The vagus nerve conveys primary afferent information produced by a meal to the brainstem. Serotonin (5‐HT), which abounds in intestinal enterochromaffin cells, is released in response to various stimuli. We have recently demonstrated that 5‐HT released from intestinal enterochromaffin cells activates 5‐HT3 receptors on vagal afferent fibres to mediate luminal non‐cholecystokinin‐stimulated pancreatic secretion. The present study was designed to evaluate the responses of vagal sensory neurons to intraluminal osmotic stimulation and luminal infusion of maltose, glucose or 5‐HT. We investigated the role of endogenous 5‐HT in signal transmission evoked by luminal stimuli to activate vagal sensory neurons. The discharges of vagal primary afferent neurons innervating the intestine were recorded from rat nodose ganglia. Luminal factors such as intestinal osmotic stimuli and perfusion of carbohydrates elicited powerful vagal nodose responses. Electrical subdiaphragmatic vagal stimulation activated 364 single units; 40 of these responded to intestinal mucosal stimuli. Of these 40, 30 responded to intraduodenal perfusion of hyperosmolar NaCl (500 mosmol l−1), 27 responded to tap water (5 mosmol l−1) and 20 and 19 responded to maltose (300 mM) and glucose (277.5 mM), respectively. The 5‐HT3/4 antagonist tropisetron (ICS 205‐930) or 5‐HT3 antagonist granisetron abolished luminal stimuli‐evoked nodose neuronal responses. Intraluminal infusion of 10−5 and 10−4 M 5‐HT elicited increases in vagal afferent discharge in 25 and 31 units, respectively, by activating the 5‐HT3 receptors. Acute subdiaphragmatic vagotomy, intestinal mucosal application of the local anaesthetic lidocaine (lignocaine) or administration of 5‐HT3 antagonist each abolished the luminal 5‐HT‐induced nodose neuronal responses. In contrast, distension‐sensitive neurons did not respond to duodenal infusion of 5‐HT. Pharmacological depletion of 5‐HT stores using p‐chlorophenylalanine (PCPA), a 5‐HT‐synthesis inhibitor, abolished luminal factor‐stimulated nodose neuronal responses. In contrast, pretreatment with 5,7‐dihydroxytryptamine (5,7‐DHT), a specific 5‐HT neurotoxin that destroys 5‐HT‐containing neurons without affecting 5‐HT‐containing mucosal cells, had no effect on these responses. These results suggested that the nodose neuronal responses to luminal osmolarity and to the digestion products of carbohydrates are dependent on the release of endogenous 5‐HT from the mucosal enterochromaffin cells, which acts on the 5‐HT3 receptors on vagal afferent fibres to stimulate vagal sensory neurons.

SUMMARY BackgroundFunctional dyspepsia (FD) is a common disease without an established optimal treatment.

The anterior cingulate cortex (ACC) is critically involved in processing the affective component of pain sensation. Visceral hypersensitivity is a characteristic of irritable bowel syndrome. Electrophysiological activity of the ACC with regard to visceral sensitization has not been characterized. Single ACC neuronal activities in response to colorectal distension (CRD) were recorded in control, sham-treated rats and viscerally hypersensitive (EA) rats (induced by chicken egg albumin injection, I.P). The ACC neurones of controls failed to respond to 10 or 30 mmHg CRD; only 22% were activated by 50 mmHg CRD. Among the latter, 16.4% exhibited an excitatory response to CRD and were labelled 'CRD-excited' neurones. In contrast, CRD (10, 30 and 50 mmHg) markedly increased ACC neuronal responses of EA rats (10%, 28% and 47%, respectively). CRD produced greater pressure-dependent increases in ACC spike firing rates in EA rats compared with controls. Splanchnicectomy combined with pelvic nerve section abolished ACC responses to CRD in EA rats. Spontaneous activity in CRD-excited ACC neurones was significantly higher in EA rats than in controls. CRD-excited ACC neurones in control and EA rats (7 of 16 (42%) and 8 of 20 (40%), respectively) were activated by transcutaneous electrical and thermal stimuli. However, ACC neuronal activity evoked by noxious cutaneous stimuli did not change significantly in EA rats. This study identifies CRD-responsive neurones in the ACC and establishes for the first time that persistence of a heightened visceral afferent nociceptive input to the ACC induces ACC sensitization, characterized by increased spontaneous activity of CRD-excited neurones, decreased CRD pressure threshold, and increased response magnitude. Enhanced ACC nociceptive transmission in viscerally hypersensitive rats is restricted to visceral afferent input.

Palonosetron is the only 5-HT 3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT 3 receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT 3 crosstalk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dosedependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT 3 receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.