3. Umbruch 4.4..2005 - Online Pot

184 L.A. Parker et al.
5-HT 3 antagonists often combined with the corticosteroid, dexamethasone, during
the first chemotherapy treatment has reduced the incidence of acute vomiting
by 70–90% [1, 8–14]. If acute vomiting is prevented, the incidence of
delayed and anticipatory vomiting is reduced [2, 8–11, 20]. However, the 5-HT 3
antagonists are less effective at suppressing acute nausea than they are at suppressing
acute vomiting [1, 9, 10, 14, 20] and they are ineffective in reducing
instances of delayed nausea/vomiting [13, 15–20] and ANV [1, 10, 11, 14,
20–22] when they do occur. Therefore, it is likely that another system may be
involved in chemotherapy-induced nausea, delayed nausea/vomiting and ANV.
Two such systems include the neurokinin 1 (NK 1) tachykinin receptors for substance
P (e.g. [16, 17, 23]) and the endocannabinoid system [24–39]. The effect
of cannabinoids on nausea and vomiting is the subject of this review.
Cannabinoids as anti-emetics
The marijuana plant has been used for several centuries for a number of therapeutic
results, including nausea and vomiting [40]; however, it was only
recently that Gaoni and Mechoulam [41] isolated the major psychotropic component,
∆ 9 -tetrahydrocannabinol (∆ 9 -THC). Twenty-five years later, the specific
brain receptors for this compound, cannabinoid 1 (CB 1) and cannabinoid 2
(CB 2), were identified (for review see [42]) and cloned [43]. Therefore, it was
only natural to start the search for an endogenous ligand for the cannabinoid
receptor, which was discovered 2 years later [44]. This ligand was the
ethanolamide of arachidonic acid, and called anandamide. A second type of
endocannabioid was discovered in 1995 [45], also a derivative of arachidonic
acid, but its ester, 2-aracidonoyl glycerol (2-AG). Both anandamide and 2-AG
are rapidly inactivated after their formation and release by the enzyme fatty
acid amide hydrolase (FAAH) [46].
The anti-emetic effects of cannabinoids appear to be mediated by action at
the CB 1 receptor. CB 1 receptors are found in the gastrointestinal tract and its
enteric nervous system [47] as well as within the emetic system of the brain
[34, 35] in the dorsal vagal complex, consisting of the area postrema (AP),
nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus
(DMNX) in the brainstem of rats, ferrets and the least shrew [33, 34]. Recent
reviews on the gastrointestinal effects of cannabinoids have concluded that
cannabinoid agonists act mainly via peripheral CB 1 receptors to decrease
intestinal motility [47], but act centrally to attenuate emesis [34, 35]. The dorsal
vagal complex is involved in the nausea and/or vomiting reactions induced
by either vagal gastrointestinal activation or several humoral cytotoxic agents.
It is considered the starting point of a final common pathway for the induction
of emesis in vomiting species. CB 1 receptors in the NTS are activated by
∆ 9 -THC and this activation is blocked by the selective CB 1 antagonists
SR-141716 [28] and AM-251 [35]. Indeed, c-Fos expression induced by cisplatin
in the DMNX, specific subnuclei of the NTS and AP is significantly