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.
Eur J Pharmacol. 2014 Jan 5;722:147-55. doi: 10.1016/j.ejphar.2013.08.051. Epub 2013 Oct 22.
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.
先前的研究表明，大麻素 CB1/2 和香草素 TRPV1 激动剂（分别为 δ-9-四氢大麻酚（Δ(9)-THC）和树脂毒素（RTX））可以减轻顺铂等化疗药物的呕吐作用。在这项研究中，我们使用least shrew 来证明不同剂量 Δ(9)-THC 与 RTX 的组合是否可以对顺铂引起的呕吐产生相加的止吐效果。RTX 本身以钟形剂量依赖性方式引起呕吐，皮下（s.c.）给药时最大呕吐剂量为 18 μg/kg，但腹腔内（i.p.）给药时无呕吐。高达 10 mg/kg 的 Δ(9)-THC 仅能提供 80%的 least shrew 对顺铂引起的呕吐的保护，半数有效剂量（ID50）为 0.3-1.8 mg/kg。1 或 5 μg/kg 的 RTX 与不同剂量的 Δ(9)-THC 组合完全抑制了 least shrew 的呕吐频率和百分比，其半数有效剂量（ID50）值比单独使用 Δ(9)-THC 对抗顺铂的剂量低 5-50 倍。一种较弱的 TRPV1 激动剂辣椒素（capsaicin）本身不会引起呕吐（i.p.或 s.c.），但它会显著减少 30 分钟后给予顺铂引起的呕吐，但不会减少 2 小时后的呕吐。TRPV1 受体拮抗剂钌红（ruthenium red）在 5mg/kg 时可减轻顺铂引起的呕吐；然而，另一种 TRPV1 受体拮抗剂辣椒素（capsazepine）则不能。总之，我们提供的证据表明，CB1/2 和 TRPV1 激动剂的组合具有在单独使用时无效的剂量下完全消除顺铂引起的呕吐的能力。
