Cannabinoid receptors endocannabinoids

Endocannabinoids are endogenous mediators acting via the binding to, and activation of, cannabinoid receptors, CBX and CB2 [1]. iV-arachidonoy 1-ethanol-amine (AEA, anandamide) and 2-arachidonoyl-glycerol (2-AG) (Fig. 1) are the two most studied endocannabinoids. In the nervous system, endocannabinoids act as... 

Based on the role of endocannabinoids and cannabinoid receptors in several pathological conditions, the pharmacological manipulation of their levels or action is being developed as a therapeutic strategy. Enhancement of endocannabinoid signalling when this plays uniquely a protective role can be effected in a safer way using (i) cannabis extracts in which the presence of non-psychotropic cannabinoids with therapeutic activity per... 

Since the cloning of the cannabinoid receptors, their endogenous ligands, the endocannabinoids, have received a great deal of research interest. A number of recent review articles have extensively covered the end-ocannabinoid system [10-12], so the coverage in this article will be brief. 

Anandamide One of the endogenous ligands, or endocannabinoids, which is active at cannabinoid receptors. 

Marijuana and hashish are derivatives of the cannabis sativa plant. Although cannabinoids have been used for centuries for recreational and therapeutic purposes, dramatic advances in cannabinoid neurobiology have occurred since 1990 [34-37]. This is attributable to the cloning of cannabinoid receptors and the discovery of endogenous cannabinoids, termed endocannabinoids. 

Anandamide may reduce pain by a peripheral action, by acting on CB 1-like receptors located outside the CNS (Calignano et al. 1998). Palmitylethanolamide (PEA) is an endocannabinoid that is coreleased with anandamide and activates peripheral CB2 receptors. When the two are administered together, they show a 100-fold synergistic effect on analgesic measures. Measurements of anandamide and PEA levels in the skin show that there are sufficient amounts to create tonic activation of local cannabinoid receptors. Thus, endocannabinoids may tonically inhibit cutaneous pain. 

The endocannabinoid system might also be involved, since A9-tetrahydorcan-nabinol, the major active ingredient in cannabis, decreases somatically expressed withdrawal behaviors and the aversiveness of withdrawal in mecamylamine- and naloxone-precipitated nicotine abstinence (Balfour 2002). However, genetic knockout of the CBl cannabinoid receptors did not significantly affect somatically expressed withdrawal behaviors (Castane et al. 2002). 

Our research group expected that additional polyunsaturated fatty acid ethanolamides may be present in the brain. We also identified in porcine brain another two putative endocannabinoids, namely homo-y-linoleoylethanolamide (K = 53.4 5-5 nM) and 7,10,13,16-docosatetraenoylethanolamide (K = 34.4 3.2 nM). The isolation of these two compounds as constituents of porcine brain that bind to the cannabinoid receptor demonstrated that anandamide is not the sole representative of this class of potential mediators. 

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. 

The endocannabinoids are accompanied in the brain and other tissues by cannabinoid-like compounds, which however do not bind to the cannabinoid receptors. They are saturated and mono- or diunsaturated congeners, which may affect the metabolism and the function of the endocannabinoids... 

When marijuana is ingested or inhaled, THC binds to cannabinoid receptors throughout the brain and body, where it mimics the actions of internally produced neurotransmitters, such as the endocannabinoid known as anandamide. Anandamide is named after the Sanskrit word ananda, which means bliss. ... 

Cannabinoid and endocannabinoid-induced synaptic depression is observed in both the peripheral nervous system and the CNS. Indeed, A9-THC inhibition of transmitter release was first demonstrated in mouse vas deferens (Graham et al. 1974), and further evidence for presynaptic inhibition has been obtained using this preparation (Ishac et al. 1996 Pertwee and Fernando 1996) and in the myenteric plexus (Coutts and Pertwee 1997 Kulkami-Narla and Brown 2000). In addition, anandamide was first characterized as an EC based on its actions in the mouse vas deferens (Devane et al. 1992). Subsequently, CB1 receptor-mediated inhibition of release of several neurotransmitters has been documented in various regions of the PNS (see Szabo and Schlicker 2005 for review). Cannabinoids also inhibit neural effects on contraction in the ileum (Croci et al. 1998 Lopez-Redondo et al. 1997), although it is not clear that this is effect involves direct inhibition of neurotransmitter release (Croci et al. 1998). The CB1 receptor has been localized to enteric neurons, and thus the effect on ileum certainly involves actions on these presynaptic neurons. In addition, anandamide produces ileal relaxation via a non-CBl, non-CB2-mediated mechanism (Mang et al. 2001). 

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