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

Recent studies have shown that non-opioid defensive analgesia in male mice is potently inhibited by the 5-HT3 receptor antagonist, ondansetron. The present series of experiments was conducted to further explore the involvement of 5-HT3 receptor mechanisms in this particular form of adaptive inhibition of pain. The drug ICS 205-930 significantly attenuated the reaction at 1.25-2.5 micrograms/kg, with smaller and larger doses being ineffective. Both MDL 72222 and MDL 73147EF produced flat dose-response curves, with significant inhibition of defensive analgesia at minimum effective doses of less than or equal to 10 and 300 micrograms/kg, respectively. Although MDL 72699, the quaternary salt of MDL 72222, also inhibited the reaction, this effect was seen at comparatively large doses (0.5-1.0 mg/kg) only. None of the compounds tested had significant intrinsic effects of tail-flick latencies, over the dose ranges tested. These findings indicate that 5-HT3 receptor mechanisms may have an important modulatory role in certain forms of "stress" analgesia. Data are discussed in relation to the consistent profile of partial inhibition produced by 5-HT3 receptor antagonists in this model.
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PMID:Attenuation of defensive analgesia in male mice by 5-HT3 receptor antagonists, ICS 205-930, MDL 72222, MDL 73147EF and MDL 72699. 140 95

Ondansetron is a highly potent and selective antagonist at 5-HT3 receptors. Its anti-emetic actions were first revealed by its ability to antagonize retching and vomiting induced by chemotherapy and radiotherapy in animals and man. Subsequently, the availability of labelled 5-HT3 receptor ligands allowed identification of 5-HT3 receptors, located at highest densities in the area postrema, nucleus tractus solitarius (NTS), in other areas of the brain, and on afferent terminals of the vagus nerve. Postoperative nausea and vomiting may be caused by various factors: the anaesthetic, associated drugs, the surgical procedure, movement of the patient, sex, weight and pain. These factors mediate their effects via the higher brain circuits, the vestibular nuclei, the chemoreceptor trigger zone in the area postrema, or the upper gastrointestinal tract via the vagus nerve, influencing motor and visceral emetic outputs in the hind-brain. It is hypothesized that ondansetron blocks nausea and vomiting by 5-HT3 receptor antagonism at two specific sites: (i) centrally, in the area postrema/NTS; and (ii) peripherally on vagus nerve terminals. The absence of other pharmacological effects of ondansetron ensures an absence of side-effects.
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PMID:Pharmacology of ondansetron. 142 23

Supraspinal opioid analgesia is mediated in part by connections between the midbrain periaqueductal gray (PAG) and the ventral-medial medulla, including the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis (NRGC). A serotonergic synapse appears to participate in this pathway since methysergide microinjected into the NRM-NRGC significantly reduced morphine analgesia elicited from the PAG. The present study evaluated the role of specific serotonin receptor subtypes by pretreating rats with microinjections of either the 5HT2 antagonist, ritanserin or the 5HT3 antagonist, ICS205930, into the NRM-NRGC and examining their effects upon morphine (2.5 micrograms) analgesia elicited from the PAG. Mesencephalic morphine analgesia was significantly reduced following pretreatment with both ritanserin (0.25-2.5 micrograms) on the tail-flick (81%) and jump (65%) tests and ICS205930 (0.25-5 micrograms) on the tail-flick (91%) and jump (63%) tests. Neither ritanserin nor ICS205930 altered basal nociceptive thresholds. Medullary placements ventral or lateral to the NRM/NRGC failed to support these antagonistic effects. These data indicate that ventro-medial medullary 5HT2 and 5HT3 serotonergic receptors modulate the transmission of opioid pain-inhibitory signals from the PAG.
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PMID:Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. 147 4

Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized.
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PMID:Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. 160 46

5-Hydroxytryptamine (5-HT) is present throughout the gastrointestinal tract, which acts as the major reservoir of this substance in the body. Its physiologic role has not been clearly established, although it seems likely that 5-HT is involved in the regulation of aspects of intestinal motility such as peristalsis and the migrating motor complex. In disease states the contribution of 5-HT is perhaps more clearly established, particularly its role in chemotherapy-induced emesis, in the carcinoid syndrome, and, possibly, in mediating the effect of some intestinal secretagogues, notably cholera toxin. Many of the functions of 5-HT in the gut have been elucidated as a result of the development of antagonists to 5-HT receptors. However, some of these compounds have 5-HT agonist activity as well as 5-HT receptor blocking activity, making interpretation of their effects in health and disease difficult. Nevertheless, 5-HT receptor antagonists are finding an important place in the management of the carcinoid syndrome and in chemotherapy-induced emesis and may well evolve as important agents for modulating gut motility and for inhibiting secretory states in the small and large intestine. The suggestion that 5-HT3 receptor antagonists might also modulate visceral sensation in the gut is of great interest because of their potential to relieve symptoms of functional bowel disorders such as pain, urgency, and bowel frequency.
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PMID:5-Hydroxytryptamine and 5-hydroxytryptamine-3 receptor antagonists. 177 47

