5-HT2 Agonist Research Articles

Hypertension exhibits 5-HT4 receptor as a modulator of sympathetic neurotransmission in the rat mesenteric vasculature.

Sympathetic overdrive is a key player in hypertension, where the mesenteric vasculature plays a relevant role in modulating blood pressure. Although 5-HT inhibits noradrenergic mesenteric neurotransmission in normotensive rats, its effect on the mesenteric sympathetic drive in hypertensive rats has not been studied. We investigated the influence of in vivo 5-HT by characterizing the implicated serotonergic receptors on the mesenteric sympathetic outflow in rats with N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Hypertension was induced in male Wistar rats by L-NAME administration (30 mg/kg per day; 21 days) in drinking water. The rats were anesthetized (sodium pentobarbital; 60 mg/kg, i.p.), prepared for the in situ autoperfused rat mesentery, and subjected for monitoring their systemic blood pressure (SBP), heart rate (HR), and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency-dependent increases in MPP without altering SBP or HR. The 5-HT and cisapride (5-HT4 agonist) i.a. bolus (1-25 µg/kg) inhibited vasopressor responses by electrical stimulation of the mesenteric nerves, unlike an i.a. bolus (25 µg/kg each) of the agonist 5-carboxamidotryptamine (5-HT1/7 agonist), α-methyl-5-HT (5-HT2), or 1-PBG (5-HT3). However, i.a. cisapride (25 µg/kg) did not affect the noradrenaline-induced vasoconstriction in the mesenteric vasculature. Administration of the selective 5-HT4 receptor antagonist GR 125487 (1 mg/kg, i.v.) completely abolished cisapride- and 5-HT-evoked mesenteric sympatholytic effects. Additionally, ELISA analysis demonstrated higher 5-HT4 receptor expression in mesenteric arteries from L-NAME-hypertensive compared with normotensive rats. Our findings suggest that L-NAME-induced hypertension modifies the 5-HT modulation of the rat mesenteric sympathetic drive: prejunctional 5-HT4 receptors are involved in the serotonergic sympathoinhibitory effect.

Reprint of: Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders

Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.

Protein kinase Cδ constrains the S-pathway to phrenic motor facilitation elicited by spinal 5-HT7 receptors or severe acute intermittent hypoxia.

Concurrent 5-HT2A (Q pathway) and 5-HT7 (S pathway) serotonin receptor activation cancels phrenic motor facilitation due to mutual cross-talk inhibition. Spinal protein kinase Cδ (PKCδ) or protein kinase A inhibition restores phrenic motor facilitation with concurrent Q and S pathway activation, demonstrating a key role for these kinases in cross-talk inhibition. Spinal PKCδ inhibition enhances adenosine-dependent severe acute intermittent hypoxia-induced phrenic long-term facilitation (S pathway), consistent with relief of cross-talk inhibition. Intermittent spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation (pMF), a form of respiratory motor plasticity. When activated alone, spinal Gq protein-coupled serotonin 2A receptors (5-HT2A ) initiate pMF by a mechanism that requires ERK-MAP kinase signalling and new BDNF protein synthesis (Q pathway). Spinal Gs protein-coupled serotonin 7 (5-HT7 ) and adenosine 2A (A2A ) receptor activation also elicits pMF, but via distinct mechanisms (S pathway) that require Akt signalling and new TrkB protein synthesis. Although studies have shown inhibitory cross-talk interactions between these competing pathways, the underlying cellular mechanisms are unknown. We propose the following hypotheses: (1) concurrent 5-HT2A and 5-HT7 activation undermines pMF; (2) protein kinase A (PKA) and (3) NADPH oxidase mediate inhibitory interactions between Q (5-HT2A ) and S (5-HT7 ) pathways. Selective 5-HT2A (DOI hydrochloride) and 5HT7 (AS-19) agonists were administered intrathecally at C4 (three injections, 5-min intervals) in anaesthetized, vagotomized and ventilated male rats. With either spinal 5-HT2A or 5-HT7 activation alone, phrenic amplitude progressively increased (pMF). In contrast, concurrent 5-HT2A and 5-HT7 activation failed to elicit pMF. The 5-HT2A -induced Q pathway was restored by inhibiting PKA activity (Rp-8-Br-cAMPS). NADPH oxidase inhibition did not prevent cross-talk inhibition. Therefore, we investigated alternative mechanisms to explain Q to S pathway inhibition. Spinal protein kinase C (PKC) inhibition with Gö6983 or PKCδ peptide inhibitor restored the 5-HT7 -induced S pathway to pMF, revealing PKCδ as the relevant isoform. Spinal PKCδ inhibition enhanced the S pathway-dependent form of pMF elicited by severe acute intermittent hypoxia. We suggest that powerful constraints between 5-HT2A and 5-HT7 or A2A receptor-induced pMF are mediated by PKCδ and PKA, respectively.

