Distribution and characterization of anandamide amidohydrolase in mouse brain and liver

Watanabe, Kazuhito; Ogi, Hiroka; Nakamura, Shizuko; Kayano, Yuichiro; Matsunaga, Tamihide; Yoshimura, Hidetoshi; Yamamoto, Ikuo

doi:10.1016/s0024-3205(98)00052-6

Cited by 51 publications

(41 citation statements)

References 18 publications

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“…On the other hand, FAAH level was the highest in liver, followed by brain and several other organs. The distribution of FAAH mRNA was consistent with the previous report that among various mouse organs the anandamide-hydrolyzing activity was the highest in liver, followed by brain [49]. Since the brain showed relatively high level of NAAA mRNA, we were interested in a possible contribution of NAAA to the anandamide-hydrolyzing activity in the brain.…”

Section: Resultssupporting

confidence: 89%

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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Section: Resultssupporting

confidence: 89%

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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“…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: 57%

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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“…Among the newly identified TRPV2 agonists described here, CBD is particularly interesting, because it was the most potent and selective and its in vivo mechanism of action and molecular target are heretofore unknown. Several hypotheses have been proposed previously to explain the mechanism of action of CBD: (1) CBD is a noncompetitive binder to and allosteric modulator of -and ␦-opioid receptors (Kathmann et al, 2006); (2) CBD acts as an antagonist of CB 1 and CB 2 (Thomas et al, 2007); (3) CBD activates TRPV1 channels (Bisogno et al, 2001); (4) CBD indirectly increases levels of anandamide by inhibiting its uptake and hydrolysis (Watanabe et al, 1998); (5) CBD inhibits the adenosine transporter (Carrier et al, 2006); and (6) CBD activates a novel, as yet unidentified cannabinoid receptor that is structurally distinct from CB 1 and CB 2 (Grotenhermen, 2005). The pharmacological profile of CBDevoked CGRP release presented here suggests that it is unlikely to be mediated by opioid receptors, CB 1 /CB 2 , or TRPV1, because it was insensitive to pertussis toxin, CB 1 -and CB 2 -selective antagonists, or a TRPV1-selective antagonist.…”

Section: Discussionmentioning

confidence: 99%

TRPV2 Is Activated by Cannabidiol and Mediates CGRP Release in Cultured Rat Dorsal Root Ganglion Neurons

Qin¹,

Neeper²,

Liu³

et al. 2008

Journal of Neuroscience

341

290

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Transient receptor potential V2 (TRPV2) has been proposed to be a high-threshold thermosensor. However, further elucidation of the channel properties and physiological role of TRPV2 have been hindered by the lack of selective pharmacological tools as well as by the species-dependent differences in the activation of this channel. In the present study, we have used cell-based calcium mobilization and electrophysiological assays to identify and characterize several novel cannabinoid TRPV2 agonists. Among these, cannabidiol was found to be the most robust and potent (EC 50 ϭ 3.7 M), followed by ⌬ 9 -tetrahydrocannabinol (EC 50 ϭ 14 M) and cannabinol (EC 50 ϭ 77.7 M). We also demonstrated that cannabidiol evoked a concentration-dependent release of calcitonin gene-related peptide (CGRP) from cultured rat dorsal root ganglion neurons in a cannabinoid receptor-and TRPV1-independent manner. Moreover, the cannabidiolevoked CGRP release depended on extracellular calcium and was blocked by the nonselective TRP channel blocker, ruthenium red. We further provide evidence through the use of small interfering RNA knockdown and repetitive stimulation studies, to show that cannabidiol-evoked CGRP release is mediated, at least in part, by TRPV2. Together, these data suggest not only that TRPV2 may comprise a mechanism whereby cannabidiol exerts its clinically beneficial effects in vivo, but also that TRPV2 may constitute a viable, new drug target.

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Distribution and characterization of anandamide amidohydrolase in mouse brain and liver

Cited by 51 publications

References 18 publications

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

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

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

TRPV2 Is Activated by Cannabidiol and Mediates CGRP Release in Cultured Rat Dorsal Root Ganglion Neurons

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