Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective antagonists to the Type 3 serotonin receptor (5HT3) in combination with corticosteroids are now considered the standard of care for the prevention of emesis from moderately to highly emetogenic chemotherapy. Here we address issues of optimal dose, schedule and route of administration of four currently available selectable 5HT3 antagonists. This paper utilizes an evidence based medicine approach to the literature regarding this class of drugs, emphasizing the results large, randomized, controlled trials to make formal recommendations concerning optimal use of this important new class of anti-emetic agents. We conclude that for each drug there is a plateau in therapeutic efficacy at a definable dose level above which further dose escalation does not improve outcome. Furthermore, a single dose is as effective as multiple doses or continuous infusion, and finally, emerging data demonstrate that the oral route is equally efficacious as the intravenous route of administration, even with highly emetogenic chemotherapy.
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PMID:Consensus proposal for 5HT3 antagonists in the prevention of acute emesis related to highly emetogenic chemotherapy. Dose, schedule, and route of administration. 962 76

The cellular distribution of the type 3 serotonin receptor (5HT3R) in the rat brain was established immunocytochemically by using a polyclonal antibody raised against a synthetic peptide from the deduced amino-acid sequence of the cloned 5HT3R. The 5HT3R-immunoreactive neurons were found in the forebrain, brainstem, and spinal cord, but within each region, the intensity of the immunoreactivity differed considerably. Within the forebrain, intensely immunoreactive cells were found in layers II-III of the neocortex, anterior olfactory nucleus, hippocampal formation, and amygdala. A few strongly immunoreactive neurons were consistently observed in the caudate putamen, and moderately or weakly labeled neurons were occasionally found in the nucleus accumbens. Within the brainstem, intensely labeled neurons were found in the trigeminal motor (V) and facial (VII) nuclei. Immunostained neurons were detected in the dorsal and the ventral horn of the spinal cord. These results reveal that the 5HT3R-immunoreactive neurons are broadly distributed throughout the rat brain and spinal cord, and suggest that this receptor can subserve significant participation in central nervous system neurotransmission.
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PMID:Distribution of neurons expressing immunoreactivity for the 5HT3 receptor subtype in the rat brain and spinal cord. 985 6

Ligands with varying intrinsic activity and selectivity for the various subtypes of the serotonin receptor were tested in the rat pup ultrasonic vocalization (USV) model, a putative animal model reflecting anxiety. USV were elicited by isolating rat pups from their mother and littermates by placing them on a warm (37 degrees C) or a cold (18 degrees C) plate. Concurrently, the negative geotaxic (NG) response and rectal temperature were determined to assess the potentially sedative and hypothermic effects of putative anxiolytics. USV were reduced at low doses and in both temperature conditions by the full 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin.HBr) and the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl]butyl]-1,2-benzi-isoth iozol-3-(2H)one-1,1-dioxide. 2HCl). The 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piperazide.2H Cl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)piperazin-1 -yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and only in one of both test conditions. The selective 5-HT1A receptor antagonist DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazi nyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1, dioxide, monomesylate), did not influence USV at the cold plate up to high doses, although concomitantly the negative geotaxis was disturbed. The negative geotaxis was impaired after all 5-HT1A receptor ligands, except BMY 7378 and (+/-)-WAY 100,135. Hypothermia coincided with USV-suppression, except for NAN-190 and (S)-UH-301. The USV-suppressing action of flesinoxan (3 mg/kg) could be antagonized by DU 125530, but not its NG effect. However, the hypothermia induced by flesinoxan was antagonized by DU 125530. USV were also suppressed by the 5-HT uptake inhibitors fluvoxamine (both warm and cold plate) and clomipramine (only warm plate). The tricyclic antidepressant imipramine only decreased USV on the cold plate, however, in a U-shaped dose-response curve. At the highest dose tested, no decrease was present. The 5-HT uptake stimulant tianeptine reduced USV under both conditions. Fluvoxamine had no side effects, clomipramine induced hypothermia and tianeptine clearly had sedative properties. The 5-HT1B/2C receptor agonist TFMPP (trifluorometaphenylpiperazine) stimulated USV at a low dose at the cold plate and suppressed USV at a high dose under both conditions. The 5-HT2A/2C receptor antagonist ketanserine enhanced USV at low doses under both conditions and had no effect at a higher dose. Concurrently heavy sedation and hypothermia occurred. The 5-HT3 receptor agonist phenylbiguanide and the 5-HT3 receptor antagonist ondansetron had no effect in this paradigm. Clearly, subtypes of the 5-HT receptor affect rat pup USV differentially.
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PMID:Ultrasonic vocalizations in rat pups: effects of serotonergic ligands. 988 14