Fluoxetine oral treatment discloses 5-HT1D receptor as vagoinhibitor of the cardiac cholinergic neurotransmission in rat.

Although depression and cardiovascular diseases are related, the role of antidepressants such as fluoxetine (increasing serotonin levels) within cardiac regulation remains unclear. We aimed to determine whether fluoxetine modifies the pharmacological profile of serotonergic influence on vagal cardiac outflow. Rats were treated with fluoxetine (10 mg/kg per day; p.o.) for 14 days or equivalent volumes of drinking water (control group); then, they were pithed and prepared for vagal stimulation. Bradycardic responses were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or i.v. acetylcholine (ACh; 1, 5, and 10 μg/kg). The i.v. administration of 5-hydroxytryptamine (5-HT; 10 and 50 μg/kg) inhibited the vagally induced bradycardia. 5-CT (5-HT1/7 agonist) and L-694,247 (5-HT1D agonist) mimicked the serotonin inhibitory effect while α-methyl-5-HT (5-HT2 agonist) was devoid of any action. SB269970 (5-HT7 antagonist) did not abolish 5-CT inhibitory action on the electrically induced bradycardia. Pretreatment with LY310762 (5-HT1D antagonist) blocked the effects induced by L-694,247 and 5-CT. 5-HT and 5-CT failed to modify the bradycardia induced by exogenous ACh. Our outcomes suggest that fluoxetine treatment modifies 5-HT modulation on heart parasympathetic neurotransmission in rats, evoking inhibition of the bradycardia via prejunctional 5-HT1D in pithed rats.

Serotonin receptor regulation as a potential mechanism for sexually dimorphic oxytocin dysregulation in a model of Autism

Perinatal administration of serotonin (5HT) agonist 5-methoxytryptamine (5MT) induces developmental hyperserotonemia (DHS; elevated blood serotonin) and produces behavioral and neurochemical changes in rats relevant to Autism Spectrum Disorder (ASD), such as oxytocin dysregulation. Disruption of the oxytocin system may underlie many of the social deficits present in ASD individuals, thus we investigated the mechanism(s) underlying DHS-induced oxytocin dysregulation. The most parsimonious mechanism of 5HT action would be alteration of 5HT receptors on oxytocin cells; 5HT is known to influence cell survival as well as influence oxytocin release via 5HT1A and 5HT2A receptors, which co-localize in oxytocin-expressing (OXT+) cells in the paraventricular nucleus (PVN) of the hypothalamus. We report that both male and female DHS rats have a lower percentage of OXT+ cells co-localized with excitatory 5HT2A receptors than control animals, while only DHS females have a higher percentage of OXT+ cells co-localized with inhibitory 5HT1A receptors compared to controls. Importantly, DHS also reduces the number of OXT+ cells in the PVN of adult male, but not female, rats. This pattern suggests that females, but not males, can regulate 5HT receptors in response to DHS in a manner that promotes oxytocin cell survival and functional efficiency. In addition, it has been previously reported that DHS alters normal juvenile play, especially in males, thus we also tested play partner preference among juvenile control and DHS males. Sex differences observed using the DHS model of ASD add to its validity, given the pronounced male sex bias in the prevalence of ASD, and emphasize the need for inclusion of both sexes in ASD research.

