Metabolism of Anandamide, an Endogenous Cannabinoid Receptor Ligand, in Porcine Ocular Tissues

Matsuda, Shinji; Kanemitsu, Nobue; Nakamura, Akiyo; Mimura, Yoshihiro; Ueda, Natsuo; Kurahashi, Yuko; Yamamoto, Shozo

doi:10.1006/exer.1996.0265

Cited by 79 publications

(52 citation statements)

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“…The possible use of drugs that inhibit endocannabinoid hydrolysis to treat pain in humans has thus propagated both hope and concern (Cravatt and Lichtman, 2003). FAAH is widely distributed throughout the body (Deutsch and Chin, 1993;Cravatt et al, 1996;Matsuda et al, 1997;Watanabe et al, 1998;Maccarrone et al, 2000) and implicated in the metabolism of a variety of anandamide analogues (Desarnaud et al, 1995;Cravatt et al, 1996;Bisogno et al, 1997;Lang et al, 1999a,b;Tiger et al, 2000). Our data demonstrate that local enhancements of endocannabinoid actions at the spinal level are sufficient to potentiate SIA.…”

Section: Discussionmentioning

confidence: 56%

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

et al. 2006

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Recent work in our laboratories has demonstrated that an opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous cannabinoids [Hohmann et al., 2005. Nature 435, 1108. Non-opioid SIA, induced by a 3-min continuous foot shock, is characterized by the mobilization of two endocannabinoid lipidsd2-arachidonoylglycerol (2-AG) and anandamidedin the midbrain periaqueductal gray (PAG). The present studies were conducted to examine the contributions of spinal endocannabinoids to nonopioid SIA. Time-dependent increases in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats. Notably, 2-AG accumulation was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock. 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), whereas anandamide is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH). This metabolic segregation enabled us to manipulate endocannabinoid tone at the spinal level to further evaluate the roles of 2-AG and anandamide in nonopioid SIA. Intrathecal administration of the competitive CB 1 antagonist SR141716A (rimonabant) failed to suppress nonopioid SIA, suggesting that supraspinal rather than spinal CB 1 receptor activation plays a pivotal role in endocannabinoid-mediated SIA. By contrast, spinal inhibition of MGL using URB602, which selectively inhibits 2-AG hydrolysis in the PAG, enhanced SIA through a CB 1 -selective mechanism. Spinal inhibition of FAAH, with either URB597 or arachidonoyl serotonin (AA-5-HT), also enhanced SIA through a CB 1 -mediated mechanism, presumably by increasing accumulation of tonically released anandamide. Our results suggest that endocannabinoids in the spinal cord regulate, but do not mediate, nonopioid SIA.

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Section: Discussionmentioning

confidence: 56%

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

et al. 2006

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“…N-Palmitoylethanolamine was hydrolyzed 13 times faster than anandamide. This substrate specificity was in contrast with that of anandamide amidohydrolase, which prefers anandamide to N-palmitoylethanolamine (9,28,29,34,35). Thus, we refer to the enzyme with higher reactivity for N-palmitoylethanolamine as N-palmitoylethanolamine hydrolase.…”

Section: Discussionmentioning

confidence: 94%

“…The enzyme is widely distributed in mammalian organs (28,30,31) and characterized by an optimal pH value at 8.5-10 (9, 29) and by high sensitivity to phenylmethylsulfonyl fluoride (27) and methyl arachidonyl fluorophosphonate (MAFP) 1 (32,33). The enzyme has a broad substrate specificity but hydrolyzes N-palmitoylethanolamine at a lower rate than anandamide (9,28,29,34,35).…”

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confidence: 99%

Purification and Characterization of an Acid Amidase Selective for N-Palmitoylethanolamine, a Putative Endogenous Anti-inflammatory Substance

