Role Of 5-HT3 Receptors Research Articles

Amisulpride promotes cognitive flexibility in rats: The role of 5-HT7 receptors

The antagonism of 5-HT7 receptors may contribute to the antidepressant and procognitive actions of the atypical antipsychotic drug, amisulpride. It has been previously demonstrated that the selective 5-HT7 receptor antagonist reversed restraint stress-induced cognitive impairments in a rat model of frontal-dependent attentional set-shifting task (ASST). Therefore, the first aim of the present study was to assess the effectiveness of amisulpride against stress-evoked cognitive inflexibility. The second goal was to elucidate whether the pro-cognitive effect of amisulpride could be due to the compound's action at 5-HT7 receptors.Rats repeatedly exposed (1h daily for 7 days) to restraint stress demonstrated impaired performance on the extra-dimensional (ED) set-shifting stage of the ASST. Amisulpride (3mg/kg) given to stressed rats 30min before testing reversed this restraint-induced cognitive inflexibility and improved ED performance of the unstressed control group. The 5-HT7 receptor agonist, AS19 (10mg/kg), abolished the pro-cognitive efficacy of amisulpride (3mg/kg).The present study suggests that the antagonism of 5-HT7 receptors may contribute to the mechanisms underlining the pro-cognitive action of amisulpride. These results may have therapeutic implications in frontal-like deficits associated with stress-related disorders.

P038 Role of 5-HT3 receptors in the anti-inflammatory effects of alosetron in a rat model of colitis

P038 Role of 5-HT3 receptors in the anti-inflammatory effects of alosetron in a rat model of colitis

5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice

The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT7 receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT7 receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1–3/4weeks (thermal hyperalgesia) and prolonged at 6–7weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10mg/kg, systemic injections of AS-19, a selective 5-HT7 receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT7 receptor antagonist, at a dose that had no effect on its own (10mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT7 receptor agonists may have clinical utility in treating diabetic neuropathic pain.

The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: The role of 5-HT3 receptors

Tianeptine is an unusual tricyclic antidepressant drug. In this study, we aimed to investigate the antinociceptive effect of tianeptine on visceral pain in rats and to determine whether possible antinociceptive effect of tianeptine is mediated by serotonergic (5-HT2,3) and noradrenergic (α1,2) receptor subtypes. Male Sprague Dawley rats (250–300g) were supplied with a venous catheter, for drug administrations, and enameled nichrome electrodes, for electromyography, at external oblique musculature. Colorectal distension (CRD) was employed as the noxious visceral stimulus and the visceromotor response (VMR) to CRD was quantified electromyographically before and 5, 15, 30, 60, 90 and 120min after tianeptine administration. Antagonists were administered 10min before tianeptine for their ability to change tianeptine antinociception. Intravenous administration of tianeptine (2.5–20mg/kg) produced a dose-dependent reduction in VMR. Administration of 5-HT3 receptor antagonist ondansetron (0.5, 1 and 2mg/kg), but not 5-HT2 receptor antagonist ketanserine (0.5, 1 and 2mg/kg), reduced the antinociceptive effect of tianeptine (10mg/kg). In addition, administration of α1-adrenoceptor antagonist prazosin (1mg/kg) or α2-adrenoceptor antagonist yohimbine (1mg/kg) did not cause any significant effect on the tianeptine-induced antinociception. Our data indicate that intravenous tianeptine exerts a pronounced antinociception against CRD-induced visceral pain in rats, and suggests that the antinociceptive effect of tianeptine appears to be mediated in part by 5-HT3 receptors, but does not involve 5-HT2 receptors or α-adrenoceptors.

5-HT2A Receptor Activation Normalizes Exaggerated Fear Behavior in p-Chlorophenylalanine (PCPA)-Treated Rats.