The present study examined analgesia produced by S and R isomers of the novel 5-HT3 receptor antagonists, ADR-851 and ADR-882 (0.1-10 mg/kg s.c.) against acute thermal, mechanical and formalin-induced inflammatory pain in rats. Neither isomer of ADR-851 or ADR-882 was analgesic in the thermal or mechanical test. Similarly, neither S or R forms of ADR-882 produced significant anti-nociception in the formalin test. In contrast, ADR-851R produced significant analgesia at 3 and 10 mg/kg doses in this test, while ADR-851S produced significant analgesia only at 1 mg/kg.
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PMID:Analgesic effects of S and R isomers of the novel 5-HT3 receptor antagonists ADR-851 and ADR-882 in rats. 180 61

The present study examined patterns of analgesia by intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of the serotonin 5-HT3 receptor agonist, 2-methylserotonin (1-100 micrograms) against acute thermal, mechanical or formalin-induced chemo-inflammatory pain in male rats. Neither i.c.v. or i.t. 2-methylserotonin produced motoric, sedative or respiratory effects. I.c.v. 2-methylserotonin was not analgesic at any dose in the pain assays employed. I.t. 2-methylserotonin produced dose-related analgesia in the formalin test with significant effects at 20-100 micrograms doses. In contrast, only the 100 micrograms dose of 2-methylserotonin produced analgesia against thermal pain, and analgesia was not observed at any dose in the mechanical pain test. The effects of 2-methylserotonin (100 micrograms) in the formalin test were attenuated by pretreatment (10 micrograms i.t.) with the 5-HT3 receptor antagonist MDL-72222, opioid antagonist naloxone or GABA antagonist bicuculline; the 5-HT2-receptor antagonist ketanserin or 5-HT1 receptor antagonist mianserin did not affect 2-methylserotonin-induced analgesia. In the thermal test, i.t. pretreatment with MDL-72222, ketanserin, naloxone or bicuculline, but not mianserin, reduced analgesic effects of 2-methylserotonin (100 micrograms i.t.). These findings suggest that spinal 5-HT3, opioid and GABA receptor systems interact to mediate acute chemo-inflammatory pain, and implicate the interaction of these systems with 5-HT2 receptor substrates in analgesia against acute thermal nociception.
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PMID:Analgesic profile of centrally administered 2-methylserotonin against acute pain in rats. 195 80

A total of 25 patients (5 groups of 5) were given single i.v. doses of 5, 10, 20, 40 and 60 mg MDL 72,222 (a 5-HT3 receptor antagonist) at 15 minutes before the commencement of a 24-h cisplatin infusion (total dose, 120-200 mg) to determine the efficacy and safety of the former in the prevention of nausea and vomiting associated with such chemotherapy. All patients completed the study. The time to onset of vomiting was significantly correlated with dose. All patients vomited following doses of 5 and 10 mg (range, 1-6 episodes), with onset being noted at 5-8 h. At the 20-mg level, only one episode of vomiting was observed in 3/5 patients, with onset being observed at 18-22 h. Following doses of 40 and 60 mg, 3/10 patients did not vomit; in the remaining patients the number of episodes ranged from 1 to 6, but a significant increase occurred in the time to onset of symptoms. At the higher doses, nausea tended to be milder in nature both at onset and at the time of maximal severity. A similar dose-effect trend was seen in the time to onset of the maximal severity of nausea. The time to and requirement for escape medication was similarly extended at doses of greater than or equal to 20 mg MDL 72,222. Pain at the injection site in one patient was the only unwanted effect associated with MDL 72,222. The results suggest that the i.v. injection of 20 mg MDL 72,222 should be further explored in the control of nausea and vomiting associated with cisplatin administration.
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PMID:A single-dose-finding study of the antiemetic effect and associated plasma levels of MDL 72222 in patients receiving cisplatin. 201 17

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.
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PMID:Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. 201 33

Behavioural and pharmacological evidence indicates that non-opioid analgesia in defeated male mice is initiated by anxiety and that serotongergic (5-HT) substrates are implicated. In the present study, the effects of the novel putative 5-HT3 anxiolytic, GR38032F, on this form of adaptive inhibition of pain have been examined. The results showed that defeat analgesia was totally inhibited by 1 microgram/kg-1 mg/kg of GR38032F, with partial inhibition evident over the dose range of 0.0001-0.1 microgram/kg and loss of efficacy at smaller doses. These highly potent effects of GR38032F are consistent with its anxiolytic profile in animal models and cannot be accounted for by indirect actions on basal nociception. These findings point to a potentially important modulatory role for 5-HT3 receptor mechanisms in defeat analgesia and, more generally, provide further evidence for the involvement of 5-HT in the mediation of non-opioid forms of environmentally-induced antinociception.
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PMID:Highly potent inhibitory effects of 5-HT3 receptor antagonist, GR38032F, on non-opioid defeat analgesia in male mice. 213 63


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