A number of in vitro preparations of the central nervous system have been used to characterize with intracellular recording the cellular actions of four neuropeptides. Carnosine, the putative excitatory neurotransmitter of olfactory nerves, was found to exert little or no effect in the turtle or the frog olfactory bulb, suggesting that this peptide may have other roles, e.g. neurotropic, in this system. Substance P and TRH were found to have some characteristics of a classical excitatory transmitter since they increase membrane conductance and depolarize frog motoneurons by a direct action. However, the slow time course and subthreshold nature of the depolarization may imply that these peptides function in a background manner to set the level of excitability of motoneurons. Finally, the effects of enkephalin on a variety of inhibitory systems have been examined. Enkephalin excites hippocampal pyramidal cells indirectly by blocking both spontaneous and evoked inhibitory potentials. In addition, both feedforward and feedback inhibitory pathways are depressed by enkephalin. All these effects are blocked by naloxone. Blockade of inhibitory pathways by enkephalin appears to be a general phenomenon, since similar depressant effects were seen for dendrodendritic inhibition in olfactory bulb mitral cells as well as for presynaptic inhibition of spinal primary afferents. These results indicate that neuroactive peptides can affect principal neurons by increasing their excitability via either subthreshold excitation or disinhibition. Our results, along with those of others (MacLeod & Straughan 1979; Harding & O'Fallon 1979), cast doubt on a neurotransmitter role for carnosine at olfactory nerve synapses. However, it should be kept in mind that the detailed biochemical studies have been done in mouse, while the present physiological experiments have been carried out in frog and turtle. There are other possible roles that such a molecule might have. It might be involved in development. The formation and maintenance of olfactory nerve synapses, the growth of dendrites, or the induction of postsynaptic transmitter receptors might be influenced by carnosine. In this context, it has recently been shown that a small molecule, possibly a peptide, is released from spinal cord neurons and induces acetylcholine receptors on cultured skeletal muscle (Jessell et al. 1979). These results suggest that SP and TRH have some characteristics of classic excitatory neurotransmitters since they increase membrane conductance and depolarize the cell. These effects appear to be direct because they persist when synaptic transmission is blocked. However, the slow time course and subthreshold nature of the peptide depolarization may imply that these peptides function in a background manner to set the level of excitability of motoneurons. They may thereby facilitate transmission along powerful, fast-conducting excitatory pathways that subserve basic reflex activity. We have found that excitatory opiate effects on principal cells in various parts of the vertebrate c.n.s. appear to be largely indirect, and actually occur as the results of disinhibition. We have shown that several forms of inhibition in different regions of the c.n.s. are selectively attentuated by DALA. These include feedforward and recurrent inhibition of hippocampal CA1 pyramidal cells, dendrodendritic postsynaptic inhibition of olfactory bulb mitral cells, and presynaptic inhibition of spinal primary afferents. Such a disinhibitory mechanism at supraspinal sites could help explain the epileptic activity seen following administration of opioid peptides (Henriksen et al. 1978; Frenk et al. 1978). Furthermore, the present findings suggest that disinhibition may be an important general mechanism of opioid action in the c.n.s. and that inhibitory interneurons may be primary targets of enkephalin-containing fibre systems. Very small changes in the release of enkephalin would, by modifying the spontaneous activity of inhibitory interneurons, result in profound changes in the transmission through principal neurons and primary afferents. The direct effects of opiates, which are presumably on inbibitory interneurons, remain to be investigated.