We have evaluated the effect of cannabinoid drugs, administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.) on upper gastrointestinal transit in control and in croton oil-treated mice.
The cannabinoid agonists, WIN 55,212-2 (2–239 nmol mouse−1) and cannabinol (24–4027 nmol mouse−1), decreased while the CB1 antagonist SR141716A (2–539 nmol mouse−1) increased transit in control mice. WIN 55,212-2, cannabinol and SR141716A had lower ED50 values when administered i.c.v., than when administered i.p. The CB2 antagonist SR144528 (52 nmol mouse−1, i.p.) was without effect.
During croton oil (0.01 ml mouse−1, p.o.)-induced diarrhoea, the ED50 values of i.p.-injected WIN 55,212-2 and cannabinol (but not SR141716A) were significantly decreased (compared to control mice). However, the ED50 values of WIN 55,212-2 were similar after i.p. or i.c.v. administration.
The inhibitory effects of WIN 55,212-2 and cannabinol were counteracted by SR141716A (16 nmol mouse−1, i.p.) but not by SR144528 (52 nmol mouse−1, i.p.) both in control and croton-oil treated mice.
Ganglionic blockade with hexamethonium (69 nmol mouse−1, i.p.) did not modify the inhibitory effect of i.p.-injected cannabinoid agonists either in control or in croton-oil treated mice.
The lower ED50 values of cannabinoid drugs after i.c.v. administration suggest a central (CB1) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism.
British Journal of Pharmacology (2000) 129, 1627–1632; doi:10.1038/sj.bjp.0703265