a facilitated membrane transport [19,58], PEA can flip between the inner and outer leaflets of the plasma membrane thanks to its lipophilic nature [59]. Indeed intracellular binding proteins (i.e., fatty acid binding proteins and heat-shock proteins) are required for PEA trafficking within the cytosol [60]. Binding proteins transport PEA to catabolic enzymes (e.g., FAAH and NAAA) [41] and effector proteins [61,62,63].

Among the latter, the nuclear peroxisome proliferator-activated receptor alpha (PPARα) is of particular interest because it negatively interferes with inflammatory gene expression by regulating the IκBα/NF-κB pathway [64]. PPARα is not the only molecular target responsible for the prohomeostatic properties of PEA [65,66,67,68,69], as many other receptors are being increasingly recognized as mediating PEA functions, such as the GPR55 (G-protein-coupled receptor 55) [70,71], cannabinoid receptors type 1 and 2 (CB1 and CB2) [33,57,72,73] as well as the so-called “pain receptor” [74], i.e., the transient receptor potential vanilloid 1 (TRPV1) [75,76,77,78].

Interestingly, this heterogeneous family of PEA molecular targets is being extensively studied in companion animals, with their distribution being confirmed in several canine and feline cell types [79,80,81,82,83,84,85,86,87,88,89,90,91,92], as recently reviewed [3,32,93].

Notably, while PEA is a direct agonist of PPARα [66], its action on CB1, CB2, and even TRPV1 is indirect [73,76,77,78]. In particular, PEA can activate these latter three receptors thanks to its ability to (i) elevate their levels, (ii) reduce their degradation, or (iii) increase the receptor affinity of endocannabinoids, like AEA and 2-arachidonoylglycerol (2-AG) [35,57,72,73,76,78]. The mechanism has been termed the “entourage effect” [73,76,78] (Figure 3) and has been specifically shown in dogs [72]. In Beagle dogs, orally administered bioavailable micro-PEA (i.e., ultra-micronized, see below) resulted in a significant and up to ~20-fold increase in the plasma levels of 2-AG [72] (Figure 3B).

To date, the molecular mechanisms of other ALIAmides are much less investigated than PEA’s. Besides increasing PEA levels, as previously mentioned, these fatty acid amides are suggested to interact with different receptors. PGA, for example, is considered to exert its protective function through a toll-like receptor 4 antagonism [94], while the precise molecular targets of Adelmidrol are still debated [55,95].

4. Key Pharmacokinetic Issues

A key aspect that has to be taken into account when dealing with the use of ALIAmides for health purposes is their respective physicochemical features. Some ALIAmides are more appropriate for oral use, while others are particularly suitable for topical applications thanks to their amphipathic nature (e.g., Adelmidrol) [95,96].

PEA and PGA are both highly lipophilic compounds (log p > 5) [97,98], with their oral use being limited by their intrinsic low dissolution rate, absorption, and bioavailability [98,99]. Particle size reduction is one of the most compelling and practical strategies for improving pharmacokinetics and boosting functional properties following oral administration [100,101]. Provided the route of administration is oral, most of the studies presented below investigated “micro-PEA” and “micro-PGA” accordingly. Micro-ALIAmides result from micro-grinding a particular ALIAmide—either alone or together with adjuvants (typically antioxidants)—in order to downsize the particles to diameters in the range of 0.6–10 μm. Indeed, after the administration of micro-PEA, the plasma concentration of PEA was significantly higher compared to unprocessed (naïve) PEA [98]. Accordingly, superior effects have been shown for micro-PEA and micro -PGA compared to naïve PEA and PGA, respectively, in different inflammatory disease models [97,102,103].

Specifically, in dogs, a single oral administration of micro-PEA resulted in a five-fold increase in PEA plasma levels, with a peak between 1 and 2 h [72,104]. Interestingly, plasma levels correlated well with the clinical effects at different timepoints, although the latter lasted longer than the plasma elevation of PEA [104]. This was considered to depend on the ability of PEA to up-regulate the levels or enhance the action of other related bioactive endocannabinoids [104], according to the so-called “entourage hypothesis” briefly outlined in Figure 3.

5. Preclinical and Clinical Results in Small Animals

5.1. Dermatological Field

So far, most of the veterinary research on ALIAmides has been focused on the dermatological field [105]. Ex vivo and in vitro studies, performed on feline and canine skin mast cells, respectively, have confirmed that micro-PEA down-modulates allergic hyperactivity, prominently decreasing mediator release (i.e., degranulation) [5,7]. The ability of micro-PEA to down-modulate mast cell degranulation was also recently shown in canine skin organ cultures challenged with different concentrations of compound 48/80 (a well-known secretagogue which triggers mast cell degranulation) [6]. Not only did micro-PEA significantly counteract the increase of degranulating mast cells, but it also lowered the histamine content within the culture medium and the diameter of epidermal blood capillaries [6].

Moreover, down-modulation of skin mast cell releasability was observed in canine skin wounds (punch biopsies) topically treated with the ALIAmide Adelmidrol (2%) [106], with a parallel improvement in wound healing being detected [107].

Moving to in vivo studies, a growing body of evidence confirms that ALIAmides can efficiently benefit veterinary patients with hypersensitive skin disorders. In a double-blinded placebo-controlled cross-over study performed on dogs with experimental allergic dermatitis, the dietetic supplementation with micro-PEA at 15 mg/kg/day for 7 days delayed the development of clinical signs (i.e., pruritus and skin lesions) compared to the placebo-treated group [108]. Moreover, in a canine model of skin allergy, a single oral administration of micro-PEA (3, 10, and 30 mg/kg) significantly reduced the antigen-induced wheal area, with a maximum inhibitory effect at a 10 mg/kg dose [104]. Interestingly, topical application of Adelmidrol (2%) for 3 and 6 consecutive days gave similar results in terms of allergic wheal inhibition [96].

On the clinical side, two studies were performed on allergic cats. The first one investigated feline patients with eosinophilic plaques and eosinophilic granuloma, orally given micro-PEA (10 mg/kg daily) for 1 month as the sole intervention. Clinical improvement of pruritus, erythema, alopecia, and eosinophilic lesions was observed in 67% of them, with no side effects or adverse reactions being reported [7]. The second was conducted in 60 allergic cats with the aim of evaluating whether micro-PEA (15 mg/kg) could delay the relapse of clinical signs after steroid withdrawal [109]. A significant difference in the mean time-to-flare between the treated and placebo group was observed (40.5 days in the micro-PEA group vs. 22.2 days in the placebo group), suggesting that the ALIAmide exerts an excellent proactive function in preventing feline allergic flares after steroid withdrawal [109].

Some interesting clinical trials were also performed on allergic dogs. A double-blinded randomized placebo-controlled cross-over study in privately-owned dogs with either food-induced or non-food-induced atopic dermatitis showed that dietary integration with micro-PEA (15 mg/kg daily for 45 days) significantly decreased the severity of clinical signs (as assessed by the Canine Atopic Dermatitis Extension and Severity Index) [110].

An open multicentric study performed in 160 client-owned dogs with non-seasonal atopic dermatitis orally administered micro-PEA (10 mg/kg daily for 56 days) confirmed the ability of the ALIAmide to benefit allergic patients [111]. Pruritus (as measured on a Visual Analogue Scale) and clinically assessed skin lesions (Canine Atopic Dermatitis Lesion Index) were significantly reduced by the study end. Moreover, 45% of dogs reached the quality of life values described for healthy animals [111].

Finally, an open-label observational study was performed in privately-owned dogs with atopic dermatitis and pruritus lasting longer than 4 weeks, topically treated with Adelmidrol (2%) twice daily for 30 days. Not only a significant decrease in pruritus and erythema (both on owner and veterinarian assessment) was observed, but body odor and quality of life markedly improved by the study’s end [112].

5.2. Other Health Needs

Although studies in small animals are still scarce, there is growing evidence that endocannabinoid-like ALIAmides play key roles in the health of different body organs, such as the gastrointestinal tract [113,114] and the nervous system [32,34,37], as well as the upper and lower urinary tract [115,116,117,118] and the musculoskeletal system [97,119,120]. In addition, the deep involvement of ALIAmides in obesity-induced metainflammation is becoming increasingly evident [69,113,121,122,123].