Deficits in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission are implicated in abnormal emotional behaviors such as aggression, anxiety, and depression. However, the specific 5-HT receptor mechanisms involved are not well understood. The role of 5-HT2 receptors in fear potentiated startle, (FPS) was examined in rats chronically treated with p-chlorophenylalanine (PCPA) to reduce brain 5-HT. PCPA-treated rats show an enhanced magnitude of FPS. Systemic administration of the 5-HT2 receptor agonist (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) reduced FPS in both PCPA-treated and saline (SAL)-treated control animals, normalizing the exaggerated fear response in PCPA-treated rats. In both SAL- and PCPA-treated animals, the DOI-induced reduction of learned fear was reversed by the 5-HT2 antagonist ketanserin, but not by the 5-HT2B/2C antagonist SB 206553. Together, these findings suggest 5-HT2A receptors are critical regulators of learned fear, and that 5-HT2A receptors may be an important pharmacological target to normalize exaggerated learned fear resulting from chronic 5-HT-ergic disruption.

Alterations of Central Hypercapnic Respiratory Response Induced by Acute Central Administration of Serotonin Re-Uptake Inhibitor, Fluoxetine

Long-term neurochemical changes are responsible for therapeutic actions of fluoxetine. The role of increased central concentration of serotonin by inhibiting its re-uptake via fluoxetine on the central hypercapnic ventilatory response is complex and little is known. We aimed to research the effect of acute intracerebroventricular (ICV) injection of fluoxetine on hypercapnic ventilatory response in the absence of peripheral chemoreceptor impulses and the role of 5-HT2 receptors on responses. Eighteen anesthetized albino rabbits were divided as Fluoxetine and Ketanserin groups. For ICV administration of fluoxetine and ketanserin, a cannula was placed in the left lateral ventricle by the stereotaxic method. Respiratory frequency (fR), tidal volume (V(T)) and ventilation minute volume (V(E)) were recorded in both groups. ICV fluoxetine (10.12 mmol/kg) injection during normoxia caused significant increases in V(T) and V(E) (both P < 0.01) in the fluoxetine group. When the animals were switched to hypercapnia f/min, V(T) and V(E) increased significantly. The increases in percentage values in V(T) and V(E) in Fluoxetine + Hypercapnia phase were higher than those during hypercapnia alone (P < 0.01 and P < 0.05, respectively). On blocking of 5-HT2 receptors by ketanserin (0.25 mmol/kg), the ventilatory response to Fluoxetine was abolished and the degree of increases in V(T) and V(E) in the Ketanserin + Hypercapnia phase were lower than those during hypercapnia alone (P < 0.01 and P < 0.001, respectively). We concluded that acute central fluoxetine increases normoxic ventilation and also augments the stimulatory effect of hypercapnia on respiratory neuronal network by 5-HT2 receptors in the absence of peripheral chemoreceptor impulses.

Pharmacological Blockade of Serotonin 5-HT7 Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission

The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

Influence of Interleukin-13 in 5-HT Synthesis and Severity of Experimental Colitis

BACKGROUND: Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5hydroxytryptamine, 5-HT) content in the gut. In our previous studies, we have shown that 5-HT plays an important role in the pathogenesis of experimental colitis. Dendritic cells (DC) are important innate immune cells and play a key role in the activation of the immune response and generation of gut inflammation. DCs express the 5-HT7 receptor, and we have recently demonstrated that 5-HT plays an important role in DC activation in relation to gut inflammation. In this study, we have evaluated the effect of inhibiting 5-HT signaling by using a 5-HT7 receptor antagonist or 5-HT7 receptor knockout mice in experimental colitis. METHODS: Mice (C57BL/6) were treated with selective 5-HT7 receptor antagonist SB266970 (40mg/kg, ip) or vehicle (saline) starting one day prior to administration of 5% dextran sulfate sodium (DSS) in drinking water and were sacrificed on day 5 post-DSS to assess the extent of colitis, myeloperoxidase (MPO) activity and pro-inflammatory cytokines. Colitis was also induced in 5-HT7 receptor deficient mice on C57BL/6 background (5HT7KO) and wild type mice either by 5% DSS or intrarectal administration of dinitrobenzene sulfonic acid (DNBS, 5mg/mouse) and were sacrificed on day 5 post-DSS and day 3 postDNBS to assess the extent of colitis, MPO activity and pro-inflammatory cytokines. RESULTS: Inhibition of 5-HT signaling by blocking 5-HT7 receptor function with a 5-HT7 antagonist ameliorated DSS-induced colitis. Compared to saline treated mice, we observed significantly lower macroscopic (4.0±0.28 vs. 2.6±0.43) and histological damage scores (4.8±0.59 vs. 2.4±0.54) in antagonist treated mice on day 5 post-DSS. This was associated with downregulation of MPO activity (16.9±0.88 vs. 12.32±1.21, P<0.05) and lower production of IL-1β, TNF-α and IL-6 (P<0.05) post-DSS. There were also significantly lower histological scores, MPO and pro-inflammatory cytokine levels in 5-HT7KOmice as compared to controls post-DSS. DCs isolated from 5-HT7KO mice post-DSS produced lower levels of IL-12 and IL-1β when stimulated with LPS as compared to wild-type mice (P<0.05). We also observed significant reduction in severity of colitis in 5-HT7KO mice following induction of DNBScolitis. CONCLUSION: These results demonstrate that disruption of 5-HT7 receptor function reduces the severity of gut inflammation and identifies a key role of 5-HT7 receptor mediated signaling in the pathogenesis of experimental colitis. These observations provide us with novel information on the role of the 5-HT7 receptor in gut inflammation and highlight the potential benefit of targeting this receptor to alleviate disease severity in intestinal inflammatory conditions including inflammatory bowel disease.

