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Browning KN. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 2015; 9:413. [PMID: 26578870 PMCID: PMC4625078 DOI: 10.3389/fnins.2015.00413] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 10/15/2015] [Indexed: 12/21/2022] Open
Abstract
Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity.
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Affiliation(s)
- Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine Hershey, PA, USA
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Babic T, Browning KN. The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 2013; 722:38-47. [PMID: 24184670 DOI: 10.1016/j.ejphar.2013.08.047] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 08/20/2013] [Accepted: 08/28/2013] [Indexed: 02/07/2023]
Abstract
Nausea and vomiting are among the most frequently occurring symptoms observed by clinicians. While advances have been made in understanding both the physiological as well as the neurophysiological pathways involved in nausea and vomiting, the final common pathway(s) for emesis have yet to be defined. Regardless of the difficulties in elucidating the precise neurocircuitry involved in nausea and vomiting, it has been accepted for over a century that the locus for these neurocircuits encompasses several structures within the medullary reticular formation of the hindbrain and that the role of vagal neurocircuits in particular are of critical importance. The afferent vagus nerve is responsible for relaying a vast amount of sensory information from thoracic and abdominal organs to the central nervous system. Neurons within the nucleus of the tractus solitarius not only receive these peripheral sensory inputs but have direct or indirect connections with several other hindbrain, midbrain and forebrain structures responsible for the co-ordination of the multiple organ systems. The efferent vagus nerve relays the integrated and co-ordinated output response to several peripheral organs responsible for emesis. The important role of both sensory and motor vagus nerves, and the available nature of peripheral vagal afferent and efferent nerve terminals, provides extensive and readily accessible targets for the development of drugs to combat nausea and vomiting.
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Affiliation(s)
- Tanja Babic
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, USA.
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TOHEI A, KOJIMA SI, IKEDA M, HOKAO R, SHINODA M. Effects of Cyclophosphamide on the Kaolin Consumption (Pica Behavior) in Five Strains of Adult Male Rats. J Vet Med Sci 2011; 73:901-6. [DOI: 10.1292/jvms.10-0433] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Atsushi TOHEI
- Laboratory Animal Research Center, Dokkyo Medical University
| | | | - Masashi IKEDA
- Institute of International Education and Research, Dokkyo Medical University
| | | | - Motoo SHINODA
- Laboratory Animal Research Center, Dokkyo Medical University
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Percie du Sert N, Rudd JA, Apfel CC, Andrews PLR. Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT₃ receptor antagonists. Cancer Chemother Pharmacol 2010; 67:667-86. [PMID: 20509026 PMCID: PMC3043247 DOI: 10.1007/s00280-010-1339-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Accepted: 04/16/2010] [Indexed: 01/17/2023]
Abstract
Purpose The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT3 receptor antagonists to assess its translational validity. Methods A systematic review identified available evidence and was used to perform meta-analyses. Results Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg−1 dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg−1, which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT3 receptor antagonists reduced cisplatin (5 mg kg−1) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. Conclusion Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT3 receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret.
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Affiliation(s)
- N Percie du Sert
- Division of Basic Medical Sciences, St George's University of London, London, UK.
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Darmani NA, Ray AP. Evidence for a re-evaluation of the neurochemical and anatomical bases of chemotherapy-induced vomiting. Chem Rev 2009; 109:3158-99. [PMID: 19522506 DOI: 10.1021/cr900117p] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Nissar A Darmani
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766-1854, USA.
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6
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Schweitzer VG. Cisplatin-Induced Ototoxicity: The Effect of Pigmentation and Inhibitory Agents. Laryngoscope 2009. [DOI: 10.1002/lary.1993.103.s59.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Darmani NA, Crim JL, Janoyan JJ, Abad J, Ramirez J. A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: Evidence from the least shrew. Brain Res 2009; 1248:40-58. [DOI: 10.1016/j.brainres.2008.10.063] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2008] [Revised: 10/17/2008] [Accepted: 10/27/2008] [Indexed: 02/07/2023]
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de la Puente-Redondo VA, Tilt N, Rowan TG, Clemence RG. Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs. Am J Vet Res 2007; 68:48-56. [PMID: 17199418 DOI: 10.2460/ajvr.68.1.48] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To evaluate the efficacy of maropitant, a novel neurokinin-1 receptor antagonist, to treat and prevent emesis caused by IV infusion of a chemotherapeutic dose of cisplatin (70 mg/m(2)) in dogs. ANIMALS 64 healthy 6-month-old Beagles (32 males and 32 females). PROCEDURES To evaluate the effect of maropitant on ongoing emesis, 24 dogs were randomized to 2 treatment groups (12 dogs each). Saline (0.9% NaCl) solution or maropitant (1 mg/kg) was administered once by SC injection immediately following the first emetic event after cisplatin infusion. Dogs were assessed for emesis for 6 hours after initiation of cisplatin infusion. To evaluate the use of maropitant for the prevention of emesis, 40 dogs were randomized to 4 treatment groups (10 dogs each). Placebo or maropitant (1, 2, or 3 mg/kg) was administered PO as a tablet. Cisplatin infusion was initiated at 19 hours after treatment, and dogs were assessed for emesis for 6 hours. RESULTS No treatment-related adverse events were observed in either study. For the treatment of ongoing emesis, significantly fewer emetic events were observed for maropitant-treated dogs, compared with placebo-treated dogs (mean, 5.2 vs 15.8), and the mean time to cessation of emesis was significantly shorter (0.65 vs 1.65 hours). In the prevention of emesis, maropitant-treated dogs had significantly fewer emetic events (means, 2.7, 1.1, and 0.5 for maropitant at 1, 2, and 3 mg/kg, respectively), compared with placebo-treated dogs (mean, 20.3). CONCLUSIONS AND CLINICAL RELEVANCE Results suggest that maropitant is safe and effective in the treatment and prevention of cisplatin-induced emesis in dogs.