Involvement of prelimbic 5-HT7 receptors in the regulation of anxiety-like behaviors in hemiparkinsonian rats

ABSTRACTObjective: At present, little is known about the role of serotonin7 (5-HT7) receptor in anxiety, particularly in Parkinson’s disease-related anxiety. Here, we tested whether 5-HT7 receptors in the prelimbic (PrL) cortex are involved in the regulation of anxiety-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB).Methods: The open field and elevated plus maze (EPM) tests were performed to study the influence of MFB lesion and intra-PrL injection of 5-HT7 agonist AS19 (0.5, 1 or 2 μg/rat) and antagonist SB269970 (1.5, 3 or 6 μg/rat) on anxiety-like behaviors. Additionally, changes in monoamine levels in limbic and limbic-related brain regions were observed after intra-PrL injection of AS19 (2 μg/rat) and SB269970 (6 μg/rat).Results: The MFB lesion induced anxiety-like behaviors compared to sham-operated rats. Intra-PrL injection of AS19 showed anxiolytic effects by the open field and EPM tests in two groups of rats, and administration of SB269970 showed anxiogenic responses. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of AS19 increased dopamine, 5-HT and noradrenaline (NA) levels in the medial prefrontal cortex, ventral hippocampus and amygdala in two groups of rats, whereas SB269970 decreased 5-HT and NA levels in these brain regions.Discussion: 5-HT7 receptors in the PrL are involved in the regulation of anxiety-like behaviors, which is attributable to changes in dopamine, 5-HT and NA levels in the limbic and limbic-related brain regions after activation and blockade of 5-HT7 receptors.Abbreviations: 6-OHDA: 6-hydroxydopamine; DMSO: dimethyl sulfoxide; DA: dopamine; EPM: elevated plus maze; MFB: medial forebrain bundlem; PFC: medial prefrontal cortex; NA: noradrenaline; PD: Pakinson's disease; PrL: prelimbic; 5-HT: serotonin; vHip: ventral hippocampus

P72. Agonists and antagonists of specific serotonergic subreceptors and combined GABAA agonists and NMDA antagonists as a possible treatment of Alzheimers disease

In Alzheimer’s disease, neurotransmitter alterations, for example acetylcholine deficiency and a surplus of the excitotoxic glutamate have been described and are associated with cognitive impairment. An interaction between acetylcholine deficiency and beta-amyloid formation has also been reported. Neurotransmitter imbalances between noradrenaline, dopamine and 5-HT on the one hand, and acetylcholine, GABA and glutamate on the other hand have been reported in the temporal cortex and hippocampus. Since serotonin plays an important role in cognitive processes a question arises, whether agonists or antagonists at specific serotonergic subreceptors, for example 5-HT4 or 5-HT7 agonists or 5-HT6 antagonists, can improve cognitive functions. The neural network, in the hippocampus and prefrontal cortex, involved in cognitive deficits in Alzheimer’s disease can be described as follows: hippocampal 5-HT2A serotonergic neurons (with a diminishing activity) activate GABAergic neurons, which weakly inhibit, via GABAA receptors, alpha1 noradrenergic neurons. The latter neurons - the activity of which is first high and then decreases more and more during the progression of the Alzheimer’s disease - activate glutamatergic neurons, which strongly inhibit, via NMDA receptors, 5-HT2A serotonergic neurons. In the prefrontal cortex, M1 muscarinic cholinergic neurons (with a low activity) activate GABAergic neurons, which weakly inhibit via GABAA receptors alpha1 noradrenergic neurons. The latter neurons activate glutamatergic neurons, which strongly inhibit via NMDA receptors M1 muscarinic cholinergic neurons. Hippocampal GABAergic neurons inhibit, via GABAA receptors, alpha1 noradrenergic located in the prefrontal cortex. Finally, glutamatergic neurons located in the prefrontal cortex inhibit, via NMDA receptors, hippocampal 5-HT2A serotonergic neurons. In clinical trials, the therapeutic effects of 5HT4, 5-HT7 agonists and 5-HT3, 5-HT6 antagonists have been examined to improve cognitive symptoms in Alzheimer’s disease. In these trials, 5-HT4 agonists and 5-HT6 antagonists showed a significant better effect in improving cognitive functions than placebo. The effect of such drugs on the formation of amyloid plaques is also examined. The clinical effects of 5-HT4 and 5-HT7 agonists or 5-HT3 and 5HT6 antagonists, which might slow down the development of senile plaques, should be examined in future clinical trials. Moreover, in the hippocampus and prefrontal cortex, we describe a neurotransmitter imbalance between GABAA GABAergic neurons (with hypoactivity) and NMDA glutaminergic neurons (with hyperactivity). The prophylactic effect of such drugs in Alzheimer’s disease, for example of combined GABAA agonists and NMDA antagonists should be examined in mild Alzheimer patients.

