Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide

Calignano, Antonio; Rana, Giovanna La; Piomelli, Daniele

doi:10.1016/s0014-2999(01)00988-8

Cited by 230 publications

(202 citation statements)

References 31 publications

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“…AEA potentiates 5-HT 1A and inhibits 5-HT 2A receptors supporting a potential therapeutic efficacy in acute antimigraine treatment with triptans, which are specific agonists of 5-HT 1B/1D receptors but also exert their agonistic effect on 5-HT 1A receptors , and in antimigraine preventive treatment, with particular regard to serotonin antagonists (Kimura et al, 1998;Cheer et al, 1999). CBs also demonstrate antinociceptive and antiinflammatory effects (Calignano et al, 1998(Calignano et al, , 2001Hohmann, 2002;Cravatt and Lichtman, 2004;Di Marzo et al, 2002a, b;Pertwee, 2001;Mbvundula et al, 2004). AEA is also tonically active in the periaqueductal gray matter, which is believed to be a putative migraine generator (Vaughan et al, 2000).…”

Section: Introductionmentioning

confidence: 92%

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

Sarchielli

Pini²,

Coppola³

et al. 2006

Neuropsychopharmacol

122

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Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM + PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM + PAOH than in nonmigraineur controls (po0.01 and po0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM + PAOH patients (r ¼ 0.59, po0.01 and r ¼ À0.65, po0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM + PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

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Section: Introductionmentioning

confidence: 92%

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

Sarchielli

Pini²,

Coppola³

et al. 2006

Neuropsychopharmacol

122

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“…6,7 In particular, PEA has been shown to inhibit peripheral inflammation and mast cell degranulation 8 and to exert antinociceptive effects in rodent models of acute and chronic pain. 9 PEA has also been found to suppress pain behaviors induced by tissue injury, nerve damage, or inflammation in mice. 10 Along with PEA, other FAEs having neuromodulatory functions have been identified.…”

Section: ■ Introductionmentioning

confidence: 99%

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure−activity and structure−property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC 50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.

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“…Anandamide was also reported to be an agonist of the transient receptor potential vanilloid type 1 [7]. NPalmitoylethanolamine is inactive with cannabinoid receptors, but is known as an anti-inflammatory and analgesic substance [8][9][10]. Recently, it was shown that the anti-inflammatory action of this compound could be mediated by the activation of peroxisome proliferator-activated receptor-a (PPAR-a) [11].…”

Section: Introductionmentioning

confidence: 99%

Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages

Sun

Tsuboi

Zhao

et al. 2005

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

100

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Bioactive N-acylethanolamines including the endocannabinoid anandamide are known to be hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH). In addition, we recently cloned an isozyme termed ''N-acylethanolamine-hydrolyzing acid amidase (NAAA)'', which is active only at acidic pH [Tsuboi, Sun, Okamoto, Araki, Tonai, Ueda, J. Biol. Chem. 285 (2005) 11082 -11092]. However, physiological roles of NAAA remained unclear. Here, we examined a possible contribution of NAAA to the degradation of various Nacylethanolamines in macrophage cells. NAAA mRNA as well as FAAH mRNA was detected in several macrophage-like cells, including RAW264.7, and mouse peritoneal macrophages. The homogenates of RAW264.7 cells showed both the NAAA and FAAH activities which were confirmed with the aid of their respective specific inhibitors, N-cyclohexanecarbonylpentadecylamine (CCP) and URB597. As analyzed with intact cells, RAW264.7 cells and peritoneal macrophages degraded anandamide, N-palmitoylethanolamine, N-oleoylethanolamine, and Nstearoylethanolamine. Pretreatment of the cells with CCP or URB597 partially inhibited the degradation, and a combination of the two compounds caused more profound inhibition. In contrast, the anandamide hydrolysis in mouse brain appeared to be principally attributable to FAAH despite the expression of NAAA in the brain. These results suggested that NAAA and FAAH cooperatively degraded various N-acylethanolamines in macrophages. D

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Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide

Cited by 230 publications

References 31 publications

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages

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