Role of 5-HT3 Receptors in the Antidepressant Response

Serotonin (5-HT)3 receptors are the only ligand-gated ion channel of the 5-HT receptors family. They are present both in the peripheral and central nervous system and are localized in several areas involved in mood regulation (e.g., hippocampus or prefrontal cortex). Moreover, they are involved in regulation of neurotransmitter systems implicated in the pathophysiology of major depression (e.g., dopamine or GABA). Clinical and preclinical studies have suggested that 5-HT3 receptors may be a relevant target in the treatment of affective disorders. 5-HT3 receptor agonists seem to counteract the effects of antidepressants in non-clinical models, whereas 5-HT3 receptor antagonists, such as ondansetron, present antidepressant-like activities. In addition, several antidepressants, such as mirtazapine, also target 5-HT3 receptors. In this review, we will report major advances in the research of 5-HT3 receptor's roles in neuropsychiatric disorders, with special emphasis on mood and anxiety disorders.

Immunohistochemical and biomolecular identification of 5-HT7 receptor in rat vestibular nuclei

The association between migraine and balance disorder morbidities has been a topic of interest for many years, and serotonin (5-HT) receptor is known to be closely related with migraine and also to be associated with vestibular symptoms. However, the mechanism underlying the pathogenesis of migrainous vertigo and its association with 5-HT has not been elucidated. Of the many 5-HT receptors, 5-HT₇ receptor has recently attracted attention in the context of migraine treatment. The purpose of this study was to investigate the localization and expression of 5-HT₇ receptor in the rat vestibular nuclei by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). The present study might provide additional insight into the role of 5-HT₇ receptor in the pathogenesis of migraine-related vestibular symptoms.

Effects of 5-HT2 agonist/antagonist on sleep apnea in Sprague-Dawley rats

To evaluate the effects of 5-HT2 agonist/antagonist Ketanserin on sleep apnea in Sprague-Dawley (SD) rats. Twenty adult male SD rats were operated for implantation of EEG and EMG electrodes and a microinjection probe was placed within the fourth ventricle. After recovery for a week, rats were monitored for sleep and respiration in three continuous days. There is no intervention on the first day. Before monitoring, 40 microl ACSF were microinjected into the IV ventricle of the rats on the second day. On the third day before monitoring, 40 microl DOI were microinjected into the IV ventricle of ten rats and 40 microl Ketanserin into another ten ones. Compared with blank control and microinjection of ACSF, DOI significantly reduced the total apnea index (AI) from 18.3 (11.1, 20.3) times/h and 15.2 (11.4, 18.0) times/h to 10.8 (3.1, 14.1) times/h (P=0.005 and 0.005, respectively). Post sign apnea index (PSAI) during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep as well as spontaneous apnea index (SPAI) during NREM sleep were all significantly decreased; (P<0.05, respectively); while it had no effect on SPAI during REM sleep (P>0.05). Neither sleep efficiency (the percent of total sleep time in total monitoring time) nor the time ratio of NREM sleep and REM sleep was significantly changed. In contrast to blank control and microinjection of ACSF, Ketanserin significantly reduced the total apnea index (AI) from 19.2 (13.7, 20.9) times/h and 19.0 (12.9, 21.6) times/h to 13.1 (9.5, 14.9) times/h (P=0.005 and 0.005, respectively). PSAI during NREM and REM sleep were significantly decreased (P<0.05, respectively). SPAI during NREM and REM sleep were changed without statistically significant (P>0.05, respectively). It also had no effects on sleep efficiency and the time ratio of NREM sleep and REM sleep. Both 5-HT2 agonist and antagonist decreased the sleep apnea index and had no effects on sleep structure. It shows that the role of 5-HT2 receptor in the respiratory regulation during sleep is complex. The mechanisms involved remain to be studied in future.

