Presence Of Endocannabinoids And Cannabinoid Cbt Receptors In Gutbrain Circuits Affecting Git Motility And Emesis

Though most motility functions of the GIT are mediated by the local ENS, the brainstem plays an important role in both the initiation and coordination of GIT motility (Krowicki and Hornby, 1995). As will be discussed later in the text, both exogenous cannabinoids and endocannabinoids affect GIT motility functions and emesis via cannabinoid CE^ receptors. The first endocannabinoid to be identified in a peripheral tissue was 2-AG. Although Mechoulam et al. (1995) detected 2-AG but not anandamide in the canine small intestine, more recent studies show that relatively large amounts (44.1 ± 4 nmol/g tissue and 36.4 ±6.1 pmol/g tissue, respectively) of both endocannabinoids are present in the small intestine of mice (Izzo, Fezza, et al., 2001). The mouse small intestine is highly enriched with 2-AG, as its concentration exceeds the levels found in other peripheral tissues (liver, spleen, lung, and kidney) by 37 to 55 times and in various brain regions by 3- to 20-fold (Bisogno et al., 1999; Izzo, Fezza, et al., 2001; Sugiuraet al., 2002). On the other hand, the levels of anandamide both in the CNS and peripheral tissues of several species can be similar, lower, or greater than that present in the mouse small intestine. Both 2-AG and anandamide are differentially distributed in several regions of the rat brain, where the highest concentrations occur in the brainstem (87 ± 45 pmol/g tissue and 14 ± 7.1 nmol/g tissue, respectively), and lowest amounts are found in the diencephalon (10.2 ± 2.3 pmol/g tissue and 2 nmol/g tissue, respectively). Anandamide may be responsible for specific functions in particular areas of the GIT because its colonic tissue concentration is 10-fold higher than that found in the small intestine, whereas 2-AG concentration appears to be approximately 2 times lower in the mouse colon relative to basal levels in small intestine (Pinto, Capasso, et al., 2002). Anandamide is probably more rapidly metabolized in the mouse colon as the main enzyme responsible for its degradation is also more concentrated in this tissue. 2-AG levels both in the brain of several species and in the mouse small intestine are more than 100- to 1000-fold higher than those of anandamide. The amounts of these endocannabinoids in both the CNS and small intestine are likely to yield tissue concentrations similar to or higher than the K, values for the activation of CB receptors (Izzo, Fezza, et al., 2001). Lynn and Herkenham (1994) utilized 3H-CP55940 to visualize cannabinoid CB! binding sites in Peyer's patches located in rat jejunum, ileum, and rectum by autoradiography. However, CB! sites were not detected in the rat stomach, duodenum, cecum, or colon. These initial findings suggested that cannabinoid CBi receptors are highly localized in discrete regions such as nerve terminals in the myenteric and submucosal plexuses. On the other hand, more sensitive techniques such as immunohistochemistry and RT polymerase chain reaction have shown the presence of the CBi receptor or its markers on neurons throughout the GIT of several animal species including humans (Buckley et al., 1998; Casu et al., 2003; Kulkarni-Narla and Brown, 2000; Pinto, Izzo, et al., 2002; Ross et al., 1998; Storr et al., 2002; Shire et al., 1995). However, CBi receptors seem to be differentially distributed along the length of the GIT, with the stomach and colon being highly enriched with these sites (Casu et al., 2003). Although the brainstem appears to be relatively CBi receptor sparse, the NTS, the area postrema, and the dorsal motor nucleus of the vagus in the brainstem contain significantly moderate amounts of cannabinoid CBi receptors in nonemetic (Herkenham et al., 1991) and several emetic species including the ferret (Van Sickle et al., 2001), least shrew (Cryptotis parva) (Darmani et al., 2003) and humans (Glass et al., 1997). The NTS and area postrema are among important loci within the brainstem that control emesis. The brainstem via the vagus also controls gastric motor and secretory activities.

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