The serotonin (5-hydroxytryptamine) 5-HT7 receptor is up-regulated in Onuf's nucleus in rats with chronic spinal cord injury.

To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n=16 each). At 8weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30μg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT7 R antagonist, SB-269970 (10μg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT7 Rs in the ventral L6-S1 spinal cord in SCI rats. A 5-HT7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT7 R could be a target for therapeutic interventions.

459 - Efficacy and Safety of Novel 5-HT4 Agonist DSP-6952 in Patients with Irritable Bowel Syndrome with Constipation: A Randomized, Double-Blind, Placebo-Controlled Early Phase II Study

459 - Efficacy and Safety of Novel 5-HT4 Agonist DSP-6952 in Patients with Irritable Bowel Syndrome with Constipation: A Randomized, Double-Blind, Placebo-Controlled Early Phase II Study

PD36-01 THE 5-HT7 RECEPTOR IS UP-REGULATED IN ONUF'S NUCLEUC

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction II1 Apr 2018PD36-01 THE 5-HT7 RECEPTOR IS UP-REGULATED IN ONUF'S NUCLEUC Jianshu Ni, Baojun Gu, nailong cao, and xiaohu wang Jianshu NiJianshu Ni More articles by this author , Baojun GuBaojun Gu More articles by this author , nailong caonailong cao More articles by this author , and xiaohu wangxiaohu wang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1724AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It was previously reported that a 5-HT7 agonist, given intravenously, could enhance external urethral sphincter (EUS) activity and improve voiding efficiency after spinal cord injury (SCI). The present study examined the effect of intrathecal 5-HT7 agonist administration on voiding function, and the change of 5-HT7 receptor expression in lumbosacral cord Onuf's nucleus after SCI. METHODS Thirty-two female SD rats were divided into spinally intact (SI) group and SCI group (n=16 each). Eight weeks after transection, half of the rats underwent continuous cystometry under urethane anesthetization, and the 5-HT7 selective agonist LP44 was given intrathecally. Half of the remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence (IF) and Western Blot. RESULTS Intrathecally administered LP44 had no effect in spinally intact (SI) rats. In SCI rats, LP44 (1-30 ug/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillation (HFO) per micturition, and decrease in residual volume, bladder capacity, and peak bladder pressure. The 5-HT7 receptors antagonist, SB-269970 (10 ug/kg), partially reversed LP44-induced changes. By PRV retrograde tracing and IF, 5-HT7 receptors were demonstrated in L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly stronger in SCI rats. Western blot showed a significant increase of 5-HT7 receptors in ventral L6-S1 spinal cord in SCI rats. CONCLUSIONS A 5-HT7 agonist, given intrathecally, improved voiding efficiency in SCI rats, and the 5-HT7 receptor was significantly up-regulated in lumbosacral cord Onuf's nucleus. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e726 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Jianshu Ni More articles by this author Baojun Gu More articles by this author nailong cao More articles by this author xiaohu wang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Alteration of Depressive-like Behaviors by Psilocybe cubensis Alkaloid Extract in Mice: the Role of Glutamate Pathway

