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).
In one study, THC effectively killed pancreatic cancer cells (in Panc1, Capan2, BxPc2 and MIA PaCa-2 cell lines) at 2 μM and higher concentrations (Carracedo et al., 2006). The authors found that both CB1 and CB2 were upregulated in cancer cells. Apoptosis was CB2-dependent (but see Fogli et al.) In mice, 15 mg/kg/d THC induced tumor cell-specific apoptosis and significantly reduced tumor growth (Carracedo et al., 2006). In human pancreatic cancer cells (MIA PaCa-2) various agonists and antagonists for CB1 and CB2 were found to induce apoptosis (Fogli et al., 2006). These effects appeared to be CB1 and CB2 independent and are counterintuitive but they do suggest the involvement of the endocannabinoid system in the pathogenesis of pancreatic cancer. In human patients, high CB1 expression in pancreatic cancer cells was associated with reduced survival. Similarly, low levels of endocannabinoid-degrading enzyme FAAH and MAGL were associated with reduced survival. Interestingly, Anandamide and 2AGlevels were unchanged in pancreatic cancer. Finally, contrary to CB1 expression in cancer cells, low CB1 in nervous tissue was associated with increased cancer pain, but also increased survival (Michalski et al., 2008). The mechanistic value of these correlations remains to be elucidated. In Panc1 cells, application of both CB1 and CB2 agonists induced AMP-kinase and ROS-dependent autophagy of cancer cells (Dando et al., 2013). The anti-tumoral effect of standard anti-cancer drug Gemcitabine was greatly enhanced by use of CB1 and CB2 agonists in both cell lines and tumor xenografts in mice (Donadelli et al., 2011), suggesting synergy between classical chemotherapy and cannabinoid-based treatment.
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).
In mice, blocking or stimulating CB2 function, respectively speeds up or slows down motor deficits, synapse loss and CNS inflammation that is associated with Huntington’s (Bouchard et al., 2012).
cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013). Selective activation of CB2 reduces neuroinflammation, ischemic injury and cognitive deficits in different models of stroke, probably through modulation of AMPK/CREB signaling (Choi et al., 2013; Ronca et al., 2015; Zarruk et al., 2012). Activation of CB1 and CB2 through synthetic cannabinoid WIN 55,212-2 in different hypoxia-ischemic newborn animal models showed neuroprotective effects, decreased brain injury and reduced apoptotic cell death by acting on glutamatergic excitotoxicity, TNF-alpha release, and iNOS expression (Alonso-AlcoNADA et al., 2010, 2012; Fernández-López et al., 2006, 2007, 2010; Martínez-Orgado et al., 2003). CBD mechanisms would involve the modulation of excitotoxicity, oxidative stress and inflammation through CB2, 5HT1A, Adenosine A2A and PPAR-γ receptors (Castillo et al., 2010; Hind et al., 2015; Pazos et al., 2012, 2013).
In rats, THC dose dependently suppressed CSD amplitude, duration and propagation through CB1 but not CB2 activation (Kazemi et al., 2012). The pain phase of migraine is mediated by and can be blocked through both CB1 and CB2 receptors (Greco et al., 2014).
In a rat model of Parkinson’s Disease, THCV and CBD were neuroprotective in a CB2-independent way (García et al., 2011). In a similar study, THC and CBD were neuroprotective via CB1 or CB2 receptors (Lastres-Becker et al., 2005). In Parkinson’s patients, microglia surrounding lesions in the substantia nigra have increased CB2 levels (Gómez-Gálvez et al., 2015). Experiments in mice showed that this increase in CB2 is neuroprotective. Thus CB2 signalling may provide a therapeutic avenue to prevent neurodegeneration in Parkinson’s.
Stimulating CB1 in human keratinocytes down-regulates keratins K6 and K16 which are involved in wound healing (Ramot et al., 2013), underlining the therapeutic relevance of the cannabinoid system in the treatment of Psoriasis. The effect of cannabinoids on CB1 could lead to potential treatments for Psoriasis (Wilkinson and Williamson, 2007).
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Several clinical trials have tested the therapeutic potential of cannabinoids after Stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after Stroke (England et al., 2015). Specifically activating CB1 and/or CB2 receptors had the strongest protective effect but other receptors such as 5-TH1a and PPARα are also likely to be involved.
England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental Stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.