3. Umbruch 4.4..2005 - Online Pot

Cannabinoids: effects on vomiting and nausea in animal models 189
that have typically been used to evaluate the anti-emetic properties of drugs
and, therefore, are easier to maintain in a laboratory.
Considerable recent work by Darmani and colleagues [24–29] has evaluated
the potential of different groups of cannabinoids to inhibit emesis induced by
toxins in C. parva (the least shrew), which weighs 4–6 g. Cisplatin-induced
emesis was inhibited by WIN-55,212-2 (1–5 mg/kg, ip) and ∆ 9 -THC
(1–10 mg/kg, ip) in a dose-dependent manner with similar potency [25, 26].
However, the synthetic cannabinoid CP-55,940 (0.025–0.3 mg/kg, ip) more
potently antagonized cisplatin-induced vomiting than WIN-55,212-2 or
∆ 9 -THC and also had a higher affinity for the CB 1 receptor [29]. The synthetic
HU-210 has a higher affinity for the CB 1 receptor than CP-55,940, but has not
been systematically evaluated for its anti-emetic capacity in the shrew model.
Emesis induced by the precursor to serotonin, 5-hydroxytryptophan (5-HTP)
(100 mg/kg, ip) was suppressed by ∆ 9 -THC [28] at doses of 5–20 mg/kg, ip;
however, a dose of 20 mg/kg, ip, of ∆ 9 -THC was required to suppress the emesis
produced by 5-HT (5 mg/kg, ip) and the selective 5-HT 3 agonist
2-methylserotonin (5 mg/kg, ip). Therefore, cannabinoids appear to suppress
the emetic reaction to drugs that activate the serotonin system in the least shrew.
Since cannabinoid agonists prevent emesis, Darmani [24] predicted that
blockade of the CB 1 receptor would induce vomiting. Indeed, at a dose of
10 mg/kg, ip, or 40 mg/kg, sc, SR-141716 induced vomiting in the least shrew;
on the other hand, the CB 2 receptor antagonist, SR-144528, did not produce
vomiting at any dose tested. WIN55,212-2 (minimal dose 10 mg/kg, ip) was
more effective than ∆ 9 -THC (minimum dose 20 mg/kg, ip) in preventing
SR-141716-induced vomiting [24, 29], which was also prevented by
CP-55,940 (1 mg/kg, ip). The selective CB 1 receptor antagonist SR-141716
blocked the anti-emetic activity of cannabinoids at low doses [24–29] and produced
vomiting on its own at higher doses in least shrews [24], suggesting that
the endogenous cannabinoid system plays a role in the regulation of emesis.
Darmani [27] has also shown that the endocannabinoid 2-AG is a potent
emetogenic agent, whereas anandamide may cause weak anti-emetic effects
[27, 35]. The emetic effects of 2-AG were inhibited by CP-55,940
(0.05–0.1 mg/kg, ip), WIN-55,212-2 (1–5 mg/kg, ip), ∆ 9 -THC (2.5–5 mg/kg,
ip), anandamide (5 mg/kg, ip), methanandamide (10 mg/kg, ip) and SR-141716
(2.5–5 mg/kg, ip), but not by CBD (10–20 mg/kg, ip). These results suggest
that endogenous cannabinoids may also play a role in promoting emesis.
Over the past number of years, the S. murinus (house musk shrew) has been
used as a model for emesis research [4, 6, 7]. These shrews weigh 30–60 g in
contrast to the 4–6 g of the least shrew. Like rats, Suncus will avoid a flavor
paired with lithium chloride [69]; however, unlike rats, these animals vomit in
response to toxins, even though they possess similar neural circuitry in the
emetic regions of the brain as rats [70]. In a series of experiments, Parker et al.
[31] evaluated the emetogenic potential of lithium in Suncus and the ability of
two principal cannabinoids found in marijuana, the psychoactive ∆ 9 -THC and
the nonpsychoactive CBD, to reverse lithium-induced emesis. A prior study