Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)
methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin
via cannabinoid CB(1) receptors. This study investigates the antiemetic potential
of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl)
cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and
functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva)
brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced
emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg).
CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses.
The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A
indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic
studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution
of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent
brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius
(NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid
ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain:
This affinity order is also similar and is highly correlated to the cannabinoid EC(50)
potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol
potency order were reversed. The affinity and the potency rank order of tested cannabinoids
were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced
vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced
by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).