Effects of Serotonin on Acid Secretion in Isolated Rat Stomach: the Role of 5-HT3 Receptors

Serotonin (5-hydroxytryptamin; 5-HT) content has been measured using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The distributions of 5-HT-containing cells and 5-HT3 receptors have been determined with specific antibodies against 5-HT and 5-HT3 receptors, respectively. The effect of serotonin on acid secretion has been studied using an isolated rat stomach model. It has been shown that 5-HT concentrations in the fundus, mucosal layers of the corpus, remaining layer of the corpus and antrum are approximately 152, 498, 1494 and 972 nmol/mg protein, respectively. The distribution of 5-HT-containing cells is concentrated in the enteric plexus and enterochromaffin (EC) cells in the deep mucosal layer. Immunoreactivity to 5-HT3 receptors is localized in numerous neurons of the myenteric and submucosal plexus and concentrated in the neuronal plasma membrane, submucosa, endocrine cells and lamina propria. In the present study, the effect of 5-HT on gastric acid secretion was investigated on an everted preparation of isolated rat stomach. 5-HT at 1-100 microM reduced acid secretion stimulated by oxotremorine while 10 microM 5-HT did not modify the basal secretion of gastric acid. We further showed that 10 microM 5-HT reduced acid secretion and pepsin output stimulated by oxotremorine, histamine and pentagastrin; among the 5-HT receptors agonists tested, 2-methyl-5-HT (1-10 microM), a 5-HT3 receptor agonist, inhibited oxotremorine-, histamine- and pentagastrin-stimulated acid secretions, and this inhibitory effect was blocked by 1 microM MDL 72222, a specific 5-HT3 receptor antagonist. These results suggest that 5-HT is released from serotoninergic neurons, their processes and EC cells. The effect of 5-HT mediated by 5-HT3 receptors involves distinct neuronal and non-neuronal pathways which modulate gastric acid secretion.

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The role of 5-HT3 receptors in drug abuse and as a target for pharmacotherapy.

Alcohol and drug abuse continue to be a major public health problem in the United States and other industrialized nations. Extensive preclinical research indicates the mesolimbic dopamine (DA) pathway and associated regions mediate the rewarding and reinforcing effects of drugs of abuse and natural rewards, such as food and sex. The serotonergic (5-HT) system, in concert with others neurotransmitter systems, plays a key role in modulating neuronal systems within the mesolimbic pathway. A substantial portion of this modulation is mediated by activity at the 5-HT3 receptor. The 5-HT3 receptor is unique among the 5-HT receptors in that it directly gates an ion channel inducing rapid depolarization that, in turn, causes the release of neurotransmitters and/or peptides. Preclinical findings indicate that antagonism of the 5-HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol-associated effects. Less is known about the effects of 5-HT3 receptor activity on the self-administration of other drugs of abuse or their associated effects. Clinical findings parallel the preclinical findings such that antagonism of the 5-HT3 receptor reduces alcohol consumption and some of its subjective effects. This review provides an overview of the structure, function, and pharmacology of 5-HT3 receptors, the role of these receptors in regulating DA neurotransmission in mesolimbic brain areas, and discusses data from animal and human studies implicating 5-HT3 receptors as targets for the development of new pharmacological agents to treat addictions.

