Possible Role Of Endocannabinoids In Gi Pathological States

Whenever the GIT is challenged by infection, allergy, inflammation, or other injury, the GI immune system is called into operation, which releases a host of proinflammatory mediators including cytokines, PGs, leukotrienes, NO, etc. (Holzer, 2001). Paralytic ileus results from activation of a network of macrophages that reside in intestinal muscularis (Kalff et al., 2003). Release of some of the cited proinflammatory agents from the macrophage network in turn causes the sluggish electrical and contractile responses of the muscularis that are the hallmark of paralytic ileus. Recently, the role of endocannabinoids has been suggested in the pathogenesis of paralytic ileus induced by intraperitoneal administration of acetic acid in mice (Mascolo et al., 2002). Indeed, relative to the vehicle-treated control group, the pathological state was accompanied by increased: (1) tissue levels of intestinal anandamide, and (2) number of cannabinoid CB1 receptors in myenteric plexes and nerve bundles of fibers of the external muscles of the jejunum. The authors suggest that increased levels of anandamide coupled with the overexpression of CBj receptors result in overac-tivation of the endocannabinoid system, which inhibits the release of the excitatory cholinergic neurotransmitter acetylcholine leading to the development of paralytic ileus. The CBj antagonist SR141716A alleviated the induced hypomotility as it restored normal intestinal motility. Furthermore, the selective inhibitor of anandamide membrane transporter, VDM11, significantly delayed GI transit in acetic acid-treated mice, which further supports the role of anandamide in this pathological state. The effect of acetic acid on the tissue levels of 2-AG in this model of paralytic ileus remains unknown. In regard to feeding, the levels of both 2-AG and anandamide have been shown to be elevated in the hypothalamus of genetically obese rats with hyperphagic syndrome (Di Marzo et al., 2001), which indicates aberrant activity of the endocannabinoid system in appetitive disorders.

In another animal model of intestinal inflammation (caused by oral administration of croton oil in mice), an increased expression in the density of intestinal cannabinoid CB1 receptors has also been observed (Izzo, Fezza, et al., 2001). In line with increased CB1 expression, this and other studies (Izzo, Pinto, et al., 2000) show that cannabinoid CB1 agonists (CP55940, WIN55212-2, and can-nabinol) more potently delay intestinal motility in croton-oil-treated mice than in control mice.

SR141716A pretreatment countered these inhibitory effects, but when administered alone it increased intestinal motility to the same extent in both control and croton-oil-exposed mice. Moreover, anan-damide and 2-AG level assay showed no significant difference between inflamed and noninflamed intestinal tissue. The lack of increase in endocannabinoid levels in the inflamed intestine could be due to a more rapid turnover of both 2-AG and anandamide, which could be due to upregulation of anandamide amidohydrolase as the activity of this enzyme was significantly increased in the inflamed intestine.

As discussed earlier, studies in this laboratory have shown that 2-AG is a potent emetogenic agent, whereas anandamide possesses antiemetic and emetic effects (Darmani, 2002b). Xenobiotic cannabinoids prevent 2-AG-induced emesis as well as vomiting produced by other emetic stimuli. The emetic activity of 2-AG was also blocked by the nonselective cyclooxygenase inhibitor indo-methacin, suggesting downstream metabolites of endocannabinoids are responsible for the induced emesis. The chemotherapeutic agent cisplatin not only produces vomiting but also causes intestinal mucosal damage and inflammation, diarrhea, and ileus, as well as release of emetic agents such as serotonin, dopamine, and downstream emetic metabolites of endocannabinoids such as PGE2 and PGF2a (Darmani, 2001b, 2001c; Goto et al., 1998; Ito et al., 1994; Endo et al., 1990; Bostrom, 1988; Dewit et al., 1987). In collaboration with Di Marzo's laboratories, we have shown that IP administration of cisplatin, specifically and dose dependently, increases 2-AG but not anandamide levels in shrew brains (see Figure 17.1). These results further support a role for endocannabinoids in GI-related pathological states.

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