CB2 is primarily found in cells of the immune system, such as monocytes, macrophages, B-cells and T-cells and in organs like the spleen, tonsils and thymus gland. CB2 is also found in macrophage-derived cells such as microglia, osteocytes, osteoclasts, dendritic cells and hepatic Kupffer cells CB2 is also found throughout the gastrointestinal tract where it is involved in immune reactions. CB2 is present in brain and the peripheral nervous system but lower abundant than CB1. Where CB1 is primarily found in neurons, CB2 is mostly found in microglia, consistent with a primary function in immune responses. CB2 is overexpressed in the brain under certain injury conditions and is overexpressed in cancer cells. However, distribution of CB2 remains controversial due to discrepancies between studies and the lack of validation of some immunochemistry techniques used for its localization.
Infected cells secrete trans-activating factors (Tat), which consequently attract macrophages and macrophage-like cells. THC blocks this migration in a dose-dependent way via CB2 receptors (Raborn and Cabral, 2010).
One therapeutic indication for CB2 is the stimulation of Amyloid β plaque removal by macrophages. Similar effects were seen for 2AG and MAGL inhibitors (Chen et al., 2012). CB1 is not involved in plaque clearance.
In mice genetically deficient for CB2, experimentally induced osteoArthritis was significantly worse than in control mice (Sophocleous et al., 2015). In addition, naturally occurring osteoArthritis was more severe in CB2 deficient mice than in controls.
CB2-mediated signaling was significantly upregulated in peripheral blood mononuclear cells obtained from autistic children (Siniscalco et al., 2013).
The specific cannabinoid receptors CB2 and GPR55 are overexpressed in glioblastomas compared to non-cancer glial cells. This overexpression is also related to the prognosis of the disease, with higher overexpression of CB2 in the most aggressive tumors (Calatozzolo et al., 2007; Ellert-Miklaszewska et al., 2007; Sánchez et al., 2001). Studies in THC and synthetic CB2 agonists shown downregulation of MMP-2, cell invasion and cell viability (Blázquez et al., 2008; Galanti et al., 2008; Hernán Pérez de la Ossa et al., 2013). CBD modulates Id-1 gene and targets receptors CB1, CB2, TRPV-1 and TRPV-2 (Solinas et al., 2013; Soroceanu et al., 2013).
Leukemia cells express functional CB1 and CB2 receptors (Moaddel et al., 2011). Also, other CB1/2 agonists showed Leukemia cell growth and proliferation inhibition (Gallotta et al., 2010; Yrjölä et al., 2015).
Functional Gastro-Intestinal Disorders
CB2 plays a role in Crohn´s disease (Schicho and Storr, 2014). Cannabis extract also reduced visceral pain at 3 mg/kg in a CB2-dependent way suggesting cannabis extract has distinct beneficial effects in gastro-intestinal disorders via CB1/2-dependent and independent pathways (Wallace et al., 2013).
Several studies found that CB2 was upregulated with Cystitis (Merriam et al., 2008; Tambaro et al., 2014) and that activation of CB2 with Anandamide or PEA attenuated pain and inflammation (Jaggar et al., 1998; Wang et al., 2013, 2014).
PEA enhances AEA activity at CB1, CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1, CB2 or PPARα-dependent way (Petrosino et al., 2010). In another mouse study, experimental dermatitis increased 2AG levels and suppressed inflammation via CB2 receptors (Oka et al., 2006). In mice CB1 and CB2 suppressed inflammation in allergic contact dermatitis (Karsak et al., 2007).
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