Endocannabinoids uptake

Cabranes A, Venderova K, de Lago E, Fezza F, Valenti M, Sdnchez A, Garcfa-Merino A, Ramos JA, Di Marzo V, Fernandez-Ruiz J (2005) Decreased endocannabinoid levels in the brain and beneficial effects of certain endocannabinoid uptake inhibitors in a rat model of multiple sclerosis involvement of vanilloid TRPV 1 receptors. Neurobiol Dis (in press)... 

Lastres-Becker I, Hansen HH, Berrendero F, de Miguel R, P rez-Rosado A, Manzanares J, Ramos JA, Ferncindez-Ruiz J (2002a) Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington s disease. Synapse 44 23-35... 

Lopez-Rodriguez, M.L., Viso, A., Ortega-Gutierrez, S., Fowler, C.J., Tiger, G., de Lago, E. et al. (2003) Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake comparison with effects on fatty acid amidohydrolase. Journal of Medicinal Chemistry 46 1512-1522. 

Endocannabinoid Uptake Studies In Vitro Assay of Endocannabinoid Uptake... 

De Lago, E, Eemandez-Ruiz, J, Ortega-Gutierrez, S, Viso, A, Lopez-Rodriguez, M and Ramos, JA (2002) UCM707, a potent and selective inhibitor of endocannabinoid uptake, potentiates hypokinetic and anti-nociceptive effects of anandamide. Eur J Pharmacol,449, 99-103. 

Neuronal excitotoxicity AEA levels are elevated in the hippocampus of mice treated with kainic acid. 2-AG levels are elevated in rats treated with pilocarpine These are two animal models of epileptic seizures, where the endocannabinoids play an anti-convulsant and protective function Inhibitors of cellular re-uptake... 

The endocannabinoid membrane transporter an unknown between release and re-uptake... 

Although the endocannabinoid membrane transporter has not been cloned to date, this putative protein too has been shown to be subject to regulation. In particular, nitric oxide stimulates AEA cellular uptake in many cell types, whereas chronic treatment of cells with ethanol inhibits it (Maccarrone et al. 2000a Basavarajappa et al. 2003). In either case, no effect on FAAH activity was found, whereas leptin inhibits both AEA reuptake by, and FAAH activity in, mouse uterine tissue (Maccarrone et al. 2005). 

After their biosynthesis, AEA and 2-AG are immediately released into the extracellular medium. This occurs via an unknown mechanism, which, however, several pieces of evidence suggest is one that is dependent on the same putative membrane transporter proposed to facilitate the opposite process, i.e. endocannabinoid cellular uptake (see below). In particular ... 

However, several observations still strongly, albeit indirectly, support the existence of an EMT, or at least of some specific intracellular process distinct from FAAH for bringing about the cellular uptake of endocannabinoids (for a more detailed review see Hillard and Jarrahian 2003) ... 

AGE and NADA, two endocannabinoids that are resistant and refractory to enzymatic hydrolysis, respectively, are still taken up by cells in a temperature-dependent way their uptake is inhibited competitively by AEA (Huang et al. 2002 Fezza et al. 2002), although none of the specific EMT inhibitors mentioned above has ever been tested on the cellular uptake of these compounds. 

Under normal conditions, retrograde endocannabinoid signalling is spatially restricted in a manner likely to be determined by diffusion, uptake and enzymatic degradation. 

There is now substantial evidence for the presence of endocannabinoid and endovanilloid systems in the GI tract. The anti-inflammatory, anticancer, antiulcero-genic and antiemetic responses to CBi receptor activation holds promise for the future management of gastrointestinal diseases. Thus, exploitation of the endocannabinoid system by facilitation at sites of endocannabinoid activity by preventing cellular re-uptake or reducing EC degradation may enhance beneficial endocannabinoid effects without the psychotropic side-effects found with systemic administration of exogenous cannabinoids. Manipulation of the endocannabinoid... 

---