Actually, a preliminary study in dogs affected with chronic diarrhea demonstrated that dietetic supplementation with micro-PEA (10 mg/kg for 30 days) reduced the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) score [53], in line with recent findings from animals with experimentally-induced colitis [124]. According to the experimental studies, the enteroprotective effect of PEA may depend upon the direct and indirect activation of PPAR-α and CB2 receptors [124,125,126,127,128,129,130], whose expression has been recently confirmed in the canine and feline gastrointestinal tract [86,87].

Interestingly, a dietetic supplement containing micro-PEA was also described to benefit a Syrian hamster with urolithiasis and diminish the disease recurrence after surgical treatment [131]. Moreover, micro-PGA has recently been shown to decrease inflammation and pain in a murine model of feline interstitial cystitis [132].

In the musculoskeletal field, an open-field trial on client-owned adult dogs with chronic osteoarthritis and persistent lameness has recently been performed. Dogs were supplemented for 4 weeks with a complementary feed containing PEA co-ultramicronized with the natural antioxidant quercetin (i.e., PEA-q, 24 mg/kg body weight). The severity of chronic pain and its interference with the dog’s normal functioning significantly decreased as assessed with the Canine Brief Pain Inventory (CBPI) questionnaire. Moreover, lameness (either assessed on a 0–4 clinical scale or through a dynamic gait analysis) significantly improved [133].

Dogs with osteoarthritis also benefited from a long-term dietary integration with the ALIAmide PGA co-micronized with curcumin, administered as an add-on to conservative measures. One trial has been performed [134], where micro-PGA was added for 2 months to the individual management plan of 181 dogs with osteoarthritis. A significant decrease in lameness and pain as assessed by the veterinarian was observed. Moreover, owner-evaluated mobility impairment and pain behaviors also improved [134].

It is finally noteworthy that the topical administration of an Adelmidrol (2%) mucoadhesive gel in combination with dental prophylaxis resulted in less gingival inflammation and longer duration of dental scaling benefits in treated dogs compared to match untreated group [135].

Taken together, the data from preclinical and clinical trials point towards the promising role of ALIAmides in small animal health (Figure 4). Moreover, the presence of PEA and OEA, as well as other ALIAmides in food sources [136], in addition to their robust safety profile [36,97,137], are the foundation for their dietary use. Accordingly, several complementary feeds for dogs and cats have been developed and are being marketed in Europe and North America.

6. Conclusions

Although the field is still in its infancy, the studies presented in this review highlight the promise that ALIAmides might play a broad role in small animal health. Their physiological prohomeostatic functions represent a key rationale for their use in promoting animals’ health through an “according-to-nature” approach, i.e., mimicking or supporting the physiological mechanisms to maintain homeostasis.

Although further clinical studies are needed, ALIAmide-based products—either used as a sole intervention or associated with standard drugs—are emerging as a new and promising approach to veterinary patients.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors wish to thank Sofia Pavan for graphical support and are indebted to Francesco della Valle for opening new horizons in the nature-driven approach to animal health and wellbeing.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Figure 1. Francesco della Valle in the 1990s during brainstorming with his main scientific mentors, namely Rita Levi Montalcini (left) and Erminio Costa (right).

Figure 2. Chemical structure of the main ALIAmides. The amide bond (yellow shadow) and the fatty acid (blue color) are highlighted. ADM = Adelmidrol, OEA = oleoylethanolamide, PEA = palmitoylethanolamide, PGA = palmitoylglucosamine.

Figure 3. PEA may act on its molecular targets either directly or indirectly by increasing the agonism toward endocannabinoid receptors for which it has a low affinity. The latter mechanism is referred to as the “entourage effect”. The figure illustrates the in vitro (A) and in vivo (B) demonstrations of the entourage effect of bioavailable formulations of PEA (i.e., micro-PEA, please see next paragraph for further details) through increasing the levels of the endocannabinoid 2-AG. (A) Indirect agonism of micro-PEA on CB2 underlies the inhibitory effects on SP-induced mast cell degranulation, mediated by the stimulation of 2-AG biosynthesis [57]. (B) Following a single dietary supplementation with micro-PEA to hypersensitive Beagle dogs, not only plasma levels of PEA but also plasma levels of 2-AG significantly increase (* p < 0.05 and ** p < 0.001 versus the basal levels, time 0) [3]. (B) is slightly modified from [3]. 2-AG = 2-arachidonoylglycerol, CB2 = cannabinoid receptor type 2, micro-PEA = micronized or ultramicronized palmitoylethanolamide, SP = substance P.

Figure 4. ALIAmides for small animal health—a global view. Upon prolonged stimulation, immune-inflammatory cells may become overactivated. If uncontrolled, their beneficial protective responses may instead turn harmful, leading to local dyshomeostasis and health disorders. In order to control the risk, autoprotective mechanisms are activated. The local production of PEA starting from a glycerophospholipid precursor (dark green circle) represents one of them. Once produced, PEA (light green circle) serves as a signaling molecule through its direct and indirect interactions with multiple receptor targets resulting in cell down-modulation. Local homeostasis and body health are maintained accordingly. Exogenously administered ALIAmides mimic or sustain the autoprotective mechanism described above, mainly through restoring endogenous PEA levels. The main organs and body tissues purportedly benefiting from the aforementioned mechanism are listed in the colored circles on the bottom. GI = gastrointestinal, MS = musculoskeletal, PEA-um = ultramicronized palmitoylethanolamide, PGA-m = micronized palmitoylglucosamine.

References

1. Aloe, L.; Leon, A.; Levi-Montalcini, R. A Proposed Autacoid Mechanism Controlling Mastocyte Behaviour. Agents Actions; 1993; 39, pp. C145-C147. [DOI: https://dx.doi.org/10.1007/BF01972748] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7505999]

2. Melmon, K.L.; Rocklin, R.E.; Rosenkranz, R.P. Autacoids as Modulators of the Inflammatory and Immune Response. Am. J. Med.; 1981; 71, pp. 100-106. [DOI: https://dx.doi.org/10.1016/0002-9343(81)90264-3]

3. Gugliandolo, E.; Peritore, A.F.; Piras, C.; Cuzzocrea, S.; Crupi, R. Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing. Vet. Sci.; 2020; 7, 78. [DOI: https://dx.doi.org/10.3390/vetsci7020078] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32560159]

4. Mazzari, S.; Canella, R.; Petrelli, L.; Marcolongo, G.; Leon, A. N-(2-Hydroxyethyl)Hexadecanamide Is Orally Active in Reducing Edema Formation and Inflammatory Hyperalgesia by down-Modulating Mast Cell Activation. Eur. J. Pharmacol.; 1996; 300, pp. 227-236. [DOI: https://dx.doi.org/10.1016/0014-2999(96)00015-5]

5. Cerrato, S.; Brazis, P.; della Valle, M.F.; Miolo, A.; Puigdemont, A. Effects of Palmitoylethanolamide on Immunologically Induced Histamine, PGD2 and TNFalpha Release from Canine Skin Mast Cells. Vet. Immunol. Immunopathol.; 2010; 133, pp. 9-15. [DOI: https://dx.doi.org/10.1016/j.vetimm.2009.06.011]

6. Abramo, F.; Lazzarini, G.; Pirone, A.; Lenzi, C.; Albertini, S.; Della Valle, M.F.; Schievano, C.; Vannozzi, I.; Miragliotta, V. Ultramicronized Palmitoylethanolamide Counteracts the Effects of Compound 48/80 in a Canine Skin Organ Culture Model. Vet. Dermatol.; 2017; 28, 456-e104. [DOI: https://dx.doi.org/10.1111/vde.12456]

7. Scarampella, F.; Abramo, F.; Noli, C. Clinical and Histological Evaluation of an Analogue of Palmitoylethanolamide, PLR 120 (Comicronized Palmidrol INN) in Cats with Eosinophilic Granuloma and Eosinophilic Plaque: A Pilot Study. Vet. Dermatol.; 2001; 12, pp. 29-39. [DOI: https://dx.doi.org/10.1046/j.1365-3164.2001.00214.x]

8. Rinne, P.; Guillamat-Prats, R.; Rami, M.; Bindila, L.; Ring, L.; Lyytikäinen, L.-P.; Raitoharju, E.; Oksala, N.; Lehtimäki, T.; Weber, C. et al. Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation. Arterioscler. Thromb. Vasc. Biol.; 2018; 38, pp. 2562-2575. [DOI: https://dx.doi.org/10.1161/ATVBAHA.118.311185]