Expression and role of 5-HT7 receptor in brain and intestine in rats with irritable bowel syndrome

The 5-hydroxytryptamine7 receptor (5-HT(7) receptor, 5-HT(7)R) plays an important role in the regulation of smooth muscle relaxation and visceral sensation and might be involved in the pathogenesis of the gastrointestinal dyskinesia, abdominal pain and visceral paresthesia in irritable bowel syndrome (IBS). The aim of this study was to investigate the role of the 5-HT(7) receptor in the pathogenesis of IBS. A rat model of irritable bowel syndrome with diarrhea (IBS-D) was established by colonic instillation of acetic acid and restraint stress. A rat model with irritable bowel syndrome with constipation (IBS-C) was established by stomach irrigated with 0 - 4 degrees C cool water daily for 14 days. The content and distribution of 5-HT in the brain and gut were examined by immunohistochemistry and the mRNA expression of the 5-HT(7) receptor was determined by fluorescent quantitative reverse transcription polymerase chain reaction. The accumulation of cyclic adenosine monophosphate (cAMP) in all the same tissues was measured by radioimmunity. The models of IBS were reliable by identification. The immunohistochemistry results showed that there were significantly more 5-HT positive cells in the IBS-D group than in the control group in the hippocampus, hypothalamus, jejunum, ileum, proximate colon and distal colon (P < 0.05), as well as more than were found in the IBS-C group in jejunum and ileum (P < 0.05). There were more 5-HT positive cells in the IBS-C group than in the control hippocampus, hypothalamus, ileum, proximate colon, and distal colon (P < 0.05). Real time-PCR results showed that the expression level of the 5-HT(7) receptor in both the IBS-C and IBS-D groups were enhanced compared with the control group in the hippocampus and hypothalamus (P < 0.05). The expression level of 5-HT(7) receptors in the IBS-C group was notably greater when compared with the controls in the ileum and colon (P < 0.05). The cAMP accumulation in the hippocampus and hypothalamus in both the IBS-C and IBS-D groups was higher than that in the control group (P < 0.01 and P < 0.05). The cAMP accumulation in the IBS-C group was higher than that in the control group in the proximal and distal colon (P < 0.05). The increased 5-HT content in the brain and intestine is related to the IBS pathogenesis. The up-regulated expression of the 5-HT(7) receptor in the brain and colon might play an important role in the pathogenesis of IBS-C.

Impact of 5‐HT3 receptor blockade on colonic haemodynamic responses to ischaemia and reperfusion in the rat

5-HT(3) receptor antagonists are clinically available for treating patients with irritable bowel syndrome (IBS) but their use is restricted because of a link with some episodes of ischaemic colitis. However, the role of 5-HT3 receptors in regulating colonic blood flow has not been systematically investigated. Thus, we examined acute and chronic treatment with alosetron, a potent and selective antagonist of the 5-HT3 receptor, on baseline colonic blood flow and haemodynamic responses during occlusion and reactive hyperaemia in the pentobarbitone-anaesthetized rat. Colonic haemodynamics were assessed using ultrasonic recordings of superior mesenteric blood flow (MBF) and laser Doppler recordings of colonic vascular perfusion (VP). Blood pressure (BP) was also monitored and in some experiments tissue oxygen was detected polarographically. Alosetron (10, 30, 100 microg kg(-1), i.v.) had no effect on baseline haemodynamics nor responses to nitric oxide synthase inhibition with N(omega)-nitro-l-arginine methyl ester (l-NAME) (16 mg kg(-1)). Arterial occlusion (5 min) reduced MBF (-98.6 +/- 0.6%) and VP (-70.7 +/- 5.4%) followed by a post-occlusion reactive hyperaemia (MBF = +94.5 +/- 19.1%; VP = +60.0 +/- 22.3%) the magnitude of which was unchanged following acute (30 microg kg(-1)) or chronic alosetron administration (0.5 mg kg(-1) twice daily, 5 days). Alosetron did not significantly alter baseline colonic blood flow in the anaesthetized rat; nor did it interfere with vascular control mechanisms activated during occlusion and reactive hyperaemia.

