Olvanil: a non-pungent TRPV1 activator has anti-emetic properties in the ferret.
Anti-emetic drugs such as the tachykinin NK(1) receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse actions on the cardiovascular system and on temperature homeostasis. In the present investigations using the ferret, we examine if the non-pungent vanilloid, olvanil, has useful anti-emetic properties without adversely affecting behaviour, blood pressure or temperature control. Olvanil (0.05-5 mg/kg, s.c.) was compared to the pungent vanilloid, resiniferatoxin (RTX; 0.1 mg/kg, s.c.), and to the anandamide reuptake inhibitor, AM404 (10 mg/kg, s.c.), for a potential to inhibit emesis induced by apomorphine (0.25 mg/kg, s.c.), copper sulphate (50 mg/kg, intragastric), and cisplatin (10 mg/kg, i.p.). Changes in blood pressure and temperature were also recorded using radiotelemetry implants. In peripheral administration studies, RTX caused transient hypertension, hypothermia and reduced food and water intake, but also significantly inhibited emesis induced by apomorphine, copper sulphate, or cisplatin. Olvanil did not have a similar adverse profile, and antagonised apomorphine- and cisplatin-induced emesis but not that induced by copper sulphate. AM404 reduced only emesis induced by cisplatin without affecting other parameters measured. Following intracerebral administration only olvanil antagonised cisplatin-induced emesis, but this was associated with transient hypothermia. In conclusion, olvanil demonstrated clear anti-emetic activity in the absence of overt cardiovascular, homeostatic, or behavioural effects associated with the pungent vanilloid, RTX. Our studies indicate that non-pungent vanilloids may have a useful spectrum of anti-emetic properties via central and/or peripheral mechanisms after peripheral administration.
Chu
Kit-Man
KM
Emesis Research Group, Brain-Gut Laboratory, Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
Ngan
Man-Piu
MP
Wai
Man-Keung
MK
Yeung
Chi-Kong
CK
Andrews
Paul L R
PL
Percie du Sert
Nathalie
N
Rudd
John A
JA
D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001058:Apomorphine; D001095:Arachidonic Acids / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin; D019327:Copper Sulfate; D004224:Diterpenes / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism*; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy*
D000932:Antiemetics; D001095:Arachidonic Acids; D004224:Diterpenes; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C054256:olvanil; C024353:resiniferatoxin; D019327:Copper Sulfate; D001058:Apomorphine; D002945:Cisplatin; D002211:Capsaicin; C107594:N-(4-hydroxyphenyl)arachidonylamide