Conduction block is a mechanism of activity-dependent neuronal plasticity, but little is known about its possible neuromodulation. Extensive activity in leech touch (T), pressure (P), and nociceptive (N) mechanosensory neurons results in conduction block of their minor receptive fields. We have examined whether the duration of conduction block could be modulated by the serotonergic Retzius neurons or by application of serotonin (5-HT). Activation of one Retzius cell reduced the duration of conduction block in T and P cell posterior fields, but their anterior fields and N cell fields were unaffected. Perfusion with 5-HT had stronger effects, reducing the duration of conduction block in T, P, and lateral N cells in the posterior fields and either reducing or more often enhancing the expression of conduction block in anterior fields. The effects of 5-HT on posterior fields were blocked by the nonspecific 5-HT antagonist methysergide and were partly suppressed by the 5-HT2 antagonist ketanserin. To determine the site of 5-HT action, the central ganglion or peripheral skin was perfused independently. T and to a greater extent P cells showed a preferential sensitivity to application of 5-HT onto the central ganglion. Interestingly, medial N cells exhibited a progressive decrease in the duration of conduction block during repeated trials ("wind-up") that was unaffected by 5-HT. We conclude that secretion of 5-HT by the Retzius cells has a central modulatory effect on the duration of conduction block in T, P, and lateral N cells.