A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: evidence from the least shrew.
Although the neurotransmitter basis of chemotherapy-induced vomiting (CIV) is thought to be multifactorial, it is generally accepted that acute (immediate) CIV is mainly due to the release of serotonin (5-HT) within the gastrointestinal tract, while the delayed phase occurs following substance P (SP) release in the brainstem. The aim of the current study was to test this dogma in the least shrew model of vomiting. Thus, we initially investigated the temporal development of cisplatin's immediate and delayed emetic effects in the least shrew and subsequently determined the concomitant changes in the turnover of major emetic neurotransmitters both in the central and peripheral loci associated with CIV. Cisplatin (0, 5, 10 and 20 mg/kg, i.p.) caused dose- and time-dependent emetic effects. A 10 mg/kg dose of cisplatin produced both phases of emesis with corresponding peak mean frequencies occurring at 2-3 and 33 h post-treatment, at 5 mg/kg it failed to cause significant emesis in either phase, while its 20 mg/kg dose induced both phases earlier but toxicity restricted the full 47 hour observation. Cisplatin (10 mg/kg, i.p.)-induced peak immediate and delayed phases were associated with concomitant increases in the turnover of 5-HT, dopamine and SP in both the shrew brainstem and jejunum. The discussed increases during both phases appear to be site specific since neurotransmitter release was not persistently altered in the shrew frontal cortex or duodenum, although occasionally increases or decreases did occur. Our findings suggest that the least shrew appears to be a sensitive and rapid emesis model for both phases of CIV, and both emetic phases are associated with specific increases in the release of all of the cited neurotransmitters in both the brainstem and jejunum. Thus, the generally accepted neurotransmitter dogma needs to be updated since more recent neurochemical studies in humans as well as other clinical findings support the current basic results obtained in the least shrew.
Darmani
Nissar A
NA
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA. ndarmani@westernu.edu
Crim
Jennifer L
JL
Janoyan
Jano J
JJ
Abad
Joseph
J
Ramirez
Juan
J
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000009:adverse effects*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D004639:Emetics; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012788:Shrews; D013373:Substance P / Q000378:metabolism; D014839:Vomiting / Q000139:chemically induced*
D000970:Antineoplastic Agents; D004639:Emetics; D018377:Neurotransmitter Agents; D012701:Serotonin; D013373:Substance P; D002945:Cisplatin; D004298:Dopamine; D006719:Homovanillic Acid