Anandamide tissue levels

Burstein SH, Huang SM, Petros TJ, Rossetti RG, Walker JM, Zurier RB (2002) Regulation of anandamide tissue levels by N-arachidonylglycine. Biochem Pharmacol 64 1147-1150... 

Tissue levels of 2-AG were 10 to 100 times higher than those of anandamide in the same tissue (see Chapter 6). Taken together, it is logical to assume that 2-AG rather than anandamide is the true natural ligand of the cannabinoid receptors (CBi and CBj) (Sugiura et al., 1997, 1999, 2000 for review, Sugiura and Waku 2000). 

Schmid pathway). Presumably, this is the main pathway for the synthesis of anandamide in various mammalian tissnes. However, it is not possible to generate a large amount of anandamide via this pathway, becanse the levels of arachidonic add esterilied at the 1-position are usnally very low. This is consistent with the observation that the tissue levels of anandamide are generally low except in a few cases as already mentioned. 

There are currently five reported routes for the metabolism of anandamide, and these are outlined in Figure 8.9 (Di Marzo, De Petrocellis, et al., 1999). The principal route for the metabolism of anandamide is mediated by an amidase called FAAH that releases free arachidonic acid and ethanolamine (Ueda et al., 1997 Ueda, Katayama, et al., 1999 Ueda, Yamanaka, et al., 1999 Ueda et al., 2000 Ueda and Yamamoto, 2000 Ueda, 2002). The free acid could either be re-incorporated into phospholipids or transformed into eicosanoids with potent biological actions of their own. At this time there is little evidence to support the latter suggestion however, should this turn out to be true, it would have interesting implications for the mechanism of anandamide action. This hydrolytic transformation of anandamide is considered to be an important physiological mechanism for regulating in vivo levels of anandamide, and FAAH has become a popular target for therapeutic intervention where it is desired to maintain or elevate anandamide tissue concentrations. 

Anandamide and other NAEs are degraded by a fatty acid amide hydrolase (FAAH) (18,57,58-60). Inhibition or knockout of FAAH results in increased tissue levels of anandamide... 

As discussed earlier, anandamide but not 2-AG can bind vanilloid VRl receptors whose activation can lead to emetic/antiemetic effects, a property which anandamide shares. Though the tissue levels of both anandamide and 2-AG can be simultaneously altered by drug administration or in pathological states, there is also strong evidence that the release of 2-AG can be independently modified, which can be region specific (Pertwee and Ross, 2002). 

Anandamide was discovered as a high-affinity ligand for CB receptors in 1992 (Devane et al., 1992). Anandamide is produced in response to an increase in intracellular Ca2+ levels or activation of G-protein-coupled receptors (e.g., D2 receptors) (Piomelli, 2003). In mammalian tissues, anandamide is present at concentrations of 1-50 pmol/g (Fig. 4), and can be formed through three distinct biochemical pathways (1) the direct hydrolysis of NAPE by a NAPE-specific phospholipase D (NAPE-PLD) (Okamoto et al., 2005 Wang et al., 2006) (2) the hydrolysis of lyso-NAPE or glycerophospho-anandamide by a specific PLD (Leung et al., 2006 Simon and Cravatt, 2008 Sun et al., 2004) and (3) the hydrolysis of phospho-anandamide by a lipid phosphatase (Liu et al., 2006, 2007) (Fig. 1). 

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