Cannabis has been used for centuries for both symptomatic and prophylactic treatment of migraine. Cortical spreading depression (SD) is believed to be a putative neuronal mechanism underlying migraine aura and subsequent pain. To test the mechanism of canabinoid action, the effect of canabinol as well as cannabinoid CB(1) and CB(2) receptor agonists on SD in rat neocortical tissues was investigated. Canabinol (1-10 microM) dose dependently suppressed SD amplitude and propagation velocity. Cannabinoid CB(1) agonist, WIN 55,212-2 mesylate (0.1-10 microM), also significantly suppressed SD. However, cannabinoid CB(2) agonist, JWH-133 (0.01-10 microM), had no effect on SD characteristics. Furthermore, the effect of cannabinoid CB(1) was tested on excitatory postsynaptic potentials (EPSP) and long-term potentiation (LTP). EPSP were strongly depressed by bath application of WIN55212-2. Cannabinoid CB(1) receptor agonist also significantly reduced LTP. Thus, cannabinoid may exert its effect on SD via inhibition of synaptic plasticity. This may be responsible for the cannabis therapeutic effect on migraine headache.