Direct and indirect actions of 5‐hydroxytryptamine on the discharge of mesenteric afferent fibres innervating the rat jejunum

1 This study was performed to elucidate the actions of 5‐hydroxytryptamine (5‐HT) on mesenteric afferent discharge and to determine the receptor‐mechanisms responsible for these effects. The activity of mesenteric afferents innervating the mid‐jejunum of urethane‐anaesthetized rats was recorded with extracellular microelectrodes. The discharge of single nerves within the whole nerve recording was monitored using waveform discriminator software. 2 The intravenous injection of 5‐HT produced a complex pattern of afferent activation with two distinct components which could be distinguished both in terms of the response characteristics and the receptors involved. Initially, in 64 % of nerve bundles, there was a brief ( 2.0 ± 0.1 s) but intense activation of afferent discharge with peak afferent firing increasing with incremental doses of 5‐HT. The discharge frequency in seventeen single units from these bundles during the initial response to 10 μg 5‐HT was 13.0 ± 1.8 impulses s −1 from a baseline discharge of 1.0 ± 0.1 impulses s −1 . 3 This initial response was mimicked by the 5‐HT 3 receptor agonist, 2‐methyl‐5‐HT, whereas 5‐methoxytryptamine (5‐MEOT, 10–100 μg) had no comparable effect. Similarly, the initial 5‐HT response was completely abolished by the 5‐HT 3 receptor antagonist, granisetron (0.5 mg kg −1 ). 4 5‐HT also evoked, in approximately 35 % of nerve bundles, a delayed response that single unit analysis showed to be mediated by an entirely different population of afferents from those activated during the initial response. This secondary response to 5‐HT was characterized by a more prolonged (> 30 s) but less intense period of afferent activity which was coincident with an increase in intrajejunal pressure, and was mimicked by 5‐MEOT (10–100 μg). 5 The secondary response to 5‐HT and the response to 5‐MEOT were significantly attenuated by the 5‐HT 2A receptor antagonist, ketanserin (0.5 mg kg −1 ), which had no effect on the initial response. 6 The initial response to 5‐HT was unaffected by the L‐type calcium channel inhibitor nifedipine (1 mg kg −1 ) or the N‐type calcium channel inhibitor ω‐conotoxin GVIA (25 μg kg −1 ). However, the secondary response to 5‐HT was significantly reduced after treatment with nifedipine. 7 These results demonstrate that 5‐HT activates different populations of afferent fibres innervating the rat jejunum. One population of afferents is activated directly via stimulation of 5‐HT 3 receptors, while another population responds to 5‐HT with a time course consistent with secondary activation of mechanosensitive afferents following 5‐HT 2A ‐mediated contractile activity.