Endocannabinoids And Vomiting

Emesis is the forceful expulsion of intestinal and gastric contents through the mouth. In humans emesis is often associated with the feeling of nausea. Emesis is also preceded in humans by retching, which is a pattern of motor activity that overrides antireflux mechanisms in the GIT. Initially, a wave of reverse peristalsis begins in the distal small intestine moving intestinal content orad. The antiperistalsis may begin as far down in the GIT as the ileum, which pushes intestinal contents to the duodenum. Distension of the upper GIT, especially duodenum, becomes an excitatory factor in initiating the process of vomiting. Eventually, stronger retches develop, and a sudden strong contraction of abdominal muscles raises the diaphragm high into the thorax, and the increased intrathoracic pressure forces the GIT contents out of the mouth.

Aside from vomiting being initiated by irritative stimuli in the GIT, emesis can also be caused by different emetic neurotransmitters stimulating various areas of the brain outside the VC such as the NTS, CTZ, and vestibular apparatus (see earlier). Because of the presence of both endocannab-inoids and CB1 receptors in structures that control GIT motility and emesis, it is tempting to suggest that endocannabinoids may modulate the process of vomiting. Indeed, anandamide and its more stable analog methanandamide can protect shrews and ferrets from vomiting caused by 2-AG (Darmani, 2002b) or morphine (Van Sickle et al., 2001). The antiemetic activity of anandamide and methanandamide is in line with their discussed ability to attenuate: (1) in vitro electrically evoked contractions of both isolated MPLM preparation of guinea-pig ileum as well as circular muscle preparation of guinea-pig ileum, (2) in vitro distension-induced propulsive motility of luminally perfused guinea pig isolated ileum, (3) in vitro electrically evoked contractions of gastric smooth muscle preparation, and (4) in vivo passage of charcoal marker in the upper GIT and glass beads in distal colon of mice. In addition, as noted earlier, a large amount of anandamide is found in the brainstem, an area which is generally sparse with cannabinoid CE^ receptors. However, specific emetic loci of brainstem such as the NTS and CTZ contain significant amounts of CB x sites as well as fatty acid amide hydrolase (FAAH) that metabolizes anandamide (Darmani, Sim-Selly, et al., 2003; Van Sickle et al., 2001; Glass et al., 1997). Spurred on by our initial publication that high doses of the cannabinoid CB! receptor antagonist SR141716A produces vomiting in the least shrew (Darmani, 2001a), we and other investigators have shown that in several animal models of vomiting, structurally diverse cannabinoids (HU210, CP55, 950, WIN55212-2, A9-THC and anandamide) prevent vomiting produced by various emetic stimuli such as: (1) SR141716A (Darmani, 2001a), (2) 2-AG (Darmani 2002b), (3) cisplatin (Darmani, 2001b, 2001c; Darmani, 2002a; Darmani, Sim-Selly, et al., 2003), (4) AA (Darmani, 2002b), 5-hydroxytryptophan (5-HTP) (Darmani, 2002c), (5) apomorphine (London et al., 1979), (6) morphine (Simoneau et al., 2001; Van Sickle et al., 2001), and 7) anticipatory nausea and vomiting (Parker and Kemp, 2001). From this diverse array of antiemetic activity, one may propose that A9-THC and synthetic cannabinoids act as broad-spectrum antiemetic agonists. In addition, several of the cited studies have shown that the antiemetic activity of A9-THC and its synthetic analogs can be dose-dependently countered by nonemetic doses of SR141716A (and not SR144528), which implies an important role for the cannabinoid CB! receptor in the antiemetic activity of cannabinoids. Moreover, at higher doses (>10 mg/kg, i.p. or >40 mg/kg, s.c.), SR141716Aby itself induces emesis in the least shrew in a dose-dependent fashion. In addition, the emetic activity of SR141716A and several other stimuli were potently blocked by structurally diverse cannabinoids with an antiemetic ID50 potency order (CP55940 > WIN55212-2 > A9-THC) that is similar and is highly correlated (Darmani, Sim-Selly, et al., 2003) to their: (1) rank affinity order for cannabinoid CBi receptors in shrew brain homogenates and (2) EC50 potency order for GTPyS stimulation. In addition, the antiemetic potency of each tested cannabinoid appears to be dependent upon the stimulus-producing emesis. For example, although both WIN55212-2 and A9-THC are equipotent against cisplatin-induced emesis, WIN55212-2 is 4 to 9 times more potent than A9-THC in preventing SR141716A- and 2-AG-induced vomiting (Darmani, 2001a, 2001b, 2001c; Darmani, Sim-Selly, et al., 2003). CP55940 appears to be 4 to 20 times more potent than WIN55212-2 against the cited emetic stimuli (Darmani, 2001a, 2001b, 2001c; Darmani, Sim-Selly, et al., 2003). However, both A9-THC and WIN55212-2 provide significant emesis protection at nonsedative doses, whereas in most studies CP55940 prevented vomiting produced by the cited diverse emetic stimuli at motor suppressive doses (Darmani, 2001a, 2001b, 2001c; Darmani, Sim-Selly, et al., 2003). Overall, these findings suggest that structurally diverse classes of xenobiotic cannabinoids (and possibly the endocannabinoid anandamide) possess significant broad-spectrum antiemetic activity via stimulation of cannabinoid CBi receptors.