9. Petrosino, S.; Cristino, L.; Karsak, M.; Gaffal, E.; Ueda, N.; Tüting, T.; Bisogno, T.; De Filippis, D.; D’Amico, A.; Saturnino, C. et al. Protective Role of Palmitoylethanolamide in Contact Allergic Dermatitis. Allergy; 2010; 65, pp. 698-711. [DOI: https://dx.doi.org/10.1111/j.1398-9995.2009.02254.x]

10. Bettoni, I.; Comelli, F.; Colombo, A.; Bonfanti, P.; Costa, B. Non-Neuronal Cell Modulation Relieves Neuropathic Pain: Efficacy of the Endogenous Lipid Palmitoylethanolamide. CNS Neurol. Disord. Drug Targets; 2013; 12, pp. 34-44. [DOI: https://dx.doi.org/10.2174/1871527311312010008]

11. Luongo, L.; Guida, F.; Boccella, S.; Bellini, G.; Gatta, L.; Rossi, F.; de Novellis, V.; Maione, S. Palmitoylethanolamide Reduces Formalin-Induced Neuropathic-like Behaviour through Spinal Glial/Microglial Phenotypical Changes in Mice. CNS Neurol. Disord. Drug Targets; 2013; 12, pp. 45-54. [DOI: https://dx.doi.org/10.2174/1871527311312010009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23394524]

12. Guida, F.; Luongo, L.; Marmo, F.; Romano, R.; Iannotta, M.; Napolitano, F.; Belardo, C.; Marabese, I.; D’Aniello, A.; De Gregorio, D. et al. Palmitoylethanolamide Reduces Pain-Related Behaviors and Restores Glutamatergic Synapses Homeostasis in the Medial Prefrontal Cortex of Neuropathic Mice. Mol. Brain; 2015; 8, 47. [DOI: https://dx.doi.org/10.1186/s13041-015-0139-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26260027]

13. Gabrielsson, L.; Gouveia-Figueira, S.; Häggström, J.; Alhouayek, M.; Fowler, C.J. The Anti-Inflammatory Compound Palmitoylethanolamide Inhibits Prostaglandin and Hydroxyeicosatetraenoic Acid Production by a Macrophage Cell Line. Pharmacol. Res. Perspect.; 2017; 5, e00300. [DOI: https://dx.doi.org/10.1002/prp2.300] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28357126]

14. Chiurchiù, V.; Leuti, A.; Smoum, R.; Mechoulam, R.; Maccarrone, M. Bioactive Lipids ALIAmides Differentially Modulate Inflammatory Responses of Distinct Subsets of Primary Human T Lymphocytes. FASEB J.; 2018; 32, pp. 5716-5723. [DOI: https://dx.doi.org/10.1096/fj.201800107R]

15. Bronzuoli, M.R.; Facchinetti, R.; Steardo, L.; Romano, A.; Stecca, C.; Passarella, S.; Steardo, L.; Cassano, T.; Scuderi, C. Palmitoylethanolamide Dampens Reactive Astrogliosis and Improves Neuronal Trophic Support in a Triple Transgenic Model of Alzheimer’s Disease: In Vitro and In Vivo Evidence. Oxidative Med. Cell. Longev.; 2018; 2018, pp. 1-14. [DOI: https://dx.doi.org/10.1155/2018/4720532] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29576849]

16. Scuderi, C.; Esposito, G.; Blasio, A.; Valenza, M.; Arietti, P.; Steardo, L.; Carnuccio, R.; De Filippis, D.; Petrosino, S.; Iuvone, T. et al. Palmitoylethanolamide Counteracts Reactive Astrogliosis Induced by β-Amyloid Peptide. J. Cell Mol. Med.; 2011; 15, pp. 2664-2674. [DOI: https://dx.doi.org/10.1111/j.1582-4934.2011.01267.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21255263]

17. Ozaki, T.; Kamiyama, N.; Saechue, B.; Soga, Y.; Gotoh, R.; Nakayama, T.; Fukuda, C.; Dewayani, A.; Chalalai, T.; Ariki, S. et al. Comprehensive Lipidomics of Lupus-Prone Mice Using LC-MS/MS Identifies the Reduction of Palmitoylethanolamide That Suppresses TLR9-Mediated Inflammation. Genes Cells; 2022; 27, pp. 493-504. [DOI: https://dx.doi.org/10.1111/gtc.12944] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35485445]

18. Facchinetti, R.; Valenza, M.; Gomiero, C.; Mancini, G.F.; Steardo, L.; Campolongo, P.; Scuderi, C. Co-Ultramicronized Palmitoylethanolamide/Luteolin Restores Oligodendrocyte Homeostasis via Peroxisome Proliferator-Activated Receptor-α in an In Vitro Model of Alzheimer’s Disease. Biomedicines; 2022; 10, 1236. [DOI: https://dx.doi.org/10.3390/biomedicines10061236]

19. Bisogno, T.; Maurelli, S.; Melck, D.; De Petrocellis, L.; Di Marzo, V. Biosynthesis, Uptake, and Degradation of Anandamide and Palmitoylethanolamide in Leukocytes. J. Biol. Chem.; 1997; 272, pp. 3315-3323. [DOI: https://dx.doi.org/10.1074/jbc.272.6.3315]

20. Muccioli, G.G.; Stella, N. Microglia Produce and Hydrolyze Palmitoylethanolamide. Neuropharmacology; 2008; 54, pp. 16-22. [DOI: https://dx.doi.org/10.1016/j.neuropharm.2007.05.015]

21. Walter, L.; Franklin, A.; Witting, A.; Moller, T.; Stella, N. Astrocytes in Culture Produce Anandamide and Other Acylethanolamides. J. Biol. Chem.; 2002; 277, pp. 20869-20876. [DOI: https://dx.doi.org/10.1074/jbc.M110813200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11916961]

22. Natarajan, V.; Reddy, P.V.; Schmid, P.C.; Schmid, H.H. On the Biosynthesis and Metabolism of N-Acylethanolamine Phospholipids in Infarcted Dog Heart. Biochim. Biophys. Acta; 1981; 664, pp. 445-448. [DOI: https://dx.doi.org/10.1016/0005-2760(81)90067-9]

23. Epps, D.E.; Schmid, P.C.; Natarajan, V.; Schmid, H.H.O. N-Acylethanolamine Accumulation in Infarcted Myocardium. Biochem. Biophys. Res. Commun.; 1979; 90, pp. 628-633. [DOI: https://dx.doi.org/10.1016/0006-291X(79)91281-6]

24. Natarajan, V.; Schmid, P.C.; Reddy, P.V.; Schmid, H.H. Catabolism of N-Acylethanolamine Phospholipids by Dog Brain Preparations. J. Neurochem.; 1984; 42, pp. 1613-1619. [DOI: https://dx.doi.org/10.1111/j.1471-4159.1984.tb12750.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6726229]

25. Devane, W.A.; Hanus, L.; Breuer, A.; Pertwee, R.G.; Stevenson, L.A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor. Science; 1992; 258, pp. 1946-1949. [DOI: https://dx.doi.org/10.1126/science.1470919]

26. della Valle, F.; Gambardella, A. ‘Biological’ Revolution and Strategies for Innovation in Pharmaceutical Companies. R&D Manag.; 1993; 23, pp. 287-302. [DOI: https://dx.doi.org/10.1111/j.1467-9310.1993.tb00835.x]

27. Aloe, L. Rita Levi-Montalcini: The Discovery of Nerve Growth Factor and Modern Neurobiology. Trends Cell. Biol.; 2004; 14, pp. 395-399. [DOI: https://dx.doi.org/10.1016/j.tcb.2004.05.011]

28. Grayson, D.R.; Guidotti, A. Erminio Costa. Neuropsychopharmacology; 2010; 35, 2646. [DOI: https://dx.doi.org/10.1038/npp.2009.231]

29. Costa, E. An Early Attempt to Foster Neuroscience Globalization: An Autobiography; Good Life Press, Incorporated: Singapore, 2003; ISBN 978-0-9726121-1-1

30. Levi-Montalcini, R.; Skaper, S.D.; Dal Toso, R.; Petrelli, L.; Leon, A. Nerve Growth Factor: From Neurotrophin to Neurokine. Trends Neurosci.; 1996; 19, pp. 514-520. [DOI: https://dx.doi.org/10.1016/S0166-2236(96)10058-8]

31. Costa, E. Rrespecting Nature as a Strategy for the Development of New Drugs of the Nervous System. Proceedings of the Drugs for Human Life Conference; Rome, Italy, 23–25 October 1986.

