title: Delta 9-tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew.
abstract: Cisplatin chemotherapy frequently causes severe vomiting in two temporally separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both the emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB(1), CB(2)), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10mg/kg i.p.), and one of vehicle, Delta(9)-THC, or both Delta(9)-THC and the CB(1) receptor antagonist SR141716A (2mg/kg i.p.), and monitored for vomiting. Delta(9)-THC-pretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fos-immunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB(1) receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB(2) receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin- and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Delta(9)-THC mediated by CB(1) receptors.
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
authors: Andrew P
authors: AP
authors: Ray
authors: Lisa
authors: L
authors: Griggs
authors: Nissar A
authors: NA
authors: Darmani
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D031608:Area Postrema / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin; D013759:Dronabinol / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D000077285:Rimonabant; D012701:Serotonin / Q000378:metabolism; D012788:Shrews; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D018712:Analgesics, Non-Narcotic; D016761:Oncogene Proteins v-fos; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D012701:Serotonin; D013373:Substance P; D013759:Dronabinol; D002945:Cisplatin; D000077285:Rimonabant