2.2 Cannabinoid receptor subtypes
Endocannabinoids signal via two main cell surface receptors, CB1 and CB2, belonging to the superfamily of G-protein-coupled receptors. CB1 is the principal receptor present in the central nervous system (CNS), and is one of the most abundant G-protein–coupled receptors in the brain (Sharke and Wiley, 2016). Within the CNS, CB1 receptors are densely expressed in several brain regions such as the cortex, dorsal root and basal ganglia, thalamus, hippocampus, and periaqueductal gray, and supraspinal regions where they regulate a wide variety of neurotransmission processes including pain transmission and neuroinflammation (Martin et al., 1995; Barrie and Manolios, 2017). CB1 receptors are also densely expressed on the epithelium of the gastrointestinal (GI) tract and on all classes of enteric neurons except inhibitory motor neurons (Trautmann and Sharkey, 2015). Their widespread distribution explains the wide array of biological effects produced by cannabinoid ligands, both endogenously expressed and exogenously supplied. With the widespread distribution, it is not surprising that therapies targeting CB1 receptors are sometimes limited by challenges associated with central and peripheral nervous systems effects (Barrie and Manolios, 2017).
CB2 receptors are expressed by immune cells and also by enteric neurons and the epithelial cells in the GI tract (Trautmann and Sharkey, 2015; Wright et al., 2008). Their wide distribution in the periphery on immune cells makes them targets for modulating inflammatory processes such as inflammatory pain processing (Barrie and Manolios, 2017). This is supported by the discovery that HU-308, a selective CB2 agonist, significantly decreases nociceptive behaviour in formalin-induced rodent inflammatory pain model. CB2 receptor activation suppressed local secretion of pro-inflammatory factors by non-neural cells, thus inhibited sensitization of neighbouring nociceptive neuronal terminals (Hanus et al., 1999; Barrie and Manolios, 2017). It has therefore been proposed that, in the settings of neuropathic pain or inflammatory hyperalgesia, activation of peripheral CB2 receptors mediate anti-nociceptive responses by acting locally on immune cells in the periphery and microglia in the CNS (Ibrahim et al., 2003).