Background and objectives: Considering the increasing prevalence of depression, many studies are launched to investigate new antidepressant treatments. The present research has shown how psilocybin as an active compound of Psilocybe cubensis (Earle) Singer extract (PCE) can change the parameters related to depression and anxiety in animal models. Both serotonin (5-hydroxytryptamine: 5-HT) and glutamate modulate depressive-like behaviors and, therefore, we examined the possible interaction of psilocybin as 5-HT1 agonist with glutamate receptor N-methyl-D-aspartate (NMDA). Methods: Psilocybe cubensis extract of this mushroom was prepared by ethyl acetate. NMRI mice involved in all experiments and were treated with the vehicle, extract, or standard drug intraperitoneally. Open field (OFT), forced swimming (FST) and tail suspension tests (TST) were applied to measure the intended parameters. OFT was performed to verify the applied doses for measuring the following antidepressant activity. Results: PCE at the doses of 100 mg/kg significantly changed the locomotion, time spent in center and velocity of the animals in OFT. While treatment of the animals with PCE 10 and 40 mg/kg or ketamine 1 mg/kg did not alter the locomotor activity, co-administration of these subeffective amounts significantly reduced the immobility time in both FST and TST. Conclusion: These effects may indicate possible implication of psilocybin with NMDA receptor which consequently produces the antidepressant effects.

5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats.

5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes. In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14days from the first day of ICV-STZ. Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5mg/kg) and antagonist SB-399885 (10mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible. Thefindings in this studysupport the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.

Pharmacology of Serotonin Receptors Causing Contraction of Isolated Bovine Posterior Ciliary Arteries: Role in Ocular Blood Flow.

To determine the serotonergic (5HT) receptor subtype mediating the contraction of bovine posterior ciliary arteries (BPCAs) in vitro. Longitudinal isometric tension was measured in BPCA strips (4-5 mm) mounted in 25 mL organ baths containing oxygenated Krebs solution at 37°C. Cumulative contractile concentration-response (C-R) curves were generated for various 5-HT agonists to assess their potencies and maximal degrees of contraction. Multiple agonist C-R curves were also constructed in the presence and absence of receptor-selective antagonists to determine antagonist potencies using Schild plots. Selective and nonselective agonists for 5-HT receptors elicited concentration-dependent contractile responses in BPCAs with the following rank order of potency: MK-212 > BW723C86 > α-methyl-5-HT >5-methoxy-α-5-methyl-5-HT >> R-DO1 > >5-HT >> cabergoline >> 5-methoxy-dimethyl-tryptamine >> 2-methyl-5-HT >> tryptamine. Interestingly, both 8-OH-DPAT (5HT1A agonist) and quipazine (5HT3 agonist) did not elicit contractions in BPCAs. The contractions produced by BW723C86 (5-HT2B agonist) were antagonized by 5-HT receptor blockers, RS-127445 (5-HT2B antagonist), and M-100907 (5-HT2A antagonist), yielding antagonist pA2 values of 7.5 ± 0.12 (n = 4) and 6.2 ± 0.17 (n = 4), respectively. Furthermore, contractions elicited by MK-212 (5-HT2C agonist) was blocked by RS-102221 (5-HT2C antagonist), although noncompetitively. On the basis of the pharmacological profile of selective agonists and antagonists, we conclude that serotonin-induced contractions of the BPCA are mediated primarily by a combination of 5HT2C and/or 5HT2B receptors. It appears that 5-HT1A and 5-HT3 receptors are not involved in the contractile action of BPCAs to serotonin.