32. della Rocca, G.; Gamba, D. Chronic Pain in Dogs and Cats: Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide?. Animals; 2021; 11, 952. [DOI: https://dx.doi.org/10.3390/ani11040952]

33. Re, G.; Barbero, R.; Miolo, A.; Di Marzo, V. Palmitoylethanolamide, Endocannabinoids and Related Cannabimimetic Compounds in Protection against Tissue Inflammation and Pain: Potential Use in Companion Animals. Vet. J.; 2007; 173, pp. 21-30. [DOI: https://dx.doi.org/10.1016/j.tvjl.2005.10.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16324856]

34. Petrosino, S.; Schiano Moriello, A. Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review. Int. J. Mol. Sci.; 2020; 21, 9526. [DOI: https://dx.doi.org/10.3390/ijms21249526] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33333772]

35. Petrosino, S.; Di Marzo, V. The Pharmacology of Palmitoylethanolamide and First Data on the Therapeutic Efficacy of Some of Its New Formulations. Br. J. Pharmacol.; 2017; 174, pp. 1349-1365. [DOI: https://dx.doi.org/10.1111/bph.13580] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27539936]

36. Esposito, E.; Cuzzocrea, S. Palmitoylethanolamide Is a New Possible Pharmacological Treatment for the Inflammation Associated with Trauma. Mini Rev. Med. Chem.; 2013; 13, pp. 237-255. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22697514]

37. Scuderi, C.; Golini, L. Successful and Unsuccessful Brain Aging in Pets: Pathophysiological Mechanisms behind Clinical Signs and Potential Benefits from Palmitoylethanolamide Nutritional Intervention. Animals; 2021; 11, 2584. [DOI: https://dx.doi.org/10.3390/ani11092584]

38. Hussain, Z.; Uyama, T.; Tsuboi, K.; Ueda, N. Mammalian Enzymes Responsible for the Biosynthesis of N-Acylethanolamines. Biochim. Biophys. Acta Mol. Cell Biol. Lipids; 2017; 1862, pp. 1546-1561. [DOI: https://dx.doi.org/10.1016/j.bbalip.2017.08.006]

39. Tsuboi, K.; Uyama, T.; Okamoto, Y.; Ueda, N. Endocannabinoids and Related N-Acylethanolamines: Biological Activities and Metabolism. Inflamm. Regen.; 2018; 38, 28. [DOI: https://dx.doi.org/10.1186/s41232-018-0086-5]

40. Sun, Y.-X.; Tsuboi, K.; Okamoto, Y.; Tonai, T.; Murakami, M.; Kudo, I.; Ueda, N. Biosynthesis of Anandamide and N-Palmitoylethanolamine by Sequential Actions of Phospholipase A2 and Lysophospholipase D. Biochem. J.; 2004; 380, pp. 749-756. [DOI: https://dx.doi.org/10.1042/bj20040031]

41. Ueda, N.; Tsuboi, K.; Uyama, T. N-Acylethanolamine Metabolism with Special Reference to N-Acylethanolamine-Hydrolyzing Acid Amidase (NAAA). Prog. Lipid Res.; 2010; 49, pp. 299-315. [DOI: https://dx.doi.org/10.1016/j.plipres.2010.02.003]

42. Alhouayek, M.; Muccioli, G.G. Harnessing the Anti-Inflammatory Potential of Palmitoylethanolamide. Drug Discov. Today; 2014; 19, pp. 1632-1639. [DOI: https://dx.doi.org/10.1016/j.drudis.2014.06.007]

43. Roviezzo, F.; Rossi, A.; Caiazzo, E.; Orlando, P.; Riemma, M.A.; Iacono, V.M.; Guarino, A.; Ialenti, A.; Cicala, C.; Peritore, A. et al. Palmitoylethanolamide Supplementation during Sensitization Prevents Airway Allergic Symptoms in the Mouse. Front. Pharmacol.; 2017; 8, 857. [DOI: https://dx.doi.org/10.3389/fphar.2017.00857] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29311913]

44. Skaper, S.D.; Facci, L.; Barbierato, M.; Zusso, M.; Bruschetta, G.; Impellizzeri, D.; Cuzzocrea, S.; Giusti, P. N-Palmitoylethanolamine and Neuroinflammation: A Novel Therapeutic Strategy of Resolution. Mol. Neurobiol.; 2015; 52, pp. 1034-1042. [DOI: https://dx.doi.org/10.1007/s12035-015-9253-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26055231]

45. Petrosino, S.; Palazzo, E.; de Novellis, V.; Bisogno, T.; Rossi, F.; Maione, S.; Di Marzo, V. Changes in Spinal and Supraspinal Endocannabinoid Levels in Neuropathic Rats. Neuropharmacology; 2007; 52, pp. 415-422. [DOI: https://dx.doi.org/10.1016/j.neuropharm.2006.08.011] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17011598]

46. Charrua, A.; Matos, R.; Oliveira, R.; Marczylo, T.; Nagy, I.; Cruz, F. Fatty Acid Amide Hydrolase Inhibition Normalises Bladder Function and Reduces Pain through Normalising the Anandamide/Palmitoylethanolamine Ratio in the Inflamed Bladder of Rats. Naunyn. Schmiedebergs Arch. Pharmacol.; 2020; 393, pp. 263-272. [DOI: https://dx.doi.org/10.1007/s00210-019-01729-9]

47. Zhou, P.; Xiang, L.; Yang, Y.; Wu, Y.; Hu, T.; Liu, X.; Lin, F.; Xiu, Y.; Wu, K.; Lu, C. et al. N-Acylethanolamine Acid Amidase (NAAA) Inhibitor F215 as a Novel Therapeutic Agent for Osteoarthritis. Pharmacol. Res.; 2019; 145, 104264. [DOI: https://dx.doi.org/10.1016/j.phrs.2019.104264]

48. Fichna, J.; Wood, J.T.; Papanastasiou, M.; Vadivel, S.K.; Oprocha, P.; Sałaga, M.; Sobczak, M.; Mokrowiecka, A.; Cygankiewicz, A.I.; Zakrzewski, P.K. et al. Endocannabinoid and Cannabinoid-like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study. PLoS ONE; 2013; 8, e85073. [DOI: https://dx.doi.org/10.1371/journal.pone.0085073]

49. Sarnelli, G.; Pesce, M.; Seguella, L.; Lu, J.; Efficie, E.; Tack, J.; Elisa De Palma, F.D.; D’Alessandro, A.; Esposito, G. Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia. Cell Mol. Gastroenterol. Hepatol.; 2021; 11, pp. 841-855. [DOI: https://dx.doi.org/10.1016/j.jcmgh.2020.10.001]

50. Richardson, D.; Pearson, R.G.; Kurian, N.; Latif, M.L.; Garle, M.J.; Barrett, D.A.; Kendall, D.A.; Scammell, B.E.; Reeve, A.J.; Chapman, V. Characterisation of the Cannabinoid Receptor System in Synovial Tissue and Fluid in Patients with Osteoarthritis and Rheumatoid Arthritis. Arthritis Res. Ther.; 2008; 10, R43. [DOI: https://dx.doi.org/10.1186/ar2401]

51. Berdyshev, E.V.; Schmid, P.C.; Dong, Z.; Schmid, H.H. Stress-Induced Generation of N-Acylethanolamines in Mouse Epidermal JB6 P+ Cells. Biochem. J.; 2000; 346, Pt 2, pp. 369-374. [DOI: https://dx.doi.org/10.1042/bj3460369]

52. Abramo, F.; Campora, L.; Albanese, F.; della Valle, M.F.; Cristino, L.; Petrosino, S.; Di Marzo, V.; Miragliotta, V. Increased Levels of Palmitoylethanolamide and Other Bioactive Lipid Mediators and Enhanced Local Mast Cell Proliferation in Canine Atopic Dermatitis. BMC Vet. Res.; 2014; 10, 21. [DOI: https://dx.doi.org/10.1186/1746-6148-10-21]

53. Pengo, G.; Miolo, A. Utilizzo Di Palmitoiletanolamide Micronizzata Nell’infiammazione Gastrointestinale Idiopatica (IBD) Del Cane: Descrizione Di 7 Casi Clinici. Proceedings of the 72 International SCIVAC Congress; Milan, Italy, 23–25 March 2012; pp. 299-301.

