Plasticity in the mesenteric afferent response to cisplatin following vagotomy in the rat

Abstract

The aim of this study was to investigate the actions of the cytotoxic drug cisplatin on populations of mesenteric afferents supplying the rat jejunum. Extracellular whole mesenteric nerve discharge was monitored and the activity of individual single afferent units determined using waveform discriminator software. Baseline whole nerve discharge was 21.5 +/- 3.8 impulses s(-1). Nerve discharge began to increase approximately 10 min after cisplatin administration, reached a plateau around 30 min, and remained elevated at 60 min (35.3 +/- 5.7 impulses s(-1), p < 0.01). Granisetron reversed the increase in nerve activity indicating that the response to cisplatin was mediated by the release of endogenous 5-HT acting on 5-HT3 receptors. Single afferent units, selected by waveform analysis on the basis of their response to exogenous 5-HT, showed a similar time course of activation following cisplatin. In contrast, the discharge frequency of afferent units that were insensitive to 5-HT was unaffected by cisplatin or granisetron. The sensitivity of mesenteric afferent bundles to exogenous 5-HT was absent in chronically vagotomized animals. However, cisplatin elicited an increase in nerve discharge in vagotomized animals that was not different from control (34.6 +/- 8.9 impulses s(-1)) but this increase was unaffected by treatment with granisetron. Thus, after vagotomy there is a switch from 5-HT3 mediated activation of vagal afferents to a 5-HT3-independent activation of non-vagal (possibly splanchnic) afferents. Since this later mechanism of activation is absent in control animals, it appears that there is plasticity in the gastrointestinal afferent sensitivity to cisplatin.