It has recently become necessary to extend our concept of how information flow in the spinal cord is regulated presynaptically. Classical presynaptic inhibition occurs at terminals of primary afferent axons and is mediated through interneurons that release GABA at axo-axonic synapses. The release of GABA is associated with a depolarisation of the primary afferent terminal (PAD). Although PAD-like phenomena have been recorded from terminals of some classes of interneuron, there is no evidence that axo-axonic synapses are present on interneuron terminals. Nevertheless the discovery that receptors are present not only on primary afferent axon terminals but also on terminals of interneurons, along with the acceptance of volume transmission as a mode of signalling in the CNS, suggests that some form of presynaptic regulation is likely to occur at terminals of interneurons. Recently, we examined the organisation of two classes of receptor that are activated by descending monoamine systems: the α2c adrenergic receptor (α2c –AR) and the 5-HT3 serotonin receptor. The α2c–AR, (unlike the α2A–AR which is present on primary afferents) is found principally on terminals of spinal interneurons. The majority (84%) of these interneurons are excitatory but a small group (11%) is inhibitory. A proportion of α2C-AR-immunoreactive terminals also contain peptides such as enkephalin, somatostatin, neurotensin, neuropeptide Y but they are not present on noradrenergic terminals and thus do not function as autoreceptors. Excitatory axons that possess the α2c–AR target projection cells in lamina I that are immunoreactive for the neurokinin 1 (NK-1) receptor. Therefore noradrenaline appears to modulate excitatory synaptic transmission from spinal interneurons to projection cells by acting at α2C-ARs; this could be one of the mechanisms that underlie its antinociceptive action. Serotonin 5-HT3 receptors are present on primary afferent terminals and terminals of interneurons. This receptor is found on excitatory terminals. Like the α2c–AR axons, axons possessing the 5-HT3 receptor also form synaptic relationships with lamina 1 projection cells. However, serotonin probably facilitates excitatory transmission at such synapses and has a pronociceptive action when it acts through 5-HT3 receptors. Thus sensory transmission is not only regulated presynaptically at primary afferent synapses in the spinal cord but is also regulated presynaptically at synapses formed by interneurons which are components of polysynaptic pathways.