Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs

Richardson, B. P.; Engel, G; Donatsch, P.; Stadler, P. A.

doi:10.1038/316126a0

Cited by 826 publications

(345 citation statements)

References 25 publications

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“…Furthermore, this result supports our suggestion that 5-HT2 receptors are predominantly involved in 5-HT-mediated mouse skin inflammation. It has been reported that 5-HT excites nociceptive sensory neurons, and application of 5-HT to a blister base gives rise to the sensation of pain (29). This activation of nociceptive neurons is mimicked by 2-methyl 5-HT, while the response to 5-HT is inhibited by ICS 205-930.…”

Section: Discussionmentioning

confidence: 93%

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

Inoue

Nagata

Kinoshita

1995

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the involvement of serotonin (5-HT) in mouse ear edema induced by topical application of capsaicin (250 ,ug/ear). Application of capsaicin to the ear caused degranulation of mast cells in skin connective tissue. Capsaicin-induced ear edema was significantly inhibited by preadministration of 5-HT2 receptor antagonists such as ketanserin (2 mg/kg, i.v.) and LY 53857 (1 mg/kg, i.v.), but not 5-HT1-, 5-HT3-and 5-HT4-receptor antagonists. Intradermal injection of a-methyl 5-HT (5-HT2-receptor agonist) and 5-HT into ear skin produced edema formation more potently than 8-OH-DPAT (5-HT1A agonist) and 2-methyl 5-HT (5-HT3 agonist). 5-HT2 antagonists markedly suppressed the edema response to 5-HT and its receptor agonists, whereas any antagonist for 5-HT1, 5-HT3 and 5-HT4-receptors had no effect. Furthermore, 5-HT2-receptor antagonists partly prevented ear edema in response to substance P (SP), a putative mediator of capsaicin-induced edema, and compound 48/80, a releaser of vasoactive amines from mast cells. These results suggest that 5-HT released from mast cells is partly involved in the development of capsaicin-induced mouse ear edema via 5-HT2 receptors in the ear skin.Keywords: Capsaicin, Serotonin (5-HT), Ear edema (mouse), 5-HT receptor, 5-HT-receptor antagonist Capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent substance contained in many red peppers, evokes neurogenic inflammatory responses such as axon reflex vasodilation, plasma extravasation and painful sensitization (1). Topical application of capsaicin to the mouse ear produces neurogenic skin inflammation (2, 3), which may be mediated by neuropeptides including substance P (SP) released through activation of primary afferent sensory neurons. Virus and Gebhart (4) have suggested that in addition to SP, serotonin (5-HT) also plays a role in the pharmacological activity of capsaicin. Others have reported that treatment of newborn rats with capsaicin causes an increase in the concentrations of histamine and 5-HT in the rat skin as a result of changes of the mast cell system in response to the permanent degeneration of sensory nerves (5). In fact, evidence exists to indicate that peripheral nerve endings and mast cells are in close spatial and functional association (6 -8). Previous studies have found that methysergide is effective in inhibiting capsaicin-induced mouse ear edema (3). However, clear evidence for the involvement of 5-HT in capsaicin-induced inflammation is lacking.5-HT receptors have been classified into at least four subtypes: 5-HT1, 5-HT2, 5-HT3 and 5-HT4 (9, 10). Among them, 5-HT2 receptors participate in the increase of cutaneous vascular permeability induced by 5-HT in rats (11, 12). 5-HT3 receptors are located on neurons and elicit depolization which results in transmitter release from parasympathetic, sympathetic, sensory and enteric neurons (13). Recent studies have shown that neuropeptides are partly released by mediation of 5-HT3 receptor from capsaicin-sensitive afferent neurons (14). These evidence sugg...

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Section: Discussionmentioning

confidence: 93%

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

Inoue

Nagata

Kinoshita

1995

Japanese Journal of Pharmacology

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“…Miner & Sanger, 1986. The recent synthesis of specific 5HT-3 receptor antagonists (Richardson et al, 1985) has led to the demonstration in animal models (Miner & Sanger, 1986) and in man (Cunningham et al, 1987;Leibungut & Lancranjan, 1987) of the importance of 5HT-3 receptor antagonism in anti-emesis.BRL43694 [Endo-N-(9-methyl-9-azabicyclo-(3,3, I)-non-3-yl)-I -methyl-indazole-3-carboxamide] has been recently developed by Beecham Pharmaceuticals Research Division as a selective 5HT-3 antagonist. In common with other agents of this class it rapidly abolishes vomiting induced by cisplatin in ferrets (Boyle et al, 1987 Table I.…”

mentioning

confidence: 99%

“…Miner & Sanger, 1986). The recent synthesis of specific 5HT-3 receptor antagonists (Richardson et al, 1985) has led to the demonstration in animal models (Miner & Sanger, 1986) and in man (Cunningham et al, 1987;Leibungut & Lancranjan, 1987) of the importance of 5HT-3 receptor antagonism in anti-emesis.…”

mentioning

confidence: 99%

Pharmacokinetics and anti-emetic efficacy of BRL43694, a new selective 5HT-3 antagonist