54. Skaper, S.D.; Facci, L.; Giusti, P. Mast Cells, Glia and Neuroinflammation: Partners in Crime?. Immunology; 2014; 141, pp. 314-327. [DOI: https://dx.doi.org/10.1111/imm.12170] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24032675]

55. Del Re, A.; Palenca, I.; Seguella, L.; Pesce, M.; Corpetti, C.; Steardo, L.; Rurgo, S.; Sarnelli, G.; Esposito, G. Oral Adelmidrol Administration Up-Regulates Palmitoylethanolamide Production in Mice Colon and Duodenum through a PPAR-γ Independent Action. Metabolites; 2022; 12, 457. [DOI: https://dx.doi.org/10.3390/metabo12050457] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35629962]

56. Petrosino, S.; Puigdemont, A.; Della Valle, M.F.; Fusco, M.; Verde, R.; Allarà, M.; Aveta, T.; Orlando, P.; Di Marzo, V. Adelmidrol Increases the Endogenous Concentrations of Palmitoylethanolamide in Canine Keratinocytes and Down-Regulates an Inflammatory Reaction in an in Vitro Model of Contact Allergic Dermatitis. Vet. J.; 2016; 207, pp. 85-91. [DOI: https://dx.doi.org/10.1016/j.tvjl.2015.10.060] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26639824]

57. Petrosino, S.; Schiano Moriello, A.; Verde, R.; Allarà, M.; Imperatore, R.; Ligresti, A.; Mahmoud, A.M.; Peritore, A.F.; Iannotti, F.A.; Di Marzo, V. Palmitoylethanolamide Counteracts Substance P-Induced Mast Cell Activation in Vitro by Stimulating Diacylglycerol Lipase Activity. J. Neuroinflammation; 2019; 16, 274. [DOI: https://dx.doi.org/10.1186/s12974-019-1671-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31878942]

58. Jacobsson, S.O.; Fowler, C.J. Characterization of Palmitoylethanolamide Transport in Mouse Neuro-2a Neuroblastoma and Rat RBL-2H3 Basophilic Leukaemia Cells: Comparison with Anandamide. Br. J. Pharmacol.; 2001; 132, pp. 1743-1754. [DOI: https://dx.doi.org/10.1038/sj.bjp.0704029] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11309246]

59. Carta, G.; Murru, E.; Banni, S.; Manca, C. Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications. Front. Physiol.; 2017; 8, 902. [DOI: https://dx.doi.org/10.3389/fphys.2017.00902]

60. Bojesen, I.N.; Hansen, H.S. Membrane Transport of Anandamide through Resealed Human Red Blood Cell Membranes. J. Lipid Res.; 2005; 46, pp. 1652-1659. [DOI: https://dx.doi.org/10.1194/jlr.M400498-JLR200]

61. Kaczocha, M.; Glaser, S.T.; Maher, T.; Clavin, B.; Hamilton, J.; O’Rourke, J.; Rebecchi, M.; Puopolo, M.; Owada, Y.; Thanos, P.K. Fatty Acid Binding Protein Deletion Suppresses Inflammatory Pain through Endocannabinoid/N-Acylethanolamine-Dependent Mechanisms. Mol. Pain; 2015; 11, 52. [DOI: https://dx.doi.org/10.1186/s12990-015-0056-8]

62. Kaczocha, M.; Vivieca, S.; Sun, J.; Glaser, S.T.; Deutsch, D.G. Fatty Acid-Binding Proteins Transport N-Acylethanolamines to Nuclear Receptors and Are Targets of Endocannabinoid Transport Inhibitors. J. Biol. Chem.; 2012; 287, pp. 3415-3424. [DOI: https://dx.doi.org/10.1074/jbc.M111.304907]

63. Oddi, S.; Fezza, F.; Pasquariello, N.; D’Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agrò, A.; Maccarrone, M. Molecular Identification of Albumin and Hsp70 as Cytosolic Anandamide-Binding Proteins. Chem. Biol.; 2009; 16, pp. 624-632. [DOI: https://dx.doi.org/10.1016/j.chembiol.2009.05.004]

64. Korbecki, J.; Bobiński, R.; Dutka, M. Self-Regulation of the Inflammatory Response by Peroxisome Proliferator-Activated Receptors. Inflamm. Res.; 2019; 68, pp. 443-458. [DOI: https://dx.doi.org/10.1007/s00011-019-01231-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30927048]

65. Lo Verme, J.; Fu, J.; Astarita, G.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-Alpha Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide. Mol. Pharmacol.; 2005; 67, pp. 15-19. [DOI: https://dx.doi.org/10.1124/mol.104.006353] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15465922]

66. Lo Verme, J.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. The Search for the Palmitoylethanolamide Receptor. Life Sci.; 2005; 77, pp. 1685-1698. [DOI: https://dx.doi.org/10.1016/j.lfs.2005.05.012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15963531]

67. LoVerme, J.; Russo, R.; La Rana, G.; Fu, J.; Farthing, J.; Mattace-Raso, G.; Meli, R.; Hohmann, A.; Calignano, A.; Piomelli, D. Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-Alpha. J. Pharmacol. Exp. Ther.; 2006; 319, pp. 1051-1061. [DOI: https://dx.doi.org/10.1124/jpet.106.111385]

68. Zhou, G.; Fu, X.; Wang, L.; Cao, Y.; Zhuang, J.; Hu, J.; Li, Y.; Xu, C.; Gao, S.; Shao, A. et al. Palmitoylethanolamide Ameliorates Neuroinflammation via Modulating PPAR-α to Promote the Functional Outcome after Intracerebral Hemorrhage. Neurosci. Lett.; 2022; 781, 136648. [DOI: https://dx.doi.org/10.1016/j.neulet.2022.136648]

69. Annunziata, C.; Pirozzi, C.; Lama, A.; Senzacqua, M.; Comella, F.; Bordin, A.; Monnolo, A.; Pelagalli, A.; Ferrante, M.C.; Mollica, M.P. et al. Palmitoylethanolamide Promotes White-to-Beige Conversion and Metabolic Reprogramming of Adipocytes: Contribution of PPAR-α. Pharmaceutics; 2022; 14, 338. [DOI: https://dx.doi.org/10.3390/pharmaceutics14020338]

70. Im, D.-S. GPR119 and GPR55 as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide. Int. J. Mol. Sci.; 2021; 22, 1034. [DOI: https://dx.doi.org/10.3390/ijms22031034]

71. Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The Orphan Receptor GPR55 Is a Novel Cannabinoid Receptor. Br. J. Pharmacol.; 2007; 152, pp. 1092-1101. [DOI: https://dx.doi.org/10.1038/sj.bjp.0707460]

72. Petrosino, S.; Schiano Moriello, A.; Cerrato, S.; Fusco, M.; Puigdemont, A.; De Petrocellis, L.; Di Marzo, V. The Anti-Inflammatory Mediator Palmitoylethanolamide Enhances the Levels of 2-Arachidonoyl-Glycerol and Potentiates Its Actions at TRPV1 Cation Channels. Br. J. Pharmacol.; 2016; 173, pp. 1154-1162. [DOI: https://dx.doi.org/10.1111/bph.13084]

73. Di Marzo, V.; Melck, D.; Orlando, P.; Bisogno, T.; Zagoory, O.; Bifulco, M.; Vogel, Z.; De Petrocellis, L. Palmitoylethanolamide Inhibits the Expression of Fatty Acid Amide Hydrolase and Enhances the Anti-Proliferative Effect of Anandamide in Human Breast Cancer Cells. Biochem. J.; 2001; 358, pp. 249-255. [DOI: https://dx.doi.org/10.1042/bj3580249]

74. Julius, D. TRP Channels and Pain. Annu. Rev. Cell Dev. Biol.; 2013; 29, pp. 355-384. [DOI: https://dx.doi.org/10.1146/annurev-cellbio-101011-155833] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24099085]

75. Costa, B.; Comelli, F.; Bettoni, I.; Colleoni, M.; Giagnoni, G. The Endogenous Fatty Acid Amide, Palmitoylethanolamide, Has Anti-Allodynic and Anti-Hyperalgesic Effects in a Murine Model of Neuropathic Pain: Involvement of CB(1), TRPV1 and PPARgamma Receptors and Neurotrophic Factors. Pain; 2008; 139, pp. 541-550. [DOI: https://dx.doi.org/10.1016/j.pain.2008.06.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18602217]

