Neurotransmission in isolated hemisected spinal cord preparations from immature rats was depressed by micromolar levels of baclofen (threshold 0.5 microM). The depressant action of baclofen was not antagonised by bicuculline and baclofen, unlike GABA, did not depolarize primary afferent fibres. Neurotransmission in isolated vas deferens, anococcygeus muscle and superior cervical ganglion of the rat was unaffected by baclofen (0.1-1 mM). Depolarization of motoneurones, as recorded in ventral roots of tetrodotoxin-blocked spinal cord preparations, induced by excitant amino acids, substance P, noradrenaline or carbachol was unaffected by baclofen (250 microM or higher). The depressant action of baclofen on spinal cord preparations was similar to that produced by the excitant amino acid antagonist alpha,epsilon-diaminopimelic acid. A structure-activity study showed that the (--)-isomer of baclofen was over 20 times more potent than the (+)-isomer as a spinal depressant. Also the position and nature of the halogen substitutent in the ring is critical with baclofen giving optimal activity. It is concluded that the depressant action of baclofen from depression of the presynaptic release of excitant amino acid transmitter(s).