Differential effects of dexamethasone, ondansetron and a tachykinin NK1 receptor antagonist (GR205171) on cisplatin-induced changes in behaviour, food intake, pica and gastric function in rats.
This study aimed to dissect the mechanisms involved in malaise induced by the anti-cancer drug cisplatin by attempting to uncouple its effects on locomotor activity, arguably at least partly indicative of fatigue, from those effects indicative of emesis (pica, gastric stasis, reduced food intake) using pharmacological agents in the rat. Over 2 days cisplatin (6 mg/kg i.p.) reduced food intake, stimulated kaolin consumption, increased the wet weight of gastric contents and reduced locomotor activity. In animals treated with cisplatin: the 5-HT3 receptor antagonist ondansetron (1 mg/kg s.c. bd.) had no effect on either activity or weight of gastric contents but did increase food intake on day 1 (P<0.05) and the total over both days (27.6+/-1.8 vs. 19.9+/-2.3g, P<0.05), reducing kaolin consumption on day 2 (P<0.01) but not the total over both days; the NK1 receptor antagonist GR205171 (1 mg/kg s.c. bd.) was without effect on activity, but reduced the wet weight of gastric contents (P<0.05), increased food intake on day 2 (P<0.01) and total consumption over both days (28.1+/-1.7 g vs. 19.9+/-2.3 g; P<0.05) and reduced kaolin consumption on day 2 (P<0.05) but not over both days; dexamethasone (2 mg/kg s.c. bd.) blocked the cisplatin-induced reduction in activity on days 1 and 2 (P<0.01), reduced the wet weight of gastric contents by 43% (P<0.01), reduced kaolin consumption on both days (P<0.01) and arguably decreased the reduction in food intake caused by cisplatin. This study has revealed novel insights into the different spectra of activities of 5-HT3 and NK1 receptor antagonists and dexamethasone, which have implications for therapeutic strategies to alleviate the emetic, anorectic, dyspeptic and activity-reducing effects of anti-cancer chemotherapy.
Malik
Nasser M
NM
Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London SWl7 ORE, UK.
Liu
Yong-Ling
YL
Cole
Nicholas
N
Sanger
Gareth J
GJ
Andrews
Paul L R
PL
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D003907:Dexamethasone / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009325:Nausea / Q000139:chemically induced / Q000188:drug therapy*; D064729:Neurokinin-1 Receptor Antagonists; D017294:Ondansetron / Q000494:pharmacology; D010842:Pica / Q000139:chemically induced / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D000932:Antiemetics; D000970:Antineoplastic Agents; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D013777:Tetrazoles; D017294:Ondansetron; D003907:Dexamethasone; C103207:vofopitant; D002945:Cisplatin