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 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-
4-methylpyrazole-3-carboxamide], 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:
HU-210=
CP55,940=
SR141716A>/=WIN55,212-2>/=delta-9-
tetrahydrocannabinol>
methanandamide=
HU-211=
cannabidiol=2-arachidonoylglycerol. 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).