Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew.
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.
Darmani
Nissar A
NA
Department of Pharmacology, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766-1854, USA. ndarmani@westernu.edu
McClanahan
Bryan A
BA
Trinh
Chung
C
Petrosino
Stefania
S
Valenti
Marta
M
Di Marzo
Vincenzo
V
D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001593:Benzyl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012788:Shrews; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced
D001095:Arachidonic Acids; D001549:Benzamides; D001593:Benzyl Compounds; D002219:Carbamates; D018491:Dopamine Agonists; D063388:Endocannabinoids; D005989:Glycerides; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; C474344:OMDM-1 cpd; D011838:Radiation-Sensitizing Agents; C114007:arachidonoylserotonin; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D012701:Serotonin; C094503:glyceryl 2-arachidonate; D001058:Apomorphine; D002945:Cisplatin