IN-VIVO CHARACTERIZATION OF A SPECIFIC CANNABINOID RECEPTOR ANTAGONIST (SR141716A) - INHIBITION OF DELTA(9)-TETRAHYDROCANNABINOL-INDUCED RESPONSES AND APPARENT AGONIST ACTIVITY

SR141716A has been described as a cannabinoid receptor antagonist. Thi s study was conducted to determine whether SR141716A was capable of an tagonizing the pharmacological effects of the prototypical cannabinoid agonist Delta(9)-THC. The AD(50) (+/- 95% confidence limits) obtained after a 10-min i.v. pretreatment with SR141716A in measures of hypoac tivity, hypothermia, and antinociception were: 0.12 (0.02-0.66), 0.087 (0.037-0.201), and 0.16 (0.03-1.01) mg/kg, respectively. The effect o f SR141716A lasted up to I hr (antinociception, 10 mg/kg), 4 hr (locom otion, 1 and 3 mg/kg), or 24 hr (hypothermia, 3 mg/kg). Further evalua tion revealed an AD(50) value of 2.7 mg/kg (1.7-4.4) in the PPQ-stretc h procedure. Additionally, the ED(50) (+/- S.E.) of morphine in the ta il-flick antinociception procedure was increased by SR141716A (30 mg/k g, i.v.) from 3.2 (+/- 0.3) to 5.3 (+/- 0.6) mg/kg. Finally, SR141716A produced direct effects on locomotor activity at doses greater than 3 mg/kg. Locomotion was stimulated to more than 200% of control (20 mg/ kg), with an ED(50) value of 4.7 (+/- 1.5) mg/kg. The ED(50) value rep resents stimulation to levels approximately 150% of control. It is not clear whether this pharmacological activity represents an uncharacter ized action of SR141716A, or an index of tonic activity of an endogeno us cannabinergic system. SR141716A will be useful in establishing the biochemical events responsible for the in vivo effects of exogenous ca nnabinoids, as well as in establishing the existence of a putative end ogenous cannabinergic system.