Anandamide endogenous levels

Potent FAAH inhibitors have recently been synthesized that enhance the levels of anandamide significantly, and these compounds may have considerable therapeutic potential (Boger et al., 2000). In the event of inhibition of FAAH metabolism of anandamide, increased levels of endogenous anandamide may lead to the production of significant levels of the HPETE ethanolamides. In addition, LOX metabolism producing metabolites that are FAAH inhibitors (van der Stelt et al., 2002) of anandamide may enhance TRPV 1 receptor activation by increasing the levels of available anandamide. 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer AM, Zimmer A, Martin BR (2000b) Levels, metabolism, and pharmacological activity of anandamide in CBi cannabi-noid receptor knockout mice. Evidence for non-CBi, non-CBi receptor-mediated actions of anandamide in mouse brain. J Neurochem 75 2434-2444 Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Endocannabinoids endogenous cannabinoid receptor hgands with neuromodulatory action. Trends Neurosci 21 521-528 Dickinson T, Fleetwood-Walker SM (1999) VIP and PACAP very important in pain Trends Pharmacol Sci 20 324-329... 

Berdyshev et al. (1997) examined the effects of anandamide, palmitoylethanolamide and THC on the production of TNF-a, IL-4, IL-6, IL-8, IL-10, IFN-y, p55, and p75 TNF-a soluble receptors expressed by stimulated human peripheral blood mononuclear cells as well as [ H]-arachidonic acid release by non-stimulated and N-formyl-Met-Leu-Phe (fMLP)-stimulalcd human monocytes. Anandamide diminished IL-6 and IL-8 production at low nanomolar concentrations and inhibited the production of TNF-a, IFN-y, IL-4, and p75 TNF-a soluble receptors at higher concentrations (i.e., micromolar levels). Palmitoylethanolamide inhibited IL-4, IL-6, and IL-8 synthesis and the production of p75 TNF-a soluble receptors at concentrations similar to those of anandamide but did not affect TNF-a and IFN-y production. Neither anandamide nor palmitoylethanolamide influenced IL-10 synthesis. THC, on the other hand, exerted a biphasic effect on pro-inflammatory cytokine production. TNF-a, IL-6, and IL-8 synthesis was inhibited maximally by 3 nM THC but stimulated by 3 pM THC. A similar effect was observed for IL-8 and IFN-y. The level of IL-4, IL-10, and p75 TNF-a soluble receptors was diminished by 3 pM THC. [ H]-Arachidonate release was stimulated only by high THC and anandamide concentrations. Based on these observations, the investigators suggested that the inhibitory properties of anandamide, palmitoylethanolamide, and THC are determined by the activation of peripheral-type cannabinoid receptors (i.e., CB2) and that various endogenous fatty acid ethanolamides also participate in the regulation of the immune response. 

Another approach to examining the role of endogenous anandamide in pain has been to employ transport inhibitors such as AM404. Blocking transport would be expected to block the reuptake of anandamide and cause increased levels to... 

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