The effect of cyclosporine on the development and expression of cannabinoid tolerance in mice.

Cyclosporine, beside its immunosuppressive action, has several effects on different neuronal functions, such as modulation of neurotransmitter release, the inhibition of nitric oxide synthesis and release, the reduction of cAMP production and inhibition of morphine-induced tolerance. In the present study, the effect of cyclosporine on the expression and development of tolerance to WIN 55,212-2, a cannabinoid receptor agonist, was studied. Intra peritoneal (i.p.) injection of WIN 55,212-2 (2-6 mg/kg) induced time-dependent and dose-dependent analgesia and catalepsy in mice. Administration of cyclosporine (20 mg/kg i.p.), 30 min before WIN 55,212-2 (6 mg/kg i.p.), did not change the analgesic and cataleptic effects of WIN 55,212-2. When WIN 55,212-2 (6 mg/kg i.p.) was injected once a day, animals became completely tolerant to the analgesic and cataleptic effects within five and nine days respectively. Cyclosporine (20 mg/kg i.p.) injected once daily, 30 min before WIN 55,212-2, attenuated the development of tolerance to the analgesic and cataleptic effects of WIN 55,212-2 but did not affect the expression of tolerance. Since cyclosporine given chronically by itself did not alter the analgesia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest cyclosporine may act with some selectivity on the mechanisms involved in development of cannabinoid tolerance.