The effects of the centrally acting muscle relaxant tizanidine (DS 103-282) have been examined on the responses of laminae IV and V dorsal horn neurones to peripheral noxious and non-noxious stimuli in cats spinalized at L1. Iontophoretic ejection of tizanidine near the cell bodies of the recorded neurones or more dorsally into laminae II-III resulted in a marked and prolonged depression of excitation of laminae IV and V neurones evoked by noxious stimuli. Spontaneous firing was also depressed in many neurons but responses to innocuous stimuli were unaffected. Intravenous administration of tizanidine also produced a long lasting and selective reduction in responses of laminae IV and V neurones to noxious stimuli and depressed the long latency excitation of these neurones evoked by electrical stimulation of small diameter unmyelinated primary afferents. In contrast to the selective antinociceptive effect of tizanidine, ejection of gamma-aminobutyric acid (GABA) near laminae IV and V neurones or isoguvacine into laminae II-III produced parallel reductions in responses to noxious and non-noxious stimuli. Furthermore, ejections of the excitant amino acid kainate into laminae II-III produced parallel enhancement of responses induced by both types of stimuli. The site and mechanism of the antinociceptive action of tizanidine is not known but does not appear to involve an interaction with opiate receptors as it was not antagonized by naloxone. The possibility is discussed that tizanidine acts at synapses formed between excitatory interneurones in lamina II or III and laminae IV and V neurones, either interfering with transmitter release or its postsynaptic action. The effects of iontophoretically administered tizanidine are quite distinct from those of baclofen, which produced non-selective depression of responses to both noxious and innocuous stimuli, but were similar to those of noradrenaline. This raises the possibility that noradrenaline and tizanidine may act at a common site in the spinal cord.