Receptor mechanism and antiemetic activity of structurally-diverse cannabinoids against radiation-induced emesis in the least shrew.
Xenobiotic cannabinoid CB1/CB2-receptor agonists appear to possess broad-spectrum antiemetic activity since they prevent vomiting produced by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, serotonin 5-HT3-receptor agonists, dopamine D2/D3-receptor agonists and morphine, via the stimulation of CB1-receptors. The purpose of this study was to evaluate whether structurally-diverse cannabinoids [Delta9-THC, (delta-9-tetrahydrocannabinol); (Delta8-THC, delta-8-tetrahydrocannabinol); WIN55,212-2, (R (+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)), methyl] pyrolol [1,2,3-de]-1,4 benzoxazinyl]-(1-naphthalenyl) methenone mesylate); and CP55,940, ((-)-3-[2-hydroxy-4-(1,1-dimethylheptyl]-4-[3-hydroxypropyl] cyclohexane-1-ol)), can prevent radiation-induced emesis. Exposure to total body radiation (0, 5, 7.5 and 10 Gy) caused robust emesis in the least shrew (Cryptotis parva) in a dose-dependent manner (ED50=5.99 (5.77-6.23) Gy) and all animals vomited at the highest tested dose of radiation. In addition, the radiation exposure reduced locomotor behaviors to a significant but mild degree in a non-dose-dependent fashion up to one hour post-treatment. Radiation-induced emesis (10 Gy) was blocked in a dose-dependent manner by the CB1/CB2-receptor agonists with the following ID50 potency order: CP55,940 (0.11 (0.09-0.12) mg/kg)>WIN55,212,2 (3.65 (3.15-4.23) mg/kg)=Delta8-THC (4.36 (3.05-6.22) mg/kg)>Delta9-THC (6.76 (5.22-8.75) mg/kg). Although the greater antiemetic potency and efficacy of Delta8-THC relative to its isomer Delta9-THC is unusual as the latter cannabinoid possesses higher affinity and potency for cannabinoid receptors in functional assays, the current data support the results of a clinical study in children suggestive of complete protection from emesis by Delta8-THC. This effect has not been clinically observed for Delta9-THC in cancer patients receiving chemo- or radiation-therapy. Cannabinoids prevented the induced emesis via the stimulation of cannabinoid CB1-receptors because the CB1 (SR141716A)--and not the CB2 (SR144528)--receptor antagonist reversed both the observed reduction in emesis frequency and shrew emesis protection afforded by either Delta9-THC or CP55,940 against radiation-induced emesis. These findings further suggest that the least shrew can be utilized as a versatile and inexpensive small animal model to rapidly screen the efficacy of investigational antiemetics for the prevention of radiation-induced emesis.
Darmani
Nissar A
NA
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. ndarmani@westernu.edu
Janoyan
Jano J
JJ
Crim
Jennifer
J
Ramirez
Juan
J
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology* / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D003511:Cyclohexanols / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D005720:Gamma Rays; D008124:Locomotion / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D012788:Shrews; D014839:Vomiting / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
D000932:Antiemetics; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C035731:delta-8-tetrahydrocannabinol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol