Previous studies have shown that cannabinoid CB_1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ⁹-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Δ⁹-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ⁹-THC up to 10mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID₅₀ of 0.3-1.8mg/kg. Combinations of 1 or 5μg/kg RTX with varying doses of Δ⁹-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID₅₀ dose values 5-50 times lower than Δ⁹-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30 minutes but not at 2 hours. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5mg/kg; however another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB_1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually.
© 2013 Published by Elsevier B.V.

PMID:

 

24157976

 

[PubMed – as supplied by publisher]