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

K. Hillsley, A. J. Kirkup and D. Grundy

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-HT₃ 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-HT₃ 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 -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-HT₃ 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.

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