76. De Petrocellis, L.; Davis, J.B.; Di Marzo, V. Palmitoylethanolamide Enhances Anandamide Stimulation of Human Vanilloid VR1 Receptors. FEBS Lett.; 2001; 506, pp. 253-256. [DOI: https://dx.doi.org/10.1016/S0014-5793(01)02934-9]

77. Ambrosino, P.; Soldovieri, M.V.; Russo, C.; Taglialatela, M. Activation and Desensitization of TRPV1 Channels in Sensory Neurons by the PPARα Agonist Palmitoylethanolamide. Br. J. Pharmacol.; 2013; 168, pp. 1430-1444. [DOI: https://dx.doi.org/10.1111/bph.12029] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23083124]

78. Ho, W.-S.V.; Barrett, D.A.; Randall, M.D. “Entourage” Effects of N-Palmitoylethanolamide and N-Oleoylethanolamide on Vasorelaxation to Anandamide Occur through TRPV1 Receptors. Br. J. Pharmacol.; 2008; 155, pp. 837-846. [DOI: https://dx.doi.org/10.1038/bjp.2008.324]

79. Campora, L.; Miragliotta, V.; Ricci, E.; Cristino, L.; Di Marzo, V.; Albanese, F.; Federica Della Valle, M.; Abramo, F. Cannabinoid Receptor Type 1 and 2 Expression in the Skin of Healthy Dogs and Dogs with Atopic Dermatitis. Am. J. Vet. Res.; 2012; 73, pp. 988-995. [DOI: https://dx.doi.org/10.2460/ajvr.73.7.988]

80. Barbero, R.; Vercelli, C.; Cuniberti, B.; Della Valle, M.F.; Martano, M.; Re, G. Expression of Functional TRPV1 Receptor in Primary Culture of Canine Keratinocytes. J. Vet. Pharmacol. Ther.; 2018; 41, pp. 795-804. [DOI: https://dx.doi.org/10.1111/jvp.12694]

81. Dall’Aglio, C.; Mercati, F.; Pascucci, L.; Boiti, C.; Pedini, V.; Ceccarelli, P. Immunohistochemical Localization of CB1 Receptor in Canine Salivary Glands. Vet. Res. Commun; 2010; 34, (Suppl. S1), pp. S9-S12. [DOI: https://dx.doi.org/10.1007/s11259-010-9379-0]

82. Mercati, F.; Dall’Aglio, C.; Pascucci, L.; Boiti, C.; Ceccarelli, P. Identification of Cannabinoid Type 1 Receptor in Dog Hair Follicles. Acta Histochem.; 2012; 114, pp. 68-71. [DOI: https://dx.doi.org/10.1016/j.acthis.2011.01.003]

83. Fernández-Trapero, M.; Espejo-Porras, F.; Rodríguez-Cueto, C.; Coates, J.R.; Pérez-Díaz, C.; de Lago, E.; Fernández-Ruiz, J. Upregulation of CB2 Receptors in Reactive Astrocytes in Canine Degenerative Myelopathy, a Disease Model of Amyotrophic Lateral Sclerosis. Dis. Model. Mech.; 2017; 10, pp. 551-558. [DOI: https://dx.doi.org/10.1242/dmm.028373]

84. Freundt-Revilla, J.; Kegler, K.; Baumgärtner, W.; Tipold, A. Spatial Distribution of Cannabinoid Receptor Type 1 (CB1) in Normal Canine Central and Peripheral Nervous System. PLoS ONE; 2017; 12, e0181064. [DOI: https://dx.doi.org/10.1371/journal.pone.0181064]

85. Freundt-Revilla, J.; Heinrich, F.; Zoerner, A.; Gesell, F.; Beyerbach, M.; Shamir, M.; Oevermann, A.; Baumgärtner, W.; Tipold, A. The Endocannabinoid System in Canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis. PLoS ONE; 2018; 13, e0187197. [DOI: https://dx.doi.org/10.1371/journal.pone.0187197]

86. Galiazzo, G.; Giancola, F.; Stanzani, A.; Fracassi, F.; Bernardini, C.; Forni, M.; Pietra, M.; Chiocchetti, R. Localization of Cannabinoid Receptors CB1, CB2, GPR55, and PPARα in the Canine Gastrointestinal Tract. Histochem. Cell Biol.; 2018; 150, pp. 187-205. [DOI: https://dx.doi.org/10.1007/s00418-018-1684-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29882158]

87. Stanzani, A.; Galiazzo, G.; Giancola, F.; Tagliavia, C.; De Silva, M.; Pietra, M.; Fracassi, F.; Chiocchetti, R. Localization of Cannabinoid and Cannabinoid Related Receptors in the Cat Gastrointestinal Tract. Histochem. Cell Biol.; 2020; 153, pp. 339-356. [DOI: https://dx.doi.org/10.1007/s00418-020-01854-0]

88. Gebremedhin, D.; Lange, A.R.; Campbell, W.B.; Hillard, C.J.; Harder, D.R. Cannabinoid CB1 Receptor of Cat Cerebral Arterial Muscle Functions to Inhibit L-Type Ca2+ Channel Current. Am. J. Physiol.; 1999; 276, pp. H2085-H2093. [DOI: https://dx.doi.org/10.1152/ajpheart.1999.276.6.H2085]

89. Miragliotta, V.; Ricci, P.L.; Albanese, F.; Pirone, A.; Tognotti, D.; Abramo, F. Cannabinoid Receptor Types 1 and 2 and Peroxisome Proliferator-Activated Receptor-α: Distribution in the Skin of Clinically Healthy Cats and Cats with Hypersensitivity Dermatitis. Vet. Dermatol.; Online ahead of print 2018; [DOI: https://dx.doi.org/10.1111/vde.12658]

90. Pirone, A.; Cantile, C.; Miragliotta, V.; Lenzi, C.; Giannessi, E.; Cozzi, B. Immunohistochemical Distribution of the Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase in the Dog Claustrum. J. Chem. Neuroanat.; 2016; 74, pp. 21-27. [DOI: https://dx.doi.org/10.1016/j.jchemneu.2016.02.002]

91. Pirone, A.; Lenzi, C.; Briganti, A.; Abbate, F.; Levanti, M.; Abramo, F.; Miragliotta, V. Spatial Distribution of Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase in the Cat Ovary and Oviduct. Acta Histochem.; 2017; 119, pp. 417-422. [DOI: https://dx.doi.org/10.1016/j.acthis.2017.04.007]

92. Ndong, C.; O’Donnell, D.; Ahmad, S.; Groblewski, T. Cloning and Pharmacological Characterization of the Dog Cannabinoid CB₂ receptor. Eur. J. Pharmacol.; 2011; 669, pp. 24-31. [DOI: https://dx.doi.org/10.1016/j.ejphar.2011.08.002]

93. Silver, R.J. The Endocannabinoid System of Animals. Animals; 2019; 9, 686. [DOI: https://dx.doi.org/10.3390/ani9090686]

94. Iannotta, M.; Belardo, C.; Trotta, M.C.; Iannotti, F.A.; Vitale, R.M.; Maisto, R.; Boccella, S.; Infantino, R.; Ricciardi, F.; Mirto, B.F. et al. N-Palmitoyl-D-Glucosamine, a Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice. Int. J. Mol. Sci.; 2021; 22, 1491. [DOI: https://dx.doi.org/10.3390/ijms22031491] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33540826]

95. Impellizzeri, D.; Di Paola, R.; Cordaro, M.; Gugliandolo, E.; Casili, G.; Morittu, V.M.; Britti, D.; Esposito, E.; Cuzzocrea, S. Adelmidrol, a Palmitoylethanolamide Analogue, as a New Pharmacological Treatment for the Management of Acute and Chronic Inflammation. Biochem. Pharmacol.; 2016; 119, pp. 27-41. [DOI: https://dx.doi.org/10.1016/j.bcp.2016.09.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27599446]

96. Cerrato, S.; Brazis, P.; Della Valle, M.F.; Miolo, A.; Puigdemont, A. Inhibitory Effect of Topical Adelmidrol on Antigen-Induced Skin Wheal and Mast Cell Behavior in a Canine Model of Allergic Dermatitis. BMC Vet. Res.; 2012; 8, 230. [DOI: https://dx.doi.org/10.1186/1746-6148-8-230] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23181761]

