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).