Population spikes associated with the paired pulse ratio protocol were used to measure the presynaptic inhibition of corticostriatal transmission caused by mu-opioid receptor activation. A 1 microM of [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO), a selective mu-opioid receptor agonist, enhanced paired pulse facilitation by 44+/-8%. This effect was completely blocked by 2 nM of the selective mu-receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-NH (CTOP). Antagonists of N- and P/Q-type Ca(2+) channels inhibited, whereas antagonists of potassium channels enhanced, synaptic transmission. A 1 microM of omega-conotoxin GVIA, a blocker of N-type Ca(2+) channels, had no effect on the action of DAMGO, but 400 nM omega-agatoxin TK, a blocker of P/Q-type Ca(2+)-channels, partially blocked the action of this opioid. However, 5 mM Cs(2+) and 400 microM Ba(2+), unselective antagonists of potassium conductances, completely prevented the action of DAMGO on corticostriatal transmission. These data suggest that presynaptic inhibition of corticostriatal afferents by mu-opioids is mediated by the modulation of K(+) conductances in corticostriatal afferents.