The mechanism underlying the enhancement of the high-voltage-activated (HVA) Ca2+ current (ICa) after application of baclofen, a GABAB agonist, in neurones of the rat dorsal root ganglia was studied by a combined use of the nystatin perforated patch clamp recording and our rapid superfusion system. Baclofen (50 microM) decreased the peak amplitude of HVA ICa and slowed the onset of the current, i.e. produced a typical G-protein-mediated inhibition of ICa. However, when baclofen was rapidly removed from the medium, the amplitude of the current was rather augmented, exceeding the control value obtained before application of the drug. This enhancement was not due to a shift of the voltage dependence of Ca2+ channel activation or a change in ionic permeability to other ions. The enhancement of HVA ICa by baclofen was sensitive to pertussis toxin treatment. The enhancement was evident during superfusion of baclofen. Since the inhibitory effect of baclofen on HVA ICa was not attenuated, even after a continuous application of baclofen for 10 min, the enhancement was not due to relief from tonic G-protein-mediated inhibition of the current or a desensitization of the GABAB receptor-effector system. An extremely prolonged time course of the enhancement of HVA ICa by baclofen strongly suggests an involvement of some intracellular signal transduction system.