Sensitivity to 5‐hydroxytryptamine in different afferent subpopulations within mesenteric nerves supplying the rat jejunum

Abstract

5_Hydroxytryptamine (5_HT) has widespread actions within the gastrointestinal tract with effects on both neural and non-neural target tissue. We have recently demonstrated that 5_HT stimulates mesenteric afferent nerve bundles supplying the rat jejunum via two different 5_HT receptor subtypes which appear to be located on two distinct populations of neurones innervating the intestine (Hillsley, Kirkup & Grundy, 1998). The most dramatic action of 5_HT is due to the stimulation of 5_HT× receptors since the 5_HT response can be mimicked by the 5_HT× receptor agonist 2_methyl-5_HT and abolished by the 5_HT× receptor antagonist granisetron. This is likely to be a direct action on the afferent nerve terminal since the response to 5_HT persisted after treatment with L_ and N-type calcium channel blockers (Hillsley et al. 1998) However, in approximately one-third of mesenteric bundles, this initial response was followed by a secondary response to 5_HT that was mediated by 5_HT2A receptors and attenuated by nifedipine, which also blunted the mechanical response to 5_HT (Hillsley et al. 1998 1. This study was performed to elucidate the type of afferents that mediate the multiple actions of 5_hydroxytryptamine (5_HT) on mesenteric nerve discharge. Electrophysiological recordings were made from mesenteric afferents innervating the mid-jejunum of the urethane-anaesthetized rat. The discharge of single nerves within the whole nerve recording was monitored using waveform discrimination software. 2. Afferents responded to 5_HT in one of two ways: a short latency, transient excitation mediated by 5_HT× receptors, or a delayed onset, more prolonged effect that was 5_HT2A receptor mediated. Afferents showing the 5_HT×-mediated response did not respond to luminal distension but were sensitive to intraluminal hydrochloric acid (150 mÒ) in twentyeight of twenty-nine experiments. In eight experiments, the 5_HT×-mediated response was reversibly abolished by a 2 min exposure to intraluminal application of local anaesthetic (2 % Xylocaine). 3. Mechanosensitive afferents which responded to distension (< 10 cmHµO) did not show a 5_HT×-mediated response (P = 0·92, n = 14), and maintained this mechanosensitivity after luminal anaesthesia. Mechanosensitive afferents did show a secondary response to 5_HT that was significantly attenuated by atropine (100-200 ìg kg¢), whereas hexamethonium (8 mg kg¢) had no effect. 4. In animals whose vagal afferent contribution to their mesenteric nerves had been eliminated by chronic truncal vagotomy, the 5_HT×-mediated response was absent in thirty-six of thirty-six nerve bundles. In contrast, mechanosensitivity to distension and the secondary response to 5_HT could still be evoked. 5. These results suggest that 5_HT stimulates mesenteric afferents by a direct action on 5_HT×receptors that are present on vagal mucosal afferent terminals. The mucosal afferent response to luminal acid, however, was unaffected by treatment with granisetron (0·5 mg kg¢) indicating that endogenous 5_HT from enterochromaffin cells...

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