Endogenous cannabinoids

Endogenous cannabinoids Endogenous agonists of cannabinoid receptors... 

Szolcsanyi J (2000) Are cannabinoids endogenous ligands for the VRl capsaicin receptor Trends Pharmacol Sci 21 41-42... 

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... 

Di Marzo V, De Petrocellis L (2005) Plant, synthetic and endogenous cannabinoids in medicine. Annu Rev Med 57 553-574... 

The LVA ai subunits are blocked by moderate to low (10 pM) concentrations of nickel and bind the channel blocker mibefradil and kurotoxin. Both compounds are not specific LVA channel blockers because they block also Cavl. x and Cav2.x channels at about tenfold higher concentration. Interestingly, the endogenous cannabinoid anandamide binds to LVA channels and stabilises the inactivated state. This effect decreases T-type calcium current and neuronal firing activities. 

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. 

The best studied of the endocarmabinoids are anandamide (A -arachidonyl-ethanolamine, AEA)(1) and 2-arachidonylglycerol (2-AG)(2). Anandamide was first identified from porcine brain extracts by Devane and co-workers in 1992 [13], while 2-AG was first reported in 1995 to have been isolated from canine gut [14] and rat brain [15]. More recently, noladin ether (2-arachidonyl-glyceryl ether, 2-AGE)(3) [16], virodhamine (D-arachidonyl-ethanolamine)(4) [17] and A-arachidonyl-dopamine (NADA)(5) [18] were proposed as endogenous ligands for the cannabinoid receptors. In a subsequent publication, the authors failed to detect noladin ether in mammalian brains and questioned the relevance of this compound as an endocarmabinoid [19]. Anandamide, noladin ether and NADA have functional selectivity for CBi receptors, virodhamine is CB2 selective and 2-AG is essentially non-selective. 

As outlined earlier, anandamide was the first among the endogenous cannabinoid receptor agonists to be identified. It exhibits higher binding affinity for the CBi receptor Ki — 89 nM) than for the CB2 receptor (il = 371 nM) [81]. Anandamide has typical cannabinoid activities including decreased spontaneous motor activity, immobility and production of hypothermia and analgesia [147, 148]. However, this action in vivo is of shorter duration than... 

The discovery of the cannabinoid receptors and their G-protein-coupled nature strongly suggested the existence of endogenous cannabimimetic... 

Since the discovery of anandamide in 1992, a number of studies have examined its pharmacological properties. Although its roles are still elusive, a plethora of data supports the initial postulate that anandamide is the major endogenous cannabinoid ligand. As mentioned earlier, anandamide binds to CB1 from brain preparations and displaces various well-... 

All the foregoing pharmacological effects of anandamide, in conjunction with the well-documented existence of specific systems for its biosynthesis, catabolism, and cellular reuptake to be discussed shortly, suggest that anandamide is indeed the endogenous cannabinoid ligand. The other two less studied A -acylethanolamide endocannabinoids and also 2-AG may serve similar functions. The differential roles of each of these four endocannabinoids are still unclear. 

Aceto MD, Scates SM, Razdan RK, Martin BR. Anandamide, an endogenous cannabinoid has a very low physical dependence potential. J Pharmacol Exp Ther 1998 287 598-605. 

Cadas H, di Tomaso E, Piomelli D. Occurrence and biosynthesis of endogenous cannabinoid precursor, A-arachidonyl phosphatidylethanolamine, in rat brain. J Neurosci 1997 17 1226-1242. 

Cadas H, Gaillet S, Beltramo M, Venance L, Piomelli D. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J Neurosci 1996 16 3934-3942. 

Calignano A, LaRana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature 1998 394 277-281. 

Crawley JN, Corwin RL, Robinson J, Felder CC, Derane WA, Axelrod J. Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and Hypothermia in vivo in rodents. Pharmacol Biochem Behav 1993 46 967-972. 

Devane WA, Axelrod J. Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Proc Natl Acad Sci USA 1994 91 6698-6701. 

Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 1999 2 358-363. 

Goparaju SK, Ueda N, Taniguchi K, Yamamoto S. Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem Pharmacol 2001 57 417 423. 

Hillard CJ, Cambell WB. Biochemistry and pharmacology of arachidonyl-ethanolamide, a putative endogenous cannabinoid. J Lip Res 1997 38 2383-2398. 

Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 2001 29 717-727. 

Mackie K, Devane WA, Hille B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N-18 neuroblastoma cells. Mol Pharmacol 1993 44 498-503. 

Martin BR, Mechoulam R, Razdan RK. Discovery and characterization of endogenous cannabinoids. Life Sci 1999 65 573-595. 

Mechoulam R, Feigenbaum E. The unpaved road to the endogenous brain cannabinoid ligands, the anandamides. In Pertwee RG, ed. Cannabinoid Receptors. New York Academic Press, 1995b 233-258. 

Nye JS, Voglmaier S, Martenson RE, Snyder SH. Myelin basic protein is an endogenous inhibitor of the high affinity cannabinoid binding site in brain. J Neurochem 1988 50 1170-1178. 

Ohno-Shosaku T, Maejima T, Kano M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 2001 29 729-738. 

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