A fluorescently labelled ligand for the 5-HT3 serotonin receptor was synthesised and its sub-nanomolar affinity for the purified, detergent solubilised receptor was measured. The change in the ligand's fluorescence upon receptor binding was used to directly measure its dissociation constant for receptor binding, to determine the pharmacology of the receptor, and finally to characterise the binding site of the receptor. A total internal reflection fluorescence (TIRF) assay for the 5-HT3 receptor was developed, which is suitable for high-through-put screening. Therefore, the receptor was immobilised via its C-terminal His-tag onto a nitrilotriacetic acid-modified quartz surface. The affinities of both the fluorescent ligand and several non-fluorescent compounds were rapidly determined by the TIRF assay, and were shown to agree well with both the solution and classical radioligand binding assays. This indicated that the functional integrity of the receptor was preserved at the sensor surface. Due to the extreme sensitivity of the TIRF assay allows to obtain a complete pharmacological affinity profile of a quantity of receptor provided by a small number of highly-expressing cells.
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PMID:Fluorescence techniques for fundamental and applied studies of membrane protein receptors: the 5-HT3 serotonin receptor. 1007 83

Activation of cardiac sympathetic afferents during myocardial ischaemia causes angina and induces important cardiovascular reflex responses. Reactive oxygen species (ROS) are important chemical stimuli of cardiac afferents during and after ischaemia. Iron-catalysed Fenton chemistry constitutes one mechanism of production of hydroxyl radicals. Another potential source of these species is xanthine oxidase-catalysed oxidation of purines. Polymorphonuclear leukocytes (PMNs) also contribute to the production of ROS in some conditions. The present study tested the hypothesis that both xanthine oxidase-catalysed oxidation of purines and neutrophils provide a source of ROS sufficient to activate cardiac afferents during ischaemia. We recorded single-unit activity of cardiac afferents innervating the ventricles recorded from the left thoracic sympathetic chain (T1-5) of anaesthetized cats to identify the afferents' responses to ischaemia. The role of xanthine oxidase in activation of these afferents was determined by infusion of oxypurinol (10 mg kg(-1), I.V.), an inhibitor of xanthine oxidase. The importance of neutrophils as a potential source of ROS in the activation of cardiac afferents during ischaemia was assessed by the infusion of a polyclonal antibody (3 mg ml(-1) kg(-1), I.V.) raised in rabbits immunized with cat PMNs. This antibody decreased the number of circulating PMNs and, to a smaller extent, platelets. Since previous data suggest that platelets release serotonin (5-HT), which activates cardiac afferents through a serotonin receptor (subtype 3,5-HT3 receptor) mechanism, before treatment with the antibody in another group, we blocked 5-HT3 receptors on sensory nerve endings with tropisetron (300 microg kg(-1), I.V.). We observed that oxypurinol significantly decreased the activity of cardiac afferents during myocardial ischaemia from 1.5 +/- 0.4 to 0.8 +/- 0.4 impulses s(-1). Similarly, the polyclonal antibody significantly reduced the discharge frequency of ischaemically sensitive cardiac afferents from 2.5 +/- 0.7 to 1.1 +/- 0.4 impulses s(-1). However, pre-blockade of 5-HT3 receptors eliminated the influence of the antibody on discharge activity of the afferents during ischaemia. This study demonstrates that ROS generated from the oxidation of purines contribute to the stimulation of ischaemically sensitive cardiac sympathetic afferents, whereas PMNs do not play a major role in this process.
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PMID:Xanthine oxidase, but not neutrophils, contributes to activation of cardiac sympathetic afferents during myocardial ischaemia in cats. 1218 3

The nicotinic acetylcholine receptors (nAChRs) and the 5-HT3 serotonin receptor subtype belong to a superfamily of neurotransmitter-gated ion channels involved in fast synaptic communication throughout the nervous system. Their trafficking to the neuron plasmalemma, as well as their targeting to specific subcellular compartments, is critical for understanding their physiological role. In order to investigate the cellular distribution of these receptors, we tagged the N-termini of alpha3beta4-nAChR subunits and the 5-HT3AR subunit with cyan and yellow fluorescent proteins (CFP, YFP). The fusion subunits were coexpressed in human embryonic kidney (HEK-293) cells, where they assemble into functional receptor channels, as well as in primary cultures of hippocampal neurons. Fluorescence microscopy of living cells revealed that the heteropentameric alpha3CFP-beta4 and YFP-alpha3beta4 receptors are mainly distributed in the endoplasmic reticulum, while the homopentameric YFP-5-HT3A receptor was localized both to the plasma membrane and within intracellular compartments. Moreover, the YFP-5-HT3A receptor was found to be targeted to the micropodia in HEK-293 cells and to the dendritic spines in hippocampal neurons, where it could be accessed by extracellularly applied specific fluorescent probes. The efficient targeting of the YFP-5-HT3A to the cytoplasmic membrane is in line with the large serotonin-elicited currents (nA range) measured by whole-cell voltage-clamp recordings in transfected HEK-293 cells. In contrast, alpha3beta4-nAChRs expressed in the same cells yielded weaker ACh-evoked responses. Taken together, the fluorescent and electrophysiological studies presented here demonstrate the predominant intracellular location of alpha3beta4-nACh receptors and the predominant expression of the 5-HT3AR in dendritic surface loci.
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PMID:Distinct subcellular targeting of fluorescent nicotinic alpha 3 beta 4 and serotoninergic 5-HT3A receptors in hippocampal neurons. 1500 32

