DIRECT AND INDIRECT ACTIONS OF 4-HYDROXYTRYPTAMINE ON THE DISCHARGE OF MESENTERIC AFFERENT-FIBERS INNERVATING THE RAT JEJUNUM

1. This study was performed to elucidate the actions of 5-hydroxytrypt amine (5-HT) on mesenteric afferent discharge and to determine the rec eptor-mechanisms responsible for these effects. The activity of mesent eric afferents innervating the mid-jejunum of urethane-anaesthetized r ats was recorded with extracellular microelectrodes. The discharge of single nerves within the whole nerve recording was monitored using wav eform discriminator software. 2. The intravenous injection of 5-HT pro duced a complex pattern of afferent activation with two distinct compo nents which could be distinguished both in terms of the response chara cteristics and the receptors involved. Initially, in 64% of nerve bund les, there was a brief (2.0 +/- 0.1 s) but intense activation of affer ent discharge with peak afferent firing increasing with incremental do ses of 5-HT The discharge frequency in seventeen single units from the se bundles during the initial response to 10 mu g 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 agonis t, 2-methyl-5-HT, whereas 5-methoxytryptamine (5-MEOT, 10-100 mu g) ha d no comparable effect. Similarly: the initial 5-HT response was compl etely 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 a n entirely different population of afferents from those activated duri ng the initial response. This secondary response to 5-HT was character ized by a more prolonged (> 30 s) but less intense period of afferent activity which was coincident with an increase in intrajejunal pressur e, and was mimicked by 5-MEOT (10-100 mu g). 5. The secondary response to 5-HT and the response to 5-MEOT were significantly attenuated by t he 5-HT2A receptor antagonist, ketanserin (0.5 mg kg(-1), which had no effect on the initial response. 6. The initial response to 5-HT was u naffected by the L-type calcium channel inhibitor nifedipine (1 mg kg( -1)) or the N-type calcium channel inhibitor omega-conotoxin GVIA (25 mu g kg(-1)). However, the secondary response to 5-HT was significantl y reduced after treatment with nifedipine. 7. These results demonstrat e that 5-HT activates different populations of afferent fibres innerva ting the rat jejunum. One population of afferents is activated directl y via stimulation of 5-HT3 receptors, while another population respond s to 5-HT with a time course consistent with secondary activation of m echanosensitive afferents following 5-HT2A-mediated contractile activi ty.