N-arachidonoyl-dopamine

Huang etal. assumed that N-arachidonoyl-dopamine (NADA) may exist as an endogenous capsaicin-like cannabinoid in mammalian nervous tissues and may possibly bind to the vanilloid receptor VRl. They found that NADA is indeed a natural endocannabinoid, in nervous tissues, with high concentrations found in the striatum, hippocampus, and cerebellum. They were also found in lower concentrations in the dorsal root ganglion. NADA binds to the cannabinoid receptors with a 40-fold selectivity for the CBi (K = 250 it 130 nM) over the CB2 receptors. 

Horvath G, Farkas 1, Tuboly G, Benedek G (2008a) The antinociceptive effects of intrathecal injection of N-arachidonoyl-dopamine (NADA) are mediated by cannabinoid receptors. Clin Neorosci61(Sl) 44-45... 

Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM (2004) Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. Br J Pharmacol 141 1118-1130 Proudfit HK (1988) Pharmacologic evidence for the modulation of nociception by noradrenergic neurons. Prog Brain Res 77 357-370... 

O Sullivan SE, Kendall DA, Randall MD (2004) Characterisation of the vasorelaxant properties of the novel endo cannabinoid N-arachidonoyl-dopamine (NADA). Br J Pharmacol 141 803-812... 

Al-Hayani, A., Di Marzo, V., and Davies S. (2003) Homo-N-arachidonoyl-dopamine mimics vanilloid receptor agonists in enhancing paired pulse depression of hippocampal population spikes, Int. Cannabinoid Res. Soc. Symposium, p. 83. 

Harrison, S., De Petrocellis, L., Trevisani, M., Benvenuti, E, Bifulco, M., Geppetti, R, and Di Marzo, V. (2003) Capsaicin-like effects of N-arachidonoyl-dopamine in the isolated guinea pig bronchi and urinary bladder, Eur. J. Pharmacology, 475 107-114. 

Original evidence for the formation of NADA from arachidonic acid and dopamine or tyrosine (Huang et al. 2002) suggested a biosynthetic pathway common to that of the recently discovered arachidonoyl amino acids (Huang et al. 2001), i.e. from the direct condensation between arachidonic acid and dopamine, or, alternatively, from the condensation between arachidonic acid and tyrosine followed by the transformation of N-arachidonoyl-tyrosine into NADA by the enzymes catalysing dopamine biosynthesis from tyrosine. Preliminary data have shown, however, that NADA cannot be produced from either N-arachidonoyl-tyrosine or N-arachidonoyl-L-DOPA either in vitro, in brain homogenates, or in vivo, and that the lipid formed from tyrosine and arachidonic acid is not NADA (M.J. Walker and V. Di Marzo, unpublished observations). Clearly, further studies are needed to understand the biosynthetic mechanism for this putative endocannabinoid. 

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. 

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