Peripheral 5-HT3 mediates mirror-image pain by a cross-talk with acid-sensing ion channel 3

Mirror-image pain (MIP), which occurs along with complex regional pain syndrome, rheumatoid arthritis and chronic migraine, is characterized by increased pain sensitivity of healthy body regions other than the actual injured or inflamed sites. A high level of peripheral inflammation may activate central or peripheral glia, triggering mirror-image pain. However, which receptors mediate inflammatory signals to contribute glial activation remains unclear. Intraplantarly injecting mice with 5-hydroxytryptamine (5-HT) or acidic buffer (proton) caused only unilateral hyperalgesia, but co-injection of 5-HT/acid induced bilateral hyperalgesia (MIP). Blocking 5-HT3 or acid-sensing ion channel 3 (ASIC3) abolished satellite glial activation, inhibiting MIP. Interestingly, intraplantar administration of a 5-HT3 agonist induced MIP, and 5-HT3–mediated MIP can be reversed by a 5-HT3 antagonist or an ASIC3 blocker. Similar results were found using a ASIC3 agonist. Furthermore, 5-HT3 was observed to co-localize with ASIC3 in DRG neurons; 5-HT3 activation-induced an increase in intracellular calcium that was inhibited by an ASIC3 blocker and vice versa. A cross-talk between 5-HT3 and ASIC3 mediates satellite glial activation, thereby triggering mirror-image pain.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

The effect of maternal forced exercise on offspring pain perception, motor activity and anxiety disorder: the role of 5-HT2 and D2 receptors and CREB gene expression.

The effect of maternal forced exercise on central disorders in offsprings has been shown but the mechanism is still unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise on offspring neurodevelopment and neurobehavioral symptoms is evaluated. Sixty pregnant rats were trained by forced exercise and some behavioral and molecular aspects in their offspring were evaluated in presence of 5-HT2 and D2 receptors agonists and antagonists. The results showed that maternal forced exercise causes increase of pain tolerability and increase latency of pain perception in offspring in hot plate test, writhing test and tail flick test. Also maternal forced exercise causes decrease of depression and anxiety like behavior in offsprings. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists inhibited the protective effects of forced exercise and cause disturbance in pain perception and tolerability and increase depression and anxiety in offsprings. Also expression of cyclic AMP response element binding protein (CREB) was changed in all experimental groups. In conclusion, our data suggested that maternal forced exercise causes neurobehavioral protective effect on offsprings and this effect might probably be mediated by 5-HT2 and D2 receptors and activation of CREB gene expression.

Effect of prucalopride on intestinal gas tolerance in patients with functional bowel disorders and constipation.

Patients with functional bowel disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. Stimulation of 5HT-4 receptors in the gut has both prokinetic and antinociceptive effects. The aim of this study is to determine the effect of prucalopride, a highly selective 5HT-4 agonist, on gas transit and tolerance in women with functional bowel disorders complaining of constipation. Twenty-four women with functional bowel disorders complaining of constipation were included in the study. Patients were studied twice on separate days in a cross-over design. On each study day, an intestinal gas challenge test was performed. During the five previous days, prucalopride (2mg/day) or placebo was administered. Abdominal symptoms, stool frequency, and stool consistency were recorded during the treatment period on daily questionnaires. During the gas challenge test, prucalopride did not decrease the volume of gas retained in the subset of patients who had significant gas retention (≥200mL) while on placebo. However, in those patients who had increased symptoms during the gas test (≥3 on a 0 to 6 scale) when on placebo, prucalopride did significantly reduce the perception of symptoms (2.3±0.5 mean score vs 3.5±0.3 on placebo; P=0.045). During the treatment period with prucalopride, patients exhibited an increase in the total number of bowel movements and decreased stool consistency compared with placebo. Prucalopride reduces abdominal symptoms without modifying gas retention when patients with functional bowel disorders are challenged with the gas transit and tolerance test. European Clinical Trials Database (EudraCT2011-006354-86).