Pruritus is the most distressing symptom in haemodialysis (HD) patients. Its aetiology has not yet been delineated, and thus there are no good therapeutical options. Case reports and series attribute antipruritic potency to the serotonin receptor antagonists of the 5-HT3 type in renal pruritus. It was the aim of this study to investigate the antipruritic effect of two different 5-HT3 receptor antagonists and an antihistamine in 11 patients undergoing HD. Pruritus was induced by iontophoresis with serotonin and histamine and recorded before and after HD. These data were compared to those obtained after oral pretreatment with the 5-HT3 receptor antagonists tropisetron 5 mg and ondansetron 8 mg and the antihistamine cetirizine 10 mg. Ten healthy volunteers served as a control group. Vasocutaneous parameters (wheal and flare), skin temperature and alloknesis were also determined. Itching in HD patients and controls was not significantly diminished by oral pretreatment with the serotonin receptor antagonists. In controls, but not in HD patients, cetirizine significantly reduced itching, skin temperature and vasocutaneous parameters. Our data additionally demonstrate that there are no significant differences in vasocutaneous parameters, itching and alloknesis in HD patients before and after dialysis. We conclude that 5-HT3 receptor blockers such as tropisetron and ondansetron and the antihistamine cetirizine do not sufficiently reduce serotonin- and histamine-induced itching in haemodialyis patients.
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PMID:Antipruritic effects of two different 5-HT3 receptor antagonists and an antihistamine in haemodialysis patients. 1514 20

A chimera comprising the N-terminal region of the human alpha7 nicotinic acetylcholine receptor, fused to the transmembrane/C-terminal domains of the mouse serotonin 5-HT3 receptor, was constructed. Injection of the chimera cDNA into Xenopus oocytes, or transient transfection in human embryonic kidney (HEK-293) cells, resulted in the expression of functional channels that were sensitive to nicotinic acetylcholine, but not serotonin receptor ligands. In both systems, the responses obtained from chimeric receptors inactivated more slowly than those recorded following activation of wild-type alpha7 receptors. A stable HEK-293 cell line expressing the human alpha7/mouse 5-HT3 chimera was established, which showed that the chimera displayed a similar pharmacological profile to wild-type alpha7 receptors. Use of this chimera in high-throughput screening may enable the identification of novel pharmacological agents that will help to define further the role of alpha7 nicotinic receptors in physiology and disease.
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PMID:Stable expression and characterisation of a human alpha 7 nicotinic subunit chimera: a tool for functional high-throughput screening. 1546 87

Improved understanding of the physiologic and neuropharmacologic mechanisms underlying chemotherapy-induced nausea and vomiting (CINV) has driven significant progress in the treatment of CINV over the past 2 decades. Recognition of the role of neurotransmitters and their receptors in the process of CINV has been central to this progress. Initial attention focused on dopamine, then on serotonin, and most recently on substance P, which has yielded a useful new class of antiemetic medications known as selective neurokinin-1 receptor antagonists. Preclinical studies of these neurokinin-1 receptor antagonists suggested that they would demonstrate broad antiemetic activity in acute emesis, demonstrate activity against cisplatin-induced delayed emesis, be well tolerated, and contribute to enhanced efficacy when used in combination with other classes of antiemetics. These suggestions appear to have been largely borne out in clinical trials. Pharmacogenomics may offer a means to further extend and apply our understanding of CINV by enabling more selective targeting of antiemetic therapies. To date, the application of pharmacogenomics to CINV has focused on variations in the metabolism of serotonin receptor antagonists by CYP 450 genotype and variations in the 5-HT3 receptor gene itself.
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PMID:Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. 1551 Sep 75

We will focus on spinal cord dorsal horn lamina I projection neurones, their supraspinal targets and involvement in pain processing. These spinal cord neurons respond to tonic peripheral inputs by wind-up and other intrinsic mechanisms that cause central hyper-excitability, which in turn can further enhance afferent inputs. We describe here another hierarchy of excitation - as inputs arrive in lamina I, neurones rapidly inform the parabrachial area (PBA) and periaqueductal grey (PAG), areas associated with the affective and autonomic responses to pain. In addition, PBA can connect to areas of the brainstem that send descending projections down to the spinal cord - establishing a loop. The serotonin receptor, 5HT3, in the spinal cord mediates excitatory descending inputs from the brainstem. These descending excitatory inputs are needed for the full coding of polymodal peripheral inputs from spinal neurons and are enhanced after nerve injury. Furthermore, activity in this serotonergic system can determine the actions of gabapentin (GBP) that is widely used in the treatment of neuropathic pain. Thus, a hierarchy of separate, but interacting excitatory systems exist at peripheral, spinal and supraspinal sites that all converge on spinal neurones. The reciprocal relations between pain, fear, anxiety and autonomic responses are likely to be subserved by these spinal-brainstem-spinal pathways we describe here. Understanding these pain pathways is a first step toward elucidating the complex links between pain and emotions.
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PMID:Spinal and supraspinal contributions to central sensitization in peripheral neuropathy. 1621


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