Another mechanism via which anandamide may prevent emesis can be through the stimulation of vanilloid VR1 receptor, as this endocannabinoid is also a full agonist at the latter site (Szallasi and Di Marzo, 2000). VR1 agonists such as capsaicin and resiniferatoxin initially induce emesis in shrews in a potent manner that can be blocked by VR1 antagonists (Andrews et al., 2000; Rudd and Wai, 2001). However, rapid desensitization occurs following the initial exposure to both emetic and other effects of resiniferatoxin as well as to the emetic action of other stimuli. Although the possible VR1 component of anandamide's emetic/antiemetic actions have not yet been tested directly, it is clear that anandamide produces emesis at a high dose whereas its lower doses may provide protection against some emetic stimuli (Darmani, 2002b; Van Sickle et al., 2001). Thus, anandamide shares with other vanilloid agonists emetic and antiemetic properties. In addition, some downstream metabolites of both 2-AG and anandamide [such as 12 (S) HETE and 15 (S) HETE] have similar or higher affinity for cannabinoid CE^ receptors, whereas others [e.g., 12 (S) HpETE, 15 (S) HpETE, and leukotriene BJ are more potent than anandamide at VR1 receptors (Pertwee and Ross, 2002). These metabolites may also exert emetic and antiemetic effects by themselves.

Unlike anandamide and exogenous cannabinoid agonists, the less well investigated endocan-nabinoid, 2-AG, is a potent emetogenic agent (ED50 0.48-1.13 mg/kg, i.p.) in the least shrew (Darmani, 2002b). It is unlikely that the emetic activity of 2-AG is mediated via cannabinoid CE^ receptors because indomethacin (a nonselective cyclooxygenase inhibitor) pretreatment prevented the emetogenic effect of 2-AG. This finding implies that one or more downstream metabolites of 2-AG causes vomiting. Indeed, the major metabolite of 2-AG, AA, was found to be a highly potent emetogen (ED50 = 0.58 ± 2 mg/kg, i.p.) (Darmani, 2002b). The ability of AA to induce emesis was also blocked by indomethacin, suggesting that further downstream metabolites of 2-AG induce vomiting. As detailed elsewhere in this book, free AA is metabolized to oxygenated products by distinct enzyme systems including cyclooxygenases, one of several lipoxygenases, or cytochrome 450s (Morrow and Roberts, 2001). Cyclooxygenase is a bifunctional enzyme exhibiting both cyclooxygenase and peroxidase activities. The cyclooxygenase component converts AA to PGG2, and the peroxidase component reduces PGG2 to PGH2, which is the precursor of PGs, thromboxanes, and prostacyclins. The 5-, 12- or 15-lipoxygenases are enzymes that catalyze conversion of AA to leukotrienes, HETEs, and HpETEs. Cytochrome P450 enzymes convert AA to a number of epoxy-eicosatrienoic products (EpETrEs). Overall, free AA can be converted to over 100 products, and the pharmacology of many of these metabolites has not yet been investigated. Our ongoing preliminary screening assays on some of these products in the least shrew show that though a number of AA metabolites are emetogenic (PGE2; 20 (OH) PGE2; PGG2; PGH2; PGF2a; PG 20-(C>H) F2a; 20-HETE; (±) 5 (6)-EpETrE; (±) 11 (12)-EpETrE), other tested metabolites do not produce emesis at 2 mg/kg (PGD2, PGI2; tetramer PGFM; 5 (S) HpETE; 13, 14-dihydro-15-keto PGF2a; 19 (R)-OH PGF2a; 15 keto PGF2a). There is substantial published support for our cited preliminary findings. For example: (1) Staphylococcus-aureus enterotoxin B produces vomiting in monkeys which is associated in a time-dependent manner with increases in plasma concentrations of several AA metabolites (PGF2, leukotriene B4, and 5-HETE) (Jett et al., 1990), (2) significant correlation exists between the rise in maternal PGE2 serum levels and the symptoms of nausea and vomiting in early pregnancy (Gadsby et al., 2000), (3) administration of PGE2 or PGF2a produces vomiting and diarrhea in both piglets (Wechsung, 1996) and patients (Wislicki, 1982), and (4) PG synthesis inhibitors such as dexamethasone are used as additive antiemetics for the prevention of vomiting produced by both chemo- and radiotherapy (Ioanidis et al., 2000).