97. Cordaro, M.; Siracusa, R.; Impellizzeri, D.; D’ Amico, R.; Peritore, A.F.; Crupi, R.; Gugliandolo, E.; Fusco, R.; Di Paola, R.; Schievano, C. et al. Safety and Efficacy of a New Micronized Formulation of the ALIAmide Palmitoylglucosamine in Preclinical Models of Inflammation and Osteoarthritis Pain. Arthritis Res. Ther.; 2019; 21, 254. [DOI: https://dx.doi.org/10.1186/s13075-019-2048-y]

98. Petrosino, S.; Cordaro, M.; Verde, R.; Schiano Moriello, A.; Marcolongo, G.; Schievano, C.; Siracusa, R.; Piscitelli, F.; Peritore, A.F.; Crupi, R. et al. Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-Hyperalgesic Effect. Front. Pharmacol.; 2018; 9, 249. [DOI: https://dx.doi.org/10.3389/fphar.2018.00249] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29615912]

99. Bilia, A.R.; Piazzini, V.; Guccione, C.; Risaliti, L.; Asprea, M.; Capecchi, G.; Bergonzi, M.C. Improving on Nature: The Role of Nanomedicine in the Development of Clinical Natural Drugs. Planta Med.; 2017; 83, pp. 366-381. [DOI: https://dx.doi.org/10.1055/s-0043-102949]

100. Takano, R.; Furumoto, K.; Shiraki, K.; Takata, N.; Hayashi, Y.; Aso, Y.; Yamashita, S. Rate-Limiting Steps of Oral Absorption for Poorly Water-Soluble Drugs in Dogs; Prediction from a Miniscale Dissolution Test and a Physiologically-Based Computer Simulation. Pharm. Res.; 2008; 25, pp. 2334-2344. [DOI: https://dx.doi.org/10.1007/s11095-008-9637-9]

101. Dhiman, A.; Prabhakar, P.K. Micronization in Food Processing: A Comprehensive Review of Mechanistic Approach, Physicochemical, Functional Properties and Self-Stability of Micronized Food Materials. J. Food Eng.; 2021; 292, 110248. [DOI: https://dx.doi.org/10.1016/j.jfoodeng.2020.110248]

102. Impellizzeri, D.; Bruschetta, G.; Cordaro, M.; Crupi, R.; Siracusa, R.; Esposito, E.; Cuzzocrea, S. Micronized/Ultramicronized Palmitoylethanolamide Displays Superior Oral Efficacy Compared to Nonmicronized Palmitoylethanolamide in a Rat Model of Inflammatory Pain. J. Neuroinflammat.; 2014; 11, 136. [DOI: https://dx.doi.org/10.1186/s12974-014-0136-0]

103. Impellizzeri, D.; Campolo, M.; Di Paola, R.; Bruschetta, G.; de Stefano, D.; Esposito, E.; Cuzzocrea, S. Ultramicronized Palmitoylethanolamide Reduces Inflammation an a Th1-Mediated Model of Colitis. Eur. J. Inflamm.; 2015; 13, pp. 14-31. [DOI: https://dx.doi.org/10.1177/1721727X15575869]

104. Cerrato, S.; Brazis, P.; Della Valle, M.F.; Miolo, A.; Petrosino, S.; Di Marzo, V.; Puigdemont, A. Effects of Palmitoylethanolamide on the Cutaneous Allergic Inflammatory Response in Ascaris Hypersensitive Beagle Dogs. Vet. J.; 2012; 191, pp. 377-382. [DOI: https://dx.doi.org/10.1016/j.tvjl.2011.04.002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21601500]

105. Miragliotta, V.; Noli, C. Dermatology: Endocannabinoids and Related N-Acylethanolamines in the Skin. Cannabis Therapy in Veterinary Medicine: A Complete Guide; Cital, S.; Kramer, K.; Hughston, L.; Gaynor, J.S. Springer International Publishing: Cham, Switzerland, 2021; pp. 207-230. ISBN 978-3-030-68317-7

106. Abramo, F.; Salluzzi, D.; Leotta, R.; Auxilia, S.; Noli, C.; Miolo, A.; Mantis, P.; Lloyd, D.H. Mast Cell Morphometry and Densitometry in Experimental Skin Wounds Treated with a Gel Containing Adelmidrol: A Placebo Controlled Study. Wounds; 2008; 20, pp. 149-157. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25942520]

107. Mantis, P.; Lloyd, D.H.; Pfeiffer, D.; Stevens, K.; Auxilia, S.; Noli, C.; Auxilia, S.; Noli, C.; Abramo, F.; Miolo, A. Assessment of the Effect of an Aliamide-Containing Topical Gel by Evaluation of the Reduction of Wound Volume Measured by High R. Wounds; 2007; 19, pp. 113-119. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26110305]

108. Marsella, R.; Joyce, J.; Nicklin, C.; Lopez, J. Evaluation of the Effects of Palmitoylethanolamide on Clinical Signs in House Dust Mite Allergic High IgE Beagle Dogs Using a Randomized, Double Blinded, Placebo Controlled Design. Vet. Dermatol.; 2005; 16, 202.

109. Noli, C.; Della Valle, M.F.; Miolo, A.; Medori, C.; Schievano, C. Skinalia Clinical Research Group Effect of Dietary Supplementation with Ultramicronized Palmitoylethanolamide in Maintaining Remission in Cats with Nonflea Hypersensitivity Dermatitis: A Double-Blind, Multicentre, Randomized, Placebo-Controlled Study. Vet. Dermatol.; 2019; 30, 387-e117. [DOI: https://dx.doi.org/10.1111/vde.12764]

110. Waisglass, S.; Araujio, J.; Della Valle, M.F.; Milgram, N.W. Palmitoylethanolamide in the Management of Canine Atopic Dermatitis. Randomized, Double-Blind, Placebo Controlled Study. Proceedings of the International Congress of Scivac; Rimini, Italy, 29–31 May 2009; pp. 56-61.

111. Noli, C.; Della Valle, M.F.; Miolo, A.; Medori, C.; Schievano, C. Skinalia Clinical Research Group Efficacy of Ultra-Micronized Palmitoylethanolamide in Canine Atopic Dermatitis: An Open-Label Multi-Centre Study. Vet. Dermatol.; 2015; 26, pp. 432-440. e101 [DOI: https://dx.doi.org/10.1111/vde.12250]

112. Fabbrini, F.; Leone, F. Applicazione Topica Di Adelmidrol (2%) per La Gestione Del Prurito Associato a Dermatite Atopica Del Cane: Studio Osservazionale—Veterinaria. Veterinaria; 2013; 27.

113. Schiano Moriello, A.; Di Marzo, V.; Petrosino, S. Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint. Animals; 2022; 12, 348. [DOI: https://dx.doi.org/10.3390/ani12030348]

114. Russo, R.; Cristiano, C.; Avagliano, C.; De Caro, C.; La Rana, G.; Raso, G.M.; Canani, R.B.; Meli, R.; Calignano, A. Gut-Brain Axis: Role of Lipids in the Regulation of Inflammation, Pain and CNS Diseases. Curr. Med. Chem.; 2018; 25, pp. 3930-3952. [DOI: https://dx.doi.org/10.2174/0929867324666170216113756]

115. Hedlund, P.; Gratzke, C. The Endocannabinoid System - a Target for the Treatment of LUTS?. Nat. Rev. Urol.; 2016; 13, pp. 463-470. [DOI: https://dx.doi.org/10.1038/nrurol.2016.110]

116. Zhou, S.; Ling, X.; Meng, P.; Liang, Y.; Shen, K.; Wu, Q.; Zhang, Y.; Chen, Q.; Chen, S.; Liu, Y. et al. Cannabinoid Receptor 2 Plays a Central Role in Renal Tubular Mitochondrial Dysfunction and Kidney Ageing. J. Cell Mol. Med.; 2021; 25, pp. 8957-8972. [DOI: https://dx.doi.org/10.1111/jcmm.16857] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34414658]

117. Chua, J.T.; Argueta, D.A.; DiPatrizio, N.V.; Kovesdy, C.P.; Vaziri, N.D.; Kalantar-Zadeh, K.; Moradi, H. Endocannabinoid System and the Kidneys: From Renal Physiology to Injury and Disease. Cannabis Cannabinoid Res.; 2019; 4, pp. 10-20. [DOI: https://dx.doi.org/10.1089/can.2018.0060] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31346545]

