The chemotherapeutic agent
cisplatin may produce
emesis via release of several
neurotransmitters such as
serotonin (5-HT),
substance P and/or
dopamine as well as production of
prostaglandins (PGs). Administration of synthetic
2-arachidonoylglycerol (2-AG) but not of
anandamide, which are two putative
endocannabinoids, causes
vomiting via its downstream metabolites such as
arachidonic acid (AA) and PGs in the least shrew (Cryptotis parva). We report here that
cisplatin (0, 5, 10 and 20 mg/kg, i.p.) causes dose- and time-dependent increases in brain tissue levels of 2-AG but not
anandamide in this
vomiting species. Concomitantly, intestinal tissue levels of both
endocannabinoids are relatively reduced. Selective inhibitors [arachidonoyl-
serotonin (AA-5-HT) and
URB597, 0-5 and 0-10 mg/kg, i.p.] of one of the major
endocannabinoid metabolic
enzymes, the intracellular
fatty acid amide hydrolase (FAAH), do not significantly prevent
vomiting produced by
emetic doses of i.p.-administered 2-AG,
cisplatin or the
dopamine receptor agonist apomorphine. At large doses (10 and 20 mg/kg, respectively), both FAAH inhibitors caused
emesis per se. Administration of one selective uptake inhibitor of
endocannabinoids, OMDM1 (0-5 mg/kg, i.p.), also did not significantly prevent
emesis by the direct and indirect
emetic stimuli, and likewise caused
emesis by itself at a high (10 mg/kg) dose. However, another selective uptake inhibitor,
VDM11, did not produce significant
emesis per se and prevented
emesis caused by
apomorphine. Both the
corticosteroid dexamethasone, and the
cyclooxygenase inhibitor indomethacin, reduced
vomiting produced by
cisplatin. These data: (a) provide the first evidence that
cisplatin causes a selective increase in 2-AG levels in the brain, and (b) support the established notion that 2-AG may produce some of its effects, including
emesis, via downstream metabolites produced independently of FAAH.