The 5-HT4 receptor-mediated inhibition of visceral nociceptive neurons in the rat caudal ventrolateral medulla

Activation of the serotonin type 4 (5-HT4) receptors has been reported to improve abdominal pain in patients with functional gastrointestinal disorders and reduce visceral nociception in animal models. Earlier studies have proposed that 5-HT4 agonist can produce visceral analgesia by acting at the supraspinal level, but the underlying neuronal mechanisms remain unclear. The caudal ventrolateral medulla (CVLM) is the first site for processing of visceral nociceptive signals ascending via spinal pathways and an important component of the endogenous pain modulatory system. Therefore, the objective of the present study was to examine whether activation of 5-HT4 receptors can affect the visceral pain-related neurons in the CVLM. In urethane-anesthetized adult male Wistar rats, we evaluated the effects of a 5-HT4 receptor agonist, BIMU8 on ongoing firing of the CVLM neurons and their excitatory responses to noxious colorectal distension (CRD, 80mmHg). The drug’s effect was also tested on blood pressure reactions induced by CRD–a general physiological measure of visceral nociception. Intravenous administration of BIMU8 (0.5, 1 or 2mg/kg) produced dose-dependent suppression of both the ongoing and CRD-evoked activities of the CVLM neurons and simultaneously attenuated the depressor hemodynamic reaction to CRD. The compound’s inhibitory effect was almost completely eliminated by intracerebroventricular pretreatment with GR113808, a selective 5-HT4 antagonist, indicating the preferential involvement of supraspinal 5-HT4 receptors. Results indicate that visceral nociceptive transmission through the caudal medulla is negatively modulated by descending 5-HT4-dependent mechanisms. These findings can contribute to a deeper understanding of supraspinal processing of pain signals from the abdomen.

Fast and efficient zirconia-based reversed phase chromatography for selective determination of triptans in rat plasma

Selective and fast chromatographic method was essential for the determination of triptans, selective serotonin receptor (5-HT1) agonists, in biological specimens. However, selective chromatographic separation of these highly basic drugs is a challenging problem on silica-based stationary phases. Zirconia-based stationary phases have been introduced as an efficient alternative for silica-based columns offering unique stability, selectivity, and retention ability for various classes of drugs. Herein, a new selective, fast and reproducible high performance liquid chromatographic method (HPLC) was developed and validated for the determination of four triptans in plasma samples namely; Sumatriptan (SMT), Zolmitriptan (ZLT), Eletriptan (ELT) and Rizatriptan (RZT). Zirconia-based polybutadiene (PBD) column was used for the separation and quantitation of the studied triptans in rat plasma based on mixed mode ion exchange and reversed phase chromatography. Zirconia-PBD column (ZirChrom-PBD) has enhanced chemical and thermal stability, selectivity and provides high resolution for the investigated triptans in short analysis time compared with the commonly used C18 columns. A simple isocratic separation mode was used with a mobile phase consisted of acetonitrile and 10mM phosphate buffer adjusted to pH 3.0 (20:80; v/v) at flow rate 1.0mLmin−1. The column was maintained at 50°C and effluent was monitored by photodiode array detector (PDA). The developed method was validated in agreement with US-FDA guidelines and was appropriate for analysis of triptans in plasma samples. The linearity range obtained for the developed HPLC method was 15–2000ngmL−1 with detection limits of 4.8- 6.2ngmL−1 for all the studied triptans. The developed zirchonia-PBD-HPLC method was applied successfully to study the pharmacokinetics of ZLT in rats after a single oral dose. The method was proved to be valuable for therapeutic drug monitoring and bioavailability studies of the studied triptans.

Serotonergic modulation of nicotine-induced kinetic tremor in mice

We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via α7 nicotinic acetylcholine (nACh) receptors. Since α7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT1A antagonist). In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT2 antagonist). The 5-HT3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5-HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT3 antagonist) or SB-258585 (5-HT6 antagonist). These results suggest that postsynaptic 5-HT1A receptors are involved in induction of nicotine tremor mediated by α7 nACh receptors. In addition, 5-HT2 receptors have an inhibitory modulatory role in induction of nicotine tremor.