Receptor mechanism and antiemetic activity of structurally-diverse cannabinoids against radiation-induced emesis in the least shrew.

Abstract

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.

• Authors: Nissar A Darmani, Jano J Janoyan, Jennifer Crim, Juan Ramirez
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 563 Issue 1-3 Pg. 187-96 (Jun 01 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17362921 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiemetics
• Benzoxazines
• Cannabinoids
• Cyclohexanols
• Morpholines
• Naphthalenes
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• delta-8-tetrahydrocannabinol
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
• Dronabinol
• 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

Topics

• Animals
• Antiemetics (pharmacology, therapeutic use)
• Benzoxazines (pharmacology)
• Cannabinoids (pharmacology, therapeutic use)
• Cyclohexanols (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Dronabinol (analogs & derivatives, pharmacology)
• Gamma Rays
• Locomotion (drug effects)
• Morpholines (pharmacology)
• Naphthalenes (pharmacology)
• Receptor, Cannabinoid, CB1 (agonists, metabolism)
• Receptor, Cannabinoid, CB2 (agonists)
• Shrews
• Vomiting (etiology, metabolism, physiopathology, prevention & control)