Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D 2/D 3 receptor agonists in the least shrew ( Cryptotis parva)

Abstract

The principal psychoactive component of marijuana, delta-9-tetrahydrocannabinol (Δ 9-THC), suppresses nausea and vomiting in cancer patients caused by chemotherapeutics such as cisplatin. Cisplatin induces vomiting via a number of emetic stimuli, including dopamine. Currently, there is controversy as to whether Δ 9-THC can prevent emesis produced by dopaminergic agonists such as apomorphine. The present investigation utilizes the least shrew to evaluate the antiemetic potential and the cannabinoid receptor by which Δ 9-THC may prevent emesis produced by four dopamine receptor agonists with differing selectivity for D 2 and D 3 receptors, i.e., a nonselective dopamine receptor agonist (apomorphine), a D 2-preferring receptor agonist (quinpirole), and two D 3-preferring receptor agonists (quinelorane and 7-OH DPAT). In addition, relative to its antiemetic doses, the motor suppressive doses of Δ 9-THC in dopamine D 2/D 3-receptor-agonist-treated shrews were also evaluated. Thus, different groups of shrews were injected with either vehicle (V) or varying doses of Δ 9-THC [0.5, 1, 2.5, 5, or 10 mg/kg, intraperitoneal (i.p.)] 10 min prior to administration of a 2 mg/kg dose of one of the four cited D 2/D 3 agonists. Immediately after the last injection, the frequency of vomiting for each shrew was recorded for the next 30 min. To investigate which cannabinoid receptor is involved in the antiemetic action of Δ 9-THC, various doses of the CB 1 receptor antagonist SR 141716A [0, 5, 10, and 20 mg/kg, subcutaneous (s.c.)] were administered to shrews 10 min prior to an injection of a fully effective antiemetic dose of Δ 9-THC (5 mg/kg, i.p.). Ten minutes later, each treated shrew was administered with a 2 mg/kg dose of apomorphine. The emesis frequency was recorded for the next 30 min. For locomotor studies, different groups of shrews received either vehicle or various doses of Δ 9-THC (0, 5, 10, 20, or 30 mg/kg) 10 min prior to an injection of vehicle or a 2 mg/kg dose of one of the four D 2/D 3 receptor agonists. The triad of motor behaviors (spontaneous locomotor activity, total duration of movement, and rearing frequency) were recorded for the next 30 min by a computerized video tracking system. Δ 9-THC dose-dependently attenuated the frequency of emesis as well as fully protecting shrews from vomiting produced by each one of the four cited dopamine D 2/D 3 receptor agonists with ID 50s ranging from 1 to 4 mg/kg. SR 141716A reversed the antiemetic activity of Δ 9-THC against apomorphine-induced emesis. Δ 9-THC also differentially suppressed the triad of motor activities in dopamine D 2/D 3-receptor-agonist-treated shrews with ID 50s ranging from 7 to 21 mg/kg. The results suggest that Δ 9-THC prevents emesis via cannabinoid CB 1 receptors in a potent and dose-dependent manner in D 2/D 3-receptor-agonist-treated shrews at doses well below those which cause significant motor depression.