Cassidy¹,

Raina²,

Lewis³

et al. 1988

Br J Cancer

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Summary Twenty patients receiving a variety of emetogenic cytotoxics (including cisplatin in 5) were given a single i.v. infusion of 40,ugkg-1 of BRL43694 (as the hydrochloride salt) in successive groups of 3-4 patients between 0-6 hours after chemotherapy. Eleven patients were completely protected from vomiting; 9 had mild to moderate nausea and vomiting, but none severe enough to require alternative anti-emetic 'rescue'. In 4 of the patients in whom BRL43694 was delayed until 4-6h after chemotherapy, vomiting had already begun; in each case There is increasing evidence that the anti-emetic effect of high dose metoclopramide is mediated by 5-hydroxytryptamine antagonism at the 5HT-3 receptor (Costall et al., 1986. Fozard & Mobarok, 1978. Miner & Sanger, 1986. The recent synthesis of specific 5HT-3 receptor antagonists (Richardson et al., 1985) has led to the demonstration in animal models (Miner & Sanger, 1986) and in man (Cunningham et al., 1987;Leibungut & Lancranjan, 1987) of the importance of 5HT-3 receptor antagonism in anti-emesis.BRL43694 [Endo-N-(9-methyl-9-azabicyclo-(3,3, I)-non-3-yl)-I -methyl-indazole-3-carboxamide] has been recently developed by Beecham Pharmaceuticals Research Division as a selective 5HT-3 antagonist. In common with other agents of this class it rapidly abolishes vomiting induced by cisplatin in ferrets (Boyle et al., 1987 Table I.Patients with serious concurrent illness, myocardial infarction within the previous 6 months, cardiac arrythmias or conduction disturbance, and those with significant hepatic (>2 times normal range of bilirubin or transaminases) or renal (creatinine > 150 4umol 1 -1) dysfunction were excluded from the study. All patients gave written informed consent and the study protocol was approved by our local Ethical Committee.Successive groups of 4-6 patients were given BRL43694 at a dose of 40 ,ig kg -1 as a single i.v. infusion over 30 min at 0, 2, 4 or 6 h after completion of their first course of chemotherapy. In all subsequent courses they were treated with standard anti-emetics (usually a combination of nabilone and prochlorperazine). Provision was made in the protocol for alternative anti-emetic 'rescue' of patients who did not respond to BRL43694. Patients completed visual analogue scales (VAS) of nausea, drowsiness and anxiety at 4-hourly intervals over 24 h. Nausea, vomiting and adverse effects were also assessed 4-hourly by trained observers. In view of the CVS effects in animals of high doses of BRL43694, the first 6 patients on this study were electrocardiographically monitored for 30 min following the infusion of BRL43694. All patients had 24 h ambulatory ECG performed. All patients also had hourly pulse and blood pressure measurements for 8 hours following BRL43694 administration.Blood samples were obtained before commencing the infusion of BRL43694 and at the following times thereafter for pharmacokinetic analyses: 0,1,2, 3,4,5,6, 7,8,24h.The samples were taken into EDTA tubes and the plasma separated by centrifugation, then frozen at -20°C and s...

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“…Following the demonstration that metoclopramide was more effective at high doses (Gralla et al, 1981) and that high dose metoclopramide showed antagonism at the 5HT3 (or M) type receptor (Fozard, 1984) a new group of selective 5HT3 receptor antagonists, then recently developed (Brittain et al, 1987;Fake et al, 1987;Fozard, 1984;Richardson et al, 1985) were investigated as possible anti-emetics. Their effectiveness has surpassed other anti-emetic therapies in both animal models (Miner & Sanger, 1986;Miner, Sanger & Turner, 1987;Costall et al, 1986;Stables et al, 1987;Bermudez et al, 1988) and human studies (Cunningham et al, 1988;Liebundgut et at., 1988;Carmichael et al, 1988). So far they have only been employed singly and hence it was of interest to evaluate whether the effect of a 5HT3 receptor antagonist, GR38032F (Glaxo), against cyclophosphamideinduced vomiting in the ferret could be improved by combination with dexamethasone.…”

mentioning

confidence: 99%

“…The ferret is an animal that is well established for studies of emesis (Florczyck et al, 1982;Gylys & Gidda, 1986;King, 1988;Tuor et al, 1988) shows behavioural perturbations which may indicate nausea (Bermudez et al, 1987; and is a good predictive model of antiemetics for man (Miner et al, 1987). We employed a dose of GR38032F that had been established as effective in delaying but not reducing the emesis in this model (Stables et al, 1987) and observed whether this was influenced by dexamethasone. We also studied the effect of dexamethasone alone.…”

mentioning

confidence: 99%

Dexamethasone can potentiate the anti-emetic action of a 5HT3 receptor antagonist on cyclophosphamide induced vomiting in the ferret

Hawthorn

Cunningham²

1990

Br J Cancer

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A new group of selective 5HT3 antagonists are proving to be effective anti-emetics for cytotoxic and radiation induced vomiting in both animal models and man. Current anti-emetic regimens often benefit from combination therapy, in particular the efficacy of metoclopramide (which can be a weak 5HT3 antagonist), can be improved by combination with dexamethasone, another anti-emetic. Hence it was of interest to evaluate whether a 5HT3 receptor antagonist GR38032F could be improved by combination with dexamethasone. Vomiting induced by cyclophosphamide in the ferret was observed after pre-treatment with dexamethasone alone or in combination with GR38032F. Animals were also observed for signs of 'nausea'. Dexamethasone alone proved a weak anti-emetic in this system but did have significant effects on 'nausea'. GR38032F has previously been shown to be capable of totally controlling emesis due to cyclophosphamide in the ferret. Here a dose of GR38032F that is not 100% effective was employed; this was shown to have effects on 'nausea' but most interestingly its anti-emetic action was increased by combination with dexamethasone. This may be important for the minority of patients whose vomiting is not completely controlled by GR38032F alone.

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Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs

Cited by 826 publications

References 25 publications

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

Pharmacokinetics and anti-emetic efficacy of BRL43694, a new selective 5HT-3 antagonist

Dexamethasone can potentiate the anti-emetic action of a 5HT3 receptor antagonist on cyclophosphamide induced vomiting in the ferret

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