The effect of chronic administration of cannabinoids to the survival of G93A mice was next examined. Current evidence indicates that ALS is a disease characterized by chronic inflammation. More over, CB2 receptors are upregulated within the target cells of a few neuroinflammatory diseases. The primary Dalcetrapib clinical trial site of pathology in ALS patients is the spinal-cord, with involvement of lower brain stem regions late in the disease process. In G93A rats, CB2 receptor mRNA is selectively up regulated in the spinal cord in a temporal pattern directly paralleling illness advancement. Moreover, increased mRNA levels are correlated with elevated CB2 receptor protein levels in the spinal cords of end point G93A mice. These studies suggest that, similar to other neuroinflammatory conditions, components of the cannabinoid system are selectively altered in the target tissue related to ALS pathogenesis. Additionally, reduced amounts of both CB2 receptor mRNA and protein noticed in WT OE spinal cords reported here have been in agreement with recent studies indicating the existence of functional CB2 receptors within the CNS of rodents. Drugs which activate CB2 receptors, effectively increase the symptoms of many inflammatory diseases including abdominal hypermotility as a result of atherosclerosis, endotoxic shock, Eumycetoma multiple sclerosis and Alzheimer s illness. Recent in vitro studies show that CB2 receptors are up regulated in microglia in response to inflammatory stimuli and that CB2 agonists suppress microglial activation. In the present study, we show that not only are CB2 receptors dramatically up regulated in the spinal cords of systematic G93A rats, they are also in a position to functionally stimulate G proteins when activated by cannabinoid agonists. Specifically, we suggest that in the first stages of motor neuron degeneration, CB2 receptors and endocannabinoids are c-Met Inhibitor selectively up regulated in spinal microglia as a compensatory, protective measure to reduce inflammation. Contrary to the above theory, it is very important to note that at least one study has indicated that the CB2 particular agonist AM 1241 might act as a protean agonist, displaying villain, inverse agonist or partial agonist activity depending on the assay and/or tissue examined. More over, in the present study, AM 1241 made little to no stimulation of G proteins in symptomatic G93A spinal-cord membranes. While the lack of agonist activity described here might be the result of less-than optimal experimental conditions, it’s also possible that the therapeutic effect of AM 1241 in this animal model might rather result from antagonism of CB2 receptor activation produced by the endogenous cannabinoid agonists 2 arachido noyl glycerol and/or anandamide, considered to be improved in the spinal cords of symptomatic G93A rats.