DOSE-DEPENDENT EFFECTS ON VENTILATION AT REST INDUCED BY HIGH DOSES OF CANNABINOIDS IN RATS

Rationale: Delta-9-tetrahydrocannabinol, the major psychoactive compound of cannabis, profoundly affects neuronal and physiological functions by binding with specific G protein-coupled receptors. The major receptor subtype CB1 is distributed throughout the central nervous system. In rats, CB1 receptor density is much higher in substantia nigra pars reticulate than in amygdala, thalamus, hypothalamus and brain stem (low receptor density). The low distribution in respiratory centres may account for the limited data on respiratory effects of these compounds. The effects of cannabinoids on ventilation at rest have not been determined in awake rats. Objectives: The aim of this study was to assess the ventilatory effects of high doses of cannabinoids in rats at rest. Methods: Male Sprague-Dawley rats received delta-9-tetrahydrocannabinol or WIN55,212-2, at equimolar ascending doses (0.32; 0.95; 3.2; 9.5; 32 or 95 mu mol/kg) by intraperitoneal route. Ventilation at rest was assessed using whole-body plethysmography and temperature using infra-red telemetry. Main results: Natural (delta-9-tetrahydrocannabinol) and synthetic (WIN55,212-2) cannabinergic agonists cause a significant decrease in temperature 15 min after injection (32 mu mol/kg) which plateaued during all the study period. Cannabinoids induced a decrease in respiratory frequency resulting from an increase in inspiratory and expiratory time. We observed no significant changes in tidal and minute volumes for the two compounds. Delta-9-tetrahydrocannabinol and WIN55,212-2 (0.32-95 mu mol/kg) dose-dependently decreased respiratory frequency. Hypothermia appeared with doses lower than those needed to cause ventilatory effects. Conclusions: Hypothermia is obtained for a dose which remains without effects on ventilation at rest. The decrease in respiratory frequency induced by WIN55,212-2 could be linked to an increased sensitivity of inspiratory time in the neurological command centre of ventilation.