3. Umbruch 4.4..2005 - Online Pot

Cannabinoids: effects on vomiting and nausea in animal models 195
duce conditioned rejection on its own, it potentiated the ability of lithium to
produce conditioned gaping. This same pattern has been reported in the emesis
literature. Van Sickle et al. [34] reported that although the CB 1 antagonist
AM-251 did not produce vomiting on its own, it potentiated the ability of an
emetic stimulus to produce vomiting in the ferret.
Conclusions
Since the discovery of the mechanism of action of cannabinoids, considerable
research using smaller animals (ferrets and shrews) confirms prior experimental
reports [30, 65, 66] that cannabinoids serve as effective anti-emetics. In the
ferret and shrew models, the site of action has been identified in the emetic
area of the brainstem, the dorsal vagal complex [28, 29, 34, 35]. The shrew
model, in particular, is cost-effective for the evaluation of the anti-emetic properties
of agents. It is clear that many cannabinoids act on the CB 1 receptors to
produce their anti-emetic properties; however, it is not known how the nonpsychoactive
cannabinoid, CBD, which does not act at the CB 1 receptor, produces
anti-emetic effects within a limited dose range in S. murinus [31, 32].
Research has also supported anecdotal reports that cannabis may attenuate
ANV. Using S. murinus, ∆ 9 -THC effectively prevented conditioned gaping
elicited by re-exposure to a lithium-paired chamber [77]. Further work on this
model may reveal optimal agents for alleviating ANV, which is resistant to
treatment with 5-HT 3 antagonists [1, 10, 11, 14, 20].
Finally, the conditioned gaping response appears to selectively reflect nausea
in the rat [84–89], which is not capable of vomiting in response to a toxin.
Rats display this response to flavors previously paired with emetic agents and
this response is prevented by anti-emetic pretreatments [88, 89]. Cannabinoids
suppress the establishment of this conditioned gaping when administered prior
to a taste-toxin pairing [36–39]. Cannabinoids also suppress the expression of
previously established conditioned gaping, again suggesting that they may
serve to suppress ANV. Not only psychoactive cannabinoids, but also the
non-psychoactive CBD, suppresses the establishment and the expression of
lithium-induced conditioned gaping in rats [38].
The endogenous cannabinoid system clearly plays a role in the regulation of
nausea and vomiting. The CB 1 antagonists SR-141716 and AM-251 respectively
potentiated the strength of toxin-induced conditioned gaping in rats [37,
39] and toxin-induced vomiting in ferrets [34]. However, the finding that the
endogenous cannabinoid 2-AG serves as an emetogenic agent in the least
shrew [27] suggests that the endocannabinoid system may contribute to the
control of nausea and vomiting in a complex manner.
Acknowledgements
The authors would like to thank Marion Corrick for care of the shrews. This research was supported
by research grants to L.P. from the Canadian Institutes of Health Research and the Natural Sciences
and Engineering Research Council of Canada.