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Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Δ(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva).
Eur J Pharmacol 2014; 722:147-55EJ

Abstract

Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ(9)-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 Δ(9)-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 18 μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ(9)-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3-1.8 mg/kg. Combinations of 1 or 5 μg/kg RTX with varying doses of Δ(9)-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5-50 times lower than Δ(9)-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 min but not at 2 h. 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 CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually.

Authors+Show Affiliations

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. Electronic address: ndarmani@westernu.edu.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24157976

Citation

Darmani, Nissar A., et al. "Additive Antiemetic Efficacy of Low-doses of the Cannabinoid CB(1/2) Receptor Agonist Δ(9)-THC With Ultralow-doses of the Vanilloid TRPV1 Receptor Agonist Resiniferatoxin in the Least Shrew (Cryptotis Parva)." European Journal of Pharmacology, vol. 722, 2014, pp. 147-55.
Darmani NA, Chebolu S, Zhong W, et al. Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Δ(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva). Eur J Pharmacol. 2014;722:147-55.
Darmani, N. A., Chebolu, S., Zhong, W., Trinh, C., McClanahan, B., & Brar, R. S. (2014). Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Δ(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva). European Journal of Pharmacology, 722, pp. 147-55. doi:10.1016/j.ejphar.2013.08.051.
Darmani NA, et al. Additive Antiemetic Efficacy of Low-doses of the Cannabinoid CB(1/2) Receptor Agonist Δ(9)-THC With Ultralow-doses of the Vanilloid TRPV1 Receptor Agonist Resiniferatoxin in the Least Shrew (Cryptotis Parva). Eur J Pharmacol. 2014 Jan 5;722:147-55. PubMed PMID: 24157976.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Δ(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva). AU - Darmani,Nissar A, AU - Chebolu,Seetha, AU - Zhong,Weixia, AU - Trinh,Chung, AU - McClanahan,Bryan, AU - Brar,Rajivinder S, Y1 - 2013/10/22/ PY - 2013/04/08/received PY - 2013/08/26/revised PY - 2013/08/28/accepted PY - 2013/10/26/entrez PY - 2013/10/26/pubmed PY - 2014/10/1/medline KW - Antiemetic KW - Capsaicin KW - Capsazepine KW - Cisplatin KW - Emesis KW - Least shrew KW - Resiniferatoxin KW - Ruthenium red KW - Δ(9)-THC SP - 147 EP - 55 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 722 N2 - Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ(9)-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 Δ(9)-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 18 μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ(9)-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3-1.8 mg/kg. Combinations of 1 or 5 μg/kg RTX with varying doses of Δ(9)-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5-50 times lower than Δ(9)-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 min but not at 2 h. 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 CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24157976/Additive_antiemetic_efficacy_of_low_doses_of_the_cannabinoid_CB_1/2__receptor_agonist_Δ_9__THC_with_ultralow_doses_of_the_vanilloid_TRPV1_receptor_agonist_resiniferatoxin_in_the_least_shrew__Cryptotis_parva__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(13)00767-X DB - PRIME DP - Unbound Medicine ER -