An important question remains to be resolved: Why is 2-AG a potent emetogen whereas anandamide mainly possess antiemetic activity? Although the exact mechanism is unclear, several factors may contribute to the phenomenon of differential effects of endocannabinoids on emesis:

1. Though both endocannabinoids are metabolized to a common potent emetic metabolite (AA), 2-AG is metabolized by FAAH several-fold faster than anandamide (Pertwee and Ross, 2002).

2. Besides FAAH, other enzymes such as monoglycerol lipase also convert 2-AG to AA (Sugiura et al., 2002).

3. 2-AG acts as a natural AA precursor whose metabolism by COX and generation of PGE2 (an emetic agent) participates in positive modulation of inflammatory mediators such as NO production and COX-2 induction, which may induce certain types of vomiting (Chang et al., 2001; Jeon et al., 1996).

4. In the latter studies, anandamide was shown to inhibit production of proinflammatory agents such as NO, PGE2, and IL-6, which may help to avert production of emesis under certain conditions.

Cisplatin (mg/kg)

FIGURE 17.1 Effects of cisplatin exposure on shrew brain contents of 2-AG and anandamide. Different groups of shrews (Cryptotis parva) were injected with varying doses of cisplatin (0, 5, 10, and 20 mg/kg, i.p., n = 4 per group) and 30 min later, the animals were sacrificed by rapid decapitation, and whole brains were frozen at -80°C until endocannabinoid analysis. * Significantly different from corresponding vehicle-treated control group.

5. The more stable analogs of both 2-AG (noladin ether, also a putative endocannabinoid) and anandamide (methanandamide) do not induce vomiting (Darmani, 2002b and Dar-mani, unpublished findings).

6. As discussed earlier, anandamide but not 2-AG can bind vanilloid VR1 receptors whose activation can lead to emetic/antiemetic effects, a property which anandamide shares.

7. Though the tissue levels of both anandamide and 2-AG can be simultaneously altered by drag administration or in pathological states, there is also strong evidence that the release of 2-AG can be independently modified, which can be region specific (Pertwee and Ross, 2002).

In the light of these findings, preliminary results of our recent collaboration with the Italian endocannabinoid research group suggest that a specific increase in brain 2-AG (but not anandamide) levels may contribute to cisplatin-induced vomiting (N.A. Darmani, G. Ambrosino, M.G. Cascio, V. Di Marzo). Indeed, a 30-min prior treatment with the chemotherapeutic agent cisplatin (0, 5, 10, and 20 mg/kg), specifically and dose-dependently, increased (p <.05) 2-AG but not anandamide levels in shrew whole brain (Figure 17.1). In fact, anandamide tissue level was decreased in the 5 mg/kg cisplatin dose group. This preliminary finding has been confirmed by our more recent extensive studies (Darmani et al., 2005). These findings, in conjunction with our previously published report on the potent emetic activity of 2-AG and its downstream metabolites (Darmani, 2002b), strongly suggest an important role for 2-AG and its metabolites in mediation of chemotherapy-induced vomiting.

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