118. Klawitter, J.; Sempio, C.; Jackson, M.J.; Smith, P.H.; Hopp, K.; Chonchol, M.; Gitomer, B.Y.; Christians, U.; Klawitter, J. Endocannabinoid System in Polycystic Kidney Disease. Am. J. Nephrol.; 2022; 53, pp. 264-272. [DOI: https://dx.doi.org/10.1159/000522113] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35263737]

119. Britti, D.; Crupi, R.; Impellizzeri, D.; Gugliandolo, E.; Fusco, R.; Schievano, C.; Morittu, V.M.; Evangelista, M.; Di Paola, R.; Cuzzocrea, S. A Novel Composite Formulation of Palmitoylethanolamide and Quercetin Decreases Inflammation and Relieves Pain in Inflammatory and Osteoarthritic Pain Models. BMC Vet. Res.; 2017; 13, 229. [DOI: https://dx.doi.org/10.1186/s12917-017-1151-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28768536]

120. Gugliandolo, E.; Peritore, A.F.; Impellizzeri, D.; Cordaro, M.; Siracusa, R.; Fusco, R.; D’Amico, R.; Paola, R.D.; Schievano, C.; Cuzzocrea, S. et al. Dietary Supplementation with Palmitoyl-Glucosamine Co-Micronized with Curcumin Relieves Osteoarthritis Pain and Benefits Joint Mobility. Animals; 2020; 10, E1827. [DOI: https://dx.doi.org/10.3390/ani10101827]

121. Annunziata, C.; Lama, A.; Pirozzi, C.; Cavaliere, G.; Trinchese, G.; Di Guida, F.; Nitrato Izzo, A.; Cimmino, F.; Paciello, O.; De Biase, D. et al. Palmitoylethanolamide Counteracts Hepatic Metabolic Inflexibility Modulating Mitochondrial Function and Efficiency in Diet-Induced Obese Mice. FASEB J.; 2020; 34, pp. 350-364. [DOI: https://dx.doi.org/10.1096/fj.201901510RR] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31914699]

122. Rahman, S.M.K.; Uyama, T.; Hussain, Z.; Ueda, N. Roles of Endocannabinoids and Endocannabinoid-Like Molecules in Energy Homeostasis and Metabolic Regulation: A Nutritional Perspective. Annu Rev. Nutr.; 2021; 41, pp. 177-202. [DOI: https://dx.doi.org/10.1146/annurev-nutr-043020-090216]

123. Sihag, J.; Di Marzo, V. (Wh)Olistic (E)Ndocannabinoidome-Microbiome-Axis Modulation through (N)Utrition (WHEN) to Curb Obesity and Related Disorders. Lipids Health Dis.; 2022; 21, 9. [DOI: https://dx.doi.org/10.1186/s12944-021-01609-3]

124. Esposito, G.; Capoccia, E.; Turco, F.; Palumbo, I.; Lu, J.; Steardo, A.; Cuomo, R.; Sarnelli, G.; Steardo, L. Palmitoylethanolamide Improves Colon Inflammation through an Enteric Glia/Toll like Receptor 4-Dependent PPAR-α Activation. Gut; 2014; 63, pp. 1300-1312. [DOI: https://dx.doi.org/10.1136/gutjnl-2013-305005]

125. Karwad, M.A.; Macpherson, T.; Wang, B.; Theophilidou, E.; Sarmad, S.; Barrett, D.A.; Larvin, M.; Wright, K.L.; Lund, J.N.; O’Sullivan, S.E. Oleoylethanolamine and Palmitoylethanolamine Modulate Intestinal Permeability in Vitro via TRPV1 and PPARα. FASEB J.; 2017; 31, pp. 469-481. [DOI: https://dx.doi.org/10.1096/fj.201500132]

126. Sarnelli, G.; Seguella, L.; Pesce, M.; Lu, J.; Gigli, S.; Bruzzese, E.; Lattanzi, R.; D’Alessandro, A.; Cuomo, R.; Steardo, L. et al. HIV-1 Tat-Induced Diarrhea Is Improved by the PPARalpha Agonist, Palmitoylethanolamide, by Suppressing the Activation of Enteric Glia. J. Neuroinflammat.; 2018; 15, 94. [DOI: https://dx.doi.org/10.1186/s12974-018-1126-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29573741]

127. Borrelli, F.; Romano, B.; Petrosino, S.; Pagano, E.; Capasso, R.; Coppola, D.; Battista, G.; Orlando, P.; Di Marzo, V.; Izzo, A.A. Palmitoylethanolamide, a Naturally Occurring Lipid, Is an Orally Effective Intestinal Anti-Inflammatory Agent. Br. J. Pharmacol.; 2015; 172, pp. 142-158. [DOI: https://dx.doi.org/10.1111/bph.12907] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25205418]

128. Capasso, R.; Orlando, P.; Pagano, E.; Aveta, T.; Buono, L.; Borrelli, F.; Di Marzo, V.; Izzo, A.A. Palmitoylethanolamide Normalizes Intestinal Motility in a Model of Post-Inflammatory Accelerated Transit: Involvement of CB₁ Receptors and TRPV1 Channels. Br. J. Pharmacol.; 2014; 171, pp. 4026-4037. [DOI: https://dx.doi.org/10.1111/bph.12759] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24818658]

129. Couch, D.G.; Cook, H.; Ortori, C.; Barrett, D.; Lund, J.N.; O’Sullivan, S.E. Palmitoylethanolamide and Cannabidiol Prevent Inflammation-Induced Hyperpermeability of the Human Gut In Vitro and In Vivo-A Randomized, Placebo-Controlled, Double-Blind Controlled Trial. Inflammat. Bowel Dis.; 2019; 25, pp. 1006-1018. [DOI: https://dx.doi.org/10.1093/ibd/izz017] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31054246]

130. Di Paola, R.; Impellizzeri, D.; Torre, A.; Mazzon, E.; Cappellani, A.; Faggio, C.; Esposito, E.; Trischitta, F.; Cuzzocrea, S. Effects of Palmitoylethanolamide on Intestinal Injury and Inflammation Caused by Ischemia-Reperfusion in Mice. J. Leukoc. Biol.; 2012; 91, pp. 911-920. [DOI: https://dx.doi.org/10.1189/jlb.0911485]

131. Petrini, D.; Di Giuseppe, M.; Deli, G.; De Caro Carella, C. Cystolithiasis in a Syrian Hamster: A Different Outcome. Open Vet. J.; 2016; 6, pp. 135-138. [DOI: https://dx.doi.org/10.4314/ovj.v6i2.10] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27540515]

132. Gugliandolo, E.; Crupi, R.; Peritore, A.F.; Licata, P.; Piras, C.; Cuzzocrea, S.; Britti, D. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS): Role of N-Palmitoyl-D-Glucosamine-Hesperidin. Proceedings of the 74th SISVET; Virtual Congress, 23–26 June 2021; 243.

133. Vezzoni, A.; Crupi, F.; Boiocchi, S.; Boano, S. Effect of Palmitoylethanolamide Co-Ultra Micronized with Quercetin in Dogs with Osteoarthritis by Means of Dynamic Gate Analysis and Canine Brief Pain Inventory Questionnaire. Proceedings of the 5th World Veterinary Orthopaedic Congress ESVOT-VOS; Barcelona, Spain, 12–15 October 2018; 2018; pp. 771-772.

134. Asperio, R.M. Integrazione dietetica con PGA-Cur: Indagine osservazionale su 181 cani con osteoartrite [Dietary supplementation with PGA-cur: A survey on 181 osteoarthritis dogs]. Summa; 2020; 8, pp. 39-48.

135. Bonello, D.; Squarzoni, P. Effect of a Mucoadhesive Gel and Dental Scaling on Gingivitis in Dogs. J. Vet. Dent.; 2008; 25, pp. 28-32. [DOI: https://dx.doi.org/10.1177/089875640802500108]

136. De Luca, L.; Ferracane, R.; Vitaglione, P. Food Database of N-Acyl-Phosphatidylethanolamines, N-Acylethanolamines and Endocannabinoids and Daily Intake from a Western, a Mediterranean and a Vegetarian Diet. Food Chem.; 2019; 300, 125218. [DOI: https://dx.doi.org/10.1016/j.foodchem.2019.125218]

137. Nestmann, E.R. Safety of Micronized Palmitoylethanolamide (MicroPEA): Lack of Toxicity and Genotoxic Potential. Food Sci. Nutr.; 2017; 5, pp. 292-309. [DOI: https://dx.doi.org/10.1002/fsn3.392]