Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation

Abstract

The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction.

Figures

Figure 1

Immunohistochemical analysis of CB2 receptor protein in human ileum. Archival tissue sections were retrieved from files at the Royal United Hospital (Bath, UK) with the approval of the Bath Local Research Ethics Committee (RUH Bath NHS Trust, UK). Tissue blocks were fixed in 4% (w/v) formaldehyde and embedded in paraffin. Sections were stained with a primary rabbit polyclonal anti-human CB2 antibody (Cayman Chemicals Co., Boldon, Tyne and Wear, Newcastle UK) using standard immunohistochemical techniques (Wright et al., 2005). Brown staining indicates CB2 immunoreactivity. (a) Dense CB2 immunoreactivity was found in the luminal membrane at the ulcerative margin in active Crohn's disease (right-hand side, red arrow) with weak cytoplasmic staining in the non-involved epithelium (left-hand side, blue arrow). Bar=30 μm. Enteric ganglia in the (b) myenteric plexus and the (c) submucosal plexus in normal tissue were moderately CB2 positive. Results are representative of the staining pattern noted in the assessment of 21 separate patient samples. This is the first illustration of CB2 receptor immunoreactivity in the human enteric nervous system. Unpublished data, used with kind permission from Dr Leigh Biddlestone, Rachel Seymour and Dr Karen Wright (Bath, UK). Bar=10 μm. CB, cannabinoid.

Figure 2

CB2 receptor expression in the gastrointestinal (GI) tract and its innervation. CB2 receptors are expressed in the enteric nervous system and on immune cells in the normal gut. During inflammation, there is enhanced expression on epithelial cells at the ulcer margins (red) and in infiltrating immune cells. CB2 receptor is also expressed on visceral afferent nerves and in the dorsal vagal complex in the brainstem. Commensal bacteria (yellow) and pathogens (blue) are allowed access to the mucosal and submucosal regions through breaches in the epithelial barrier during inflammation. The figure is extensively adapted from Furness et al. (1999). CB, cannabinoid.