**5. Role of cannabinoid receptors during pathological states**

Because of the ubiquitous expression of the receptor throughout the CNS, several preclinical and clinical studies have addressed the potential therapeutic value in modulating the endocannabinoid system for analgesia, weight loss, appetite stimulation, neuroprotection after ischemic injuries, and for anti-emetic, anti-epileptic and antispasmodic purposes (Nogueiras, Diaz-Arteaga et al. 2009; Bisogno and Di Marzo 2010; Karst, Wippermann et al. 2010; Scotter, Abood et al. 2010). The premise of many of these therapeutic approaches lies in the neuromodulatory function of CB1R, or in the antiinflammatory effects on CB2R activation.

During disease or following injury, cannabinoid receptor expression and levels of eCBs are altered. For example, after rat spinal cord injury, cannabinoid receptor expression is altered at the spinal level, but also in brain areas: in the spinal cord, CB1R becomes expressed in reactive astrocytes, and CB2R becomes strongly upregulated in microglia, astrocytes and macrophages. In the brain, CB1R is upregulated in thalamic and hippocampal areas, while downregulated in the amygdala and Periaqueductal Gray Area (Garcia-Ovejero, Arevalo-Martin et al. 2009; Knerlich-Lukoschus, Noack et al. 2011). In healthy spinal cords, several studies indicate that there are very low levels of CB2R, but peripheral nerve injury, for example, leads to significant upregulation of this receptor, corresponding to significant microglial activation in the spinal cord (Zhang, Hoffert et al. 2003; Romero-Sandoval, Nutile-McMenemy et al. 2008). Microglial cells contribute to the inflammatory response by producing and secreting the pro-inflammatory cytokines that contribute to excitotoxic damage in the CNS, but also to the differentiation of pathogenic lymphocytes entering the CNS (Arevalo-Martin, Garcia-Ovejero et al. 2008). Activation of CB2R in cultured microglial cells inhibits these inflammatory cytokines, making CB2R activation an anti-inflammatory target. However, the potential role of CB2R in microglial cells following injury is not clear. Cultured rat microglial cells can produce the eCBs 2-AG and AEA, which in turn autostimulate their CB2Rs to induce proliferation (Carrier, Kearn et al. 2004).

Whether these changes reflect an adaptive defense mechanism or contribute to pathology is still a matter of debate. These studies implicate CB1R and CB2R as double edged swords for CNS insult, and whether their activation promotes protection or contributes to damage likely depends on the etiology and progression of the disease or injury, but also in the localization of each receptor on specific cell types.