Ueda¹,

Yamanaka²,

Yamamoto³

2001

Journal of Biological Chemistry

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231

238

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N-Arachidonoylethanolamine (anandamide) is cannabimimetic, and N-palmitoylethanolamine is anti-inflammatory and immunosuppressive. We found an amidase that is more active with the latter than the former in contrast to the previously known anandamide amidohydrolase for which N-palmitoylethanolamine is a poor substrate. Proteins solubilized by freezing and thawing from the 12,000 ؋ g pellet of various rat organs hydrolyzed [ 14 C]N-palmitoylethanolamine to palmitic acid and ethanolamine. The specific enzyme activity was higher in the order of lung > spleen > small intestine > thymus > cecum, and high activity was found in peritoneal and alveolar macrophages. The enzyme with a molecular mass of 31 kDa was purified from rat lung to a specific activity of 1.8 mol/min/mg protein. Relative reactivities of the enzyme with various N-acylethanolamines (100 M) were as follows: N-palmitoylethanolamine, 100%; N-myristoylethanolamine, 48%; N-stearoylethanolamine, 21%; N-oleoylethanolamine, 20%; N-linoleoylethanolamine, 13%; anandamide, 8%. The enzyme was the most active at pH 5 and was activated 7-fold by Triton X-100. The enzyme was almost insensitive to methyl arachidonyl fluorophosphonate, which inhibited anandamide amidohydrolase potently. Thus, the new enzyme referred to as N-palmitoylethanolamine hydrolase was clearly distinguishable from anandamide amidohydrolase.

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“…FAAH activity was also detected in mouse uterus [88], and its expression is regulated during pregnancy [89,90]. FAAH activity was also detected in several ocular tissues including bovine retina [91], rat retina [92], porcine retina, optic nerve, iris and lacrimal glands [93]. Within the brain, activity of FAAH was the highest in globus pallidus, hippocampus, substantia nigra, cerebellum, cerebral cortex, cerebellum and the lowest in brainstem and medulla [94].…”

Section: Distributionmentioning

confidence: 97%

Focus on the Three Key Enzymes Hydrolysing Endocannabinoids as New Drug Targets

Vandevoorde¹,

Lambert

2005

CPD

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The family of endocannabinoids (i.e., the endogenous agonists of cannabinoid receptors) contains several polyunsaturated fatty acid amides such as anandamide (AEA) and oleamide but also esters such as 2-arachidonoylglycerol (2-AG). These compounds are the subject of growing interest in pharmacology for their multiple therapeutic potentials. Unfortunately, they are rapidly inactivated by enzymatic hydrolysis, which prevents their effective medical use. Inhibitors of endocannabinoid degradation seem to be necessary tools for the development of endocannabinoid therapeutics. But hitting this target is inconceivable without good knowledge of the enzymes. Fatty acid amide hydrolase (FAAH) is the oldest and the best characterised enzyme involved in the degradation of endocannabinoids. Cloning, distribution in the body and crystal structure of FAAH have been described. A large number of FAAH inhibitors have also been synthesised and tested. For a long time, FAAH was considered as the only key enzyme hydrolysing endocannabinoids. But recent findings indicate that at least two other enzymes have critical role in the endocannabinoids degradation. Monoglyceride lipase participates in 2-AG degradation and some data indicate that it is the primary mechanism for 2-AG inactivation in intact neurons. N-palmitoylethanolamine-selective acid amidase (NPAA) is a second fatty acid amide hydrolase more active with N-palmitoylethanolamine, an anti-inflammatory substance. The purpose of this review is to collect and compare the catalytic properties of these 3 key enzymes hydrolysing endocannabinoids.

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Metabolism of Anandamide, an Endogenous Cannabinoid Receptor Ligand, in Porcine Ocular Tissues

Cited by 79 publications

References 0 publications

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

Purification and Characterization of an Acid Amidase Selective for N-Palmitoylethanolamine, a Putative Endogenous Anti-inflammatory Substance

Focus on the Three Key Enzymes Hydrolysing Endocannabinoids as New Drug Targets

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