Red chili induces rectal hypersensitivity in healthy humans: possible role of 5HT‐3 receptors on capsaicin‐sensitive visceral nociceptive pathways

Red chili has been reported to modulate visceral hypersensitivity, probably by the action of its active ingredient, capsaicin. The role of 5HT-3 receptors on capsaicin-sensitive visceral nociceptive pathways is unknown. To test the hypothesis that capsaicin-containing red chili induces rectal hypersensitivity in healthy humans and 5HT-3 receptors participate in this effect. Eighteen healthy volunteers, each underwent three rectal barostat studies under three conditions: (i) oral placebo; (ii) oral chili (5 g daily x 3 days); and (iii) oral chili with 1-mg intravenous (i.v.) granisetron, in randomized, double-blinded, cross-over fashions. Rectal sensation was evaluated by using a 5-point Likert scale. Chili ingestion significantly decreased rectal threshold for first, moderate and severe urgency (18 +/- 0.9, 24 +/- 1.2, and 38 +/- 1.5 mmHg, respectively) compared with placebo (22 +/- 0.9, 31 +/- 1.3, and 45 +/- 1.4 mmHg, respectively, P < 0.01). The threshold for first, moderate and severe urgency after chili with i.v. granisetron was 20 +/- 0.9, 28 +/- 1.2 and 44 +/- 1.3 mmHg, respectively. This is a significant increase compared with chili ingestion without granisetron (P < 0.05). After placebo ingestion, i.v. granisetron produced no effect on rectal sensation compared with i.v. placebo in 10 healthy volunteers (P > 0.05). Low-dose granisetron, a 5HT-3 receptor antagonist, partially reversed chili-induced rectal hypersensitivity but had no effect on rectal perception induced only by mechanical balloon distention. This study suggests that 5HT-3 receptors may be involved in chili-induced rectal hypersensitivity and potentially participate in the capsaicin-sensitive nociceptive pathways of the human gut.

Serotonergic Modulation of Spinal Sensory Circuits

The role of serotonin (5-HT) as a mediator of the endogenous pain control system has been investigated over the last 30 years. Here we review a subset of studies that used electrophysiological techniques to study the mechanisms of action as well as the receptors mediating the spinal effects of serotonin. The works herein discussed employed in vivo or in vitro preparations of control or hyperalgesic animals. According to these reports, 5-HT triggers depressant effects on synaptic transmission limiting the release of neurotransmitters from afferent terminals or the responsiveness of NMDA receptors located in dorsal horn neurones. These mechanisms are most likely mediated by 5-HT1 receptors. In contrast, 5-HT2 receptors seem to mediate excitatory effects such as depolarisation, increased excitability, and neurotransmitter release. The role of 5-HT3 receptors is less clear as they could mediate excitatory or inhibitory effects, depending on variables such as concentration of 5-HT or the state (sensitised/unsensitised) of the spinal cord. The consequences of these spinal effects of serotonin are discussed in the context of pain and analgesia.

Effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia

Conflicting results exist regarding the role of 5-HT3 receptors in somatic and visceral nociceptive processing. We aimed to investigate the effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia. Two injections (100 μl) of either pH 4.0 or 7.2 saline were given unilaterally in the gastrocnemius (GN) muscle. In all groups, the paw withdrawal thresholds (PWT) to von Frey filaments and the visceromotor responses (VMR) to colorectal distension (CRD) were recorded before the saline injections and 72 h, and 1 week after the second injection. Intrathecal (i.t.) (25 nmol) or intravenous (i.v.) (100 μg/kg/day) alosetron was given daily following the second injection and compared to either i.v. or i.t. saline (vehicle). There was a significant decrease in the mean PWT bilaterally in all groups following pH 4.0 injections ( p < 0.05). Intravenous alosetron resulted in a significant increase in the PWT bilaterally on days 2 and 3. Intrathecal alosetron resulted in significant increase in the PWT starting at day 3 and was significantly higher than baseline on days 4–7 ( p < 0.05). At CRD pressures ⩾30 mmHg, the VMR of pH 4.0 injected rats was significantly increased at 72 h and 1 week ( p < 0.05). Both i.v. and i.t. alosetron treated rats failed to demonstrate any alteration in the VMR. Control rats (pH 7.2) failed to show any alteration in the VMR and were unaffected by alosetron. Both, systemically and centrally administered alosetron, reversed the mechanical somatic hypersensitivity and prevented the development of visceral hyperalgesia, suggesting a centrally mediated effect.

Expression and role of 5-HT7 receptors in modulating peristalsis and accommodation in the guinea pig ileum

Expression and role of 5-HT7 receptors in modulating peristalsis and accommodation in the guinea pig ileum