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Abstract
Chemotherapy-induced toxicities commonly occur in sites within the gastrointestinal (GI) tract and account for dose-limiting effects. These toxicities are major contributing factors to dose reduction, delays, and cessation of cancer treatment. Through intensive therapies including surgery, combination chemotherapy, hormonal therapy, and targeted therapy, an increasing number of patients with cancer are experiencing improved survival and long-term disease-free survival, as well as palliation of disease-related symptoms. Thus, GI toxicities should be predicted and appropriate interventions initiated to prevent them when possible and provide effective supportive measures and comprehensive follow-up care. This review will discuss the etiology, incidence, prevention, and treatment of GI toxicities of cancer chemotherapy.
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Affiliation(s)
- Edith P Mitchell
- Division of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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10
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Abstract
AIM: To establish a new, reliable vomit model of minks.
METHODS: Adult male minks were randomly divided into 8 groups (n = 6): cisplatin (7.5 mg/kg) intraperitoneal injection (ip) group, copper sulfate (40 mg/kg) intragastric injection (ig) group, apomorphine (1.6 mg/kg) subcutaneous injection (sc) group, and 18 Gy whole-body X-irradiation group, ondansetron injection group (2 mg/kg ip) 30 min later followed by cisplatin (7.5 mg/kg) ip, normal saline (NS) ip injection control group, metoclopramide injection group (4 mg/kg ip) 30 min later followed by apomorphine (1.6 mg/kg) sc, NS ig control group. The frequency of retching and vomiting was calculated. After behavioral experiment, distribution of 5-HT in the ileum was detected by immunohistologic method.
RESULTS: Cisplatin, apomorphine, copper sulfate and X-irradiation administered to minks evoked a profound emetic response in the animals. However, retching and vomiting were significantly inhibited by pretreatment with ondansetron and metoclopramide in cisplatin and copper sulfate groups (P = 0.018). Immunohistologic result showed that 5-HT released from enterochromaffin cells (EC cells) was involved in vomiting mechanism.
CONCLUSION: Mink vomit model has a great value in studying the vomiting mechanism and screening new antiemetic drugs.
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Affiliation(s)
- Fang Zhang
- Department of Pharmacology, Medical College of Qingdao University, 38 Dengzhou Road, Qingdao 266021, Shandong Province, China.
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Abstract
Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by anticancer drugs is associated with an increase in the concentration of serotonin (5-HT) (5-HT) in the intestinal mucosa and brainstem. 5-HT released from the enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells appears to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The precise role of 5-HT in the occurrence of vomiting has not been fully elucidated. The present review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagal nerve activity. Various models and methods for predicting emesis are also evaluated.
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Affiliation(s)
- Masaru Minami
- Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
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Endo T, Minami M, Hirafuji M, Ogawa T, Akita K, Nemoto M, Saito H, Yoshioka M, Parvez SH. Neurochemistry and neuropharmacology of emesis - the role of serotonin. Toxicology 2000; 153:189-201. [PMID: 11090957 DOI: 10.1016/s0300-483x(00)00314-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs and radiation is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestinal mucosa and in the brainstem. 5-HT released from enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT(3) receptors on the adjacent vagal afferent nerves. This vagal afferent nerve depolarization may evoke the vomiting reflex. This review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release from EC cells and afferent vagus nerve activity.
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Affiliation(s)
- T Endo
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757, Ishikari-Tobetsu, 061-0293, Hokkaido, Japan.
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Kobayashi K, Ishihara Y, Nukariya N, Niitani H, Furue H. Effects of anti-emetic drug (tropisetron) on quality of life during chemotherapy: use of a diary-type questionnaire and application of summary measures for assessment in a randomized, multicentre study. Joint Research Group for Tropisetron Double-Blind Comparative Study. Respirology 1999; 4:229-38. [PMID: 10489664 DOI: 10.1046/j.1440-1843.1999.00180.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The role of tropisetron as an anti-emetic drug in the prevention of delayed nausea and vomiting remains unclear. Therefore, effectiveness of tropisetron in patients receiving cancer chemotherapy was evaluated by application of summary measures using a quality of life (QOL) questionnaire. The diary-type QOL self-rating questionnaire was constituted by seven scales. A double-blind randomized, multicentre study was performed in 33 hospitals. Quality of life was measured in 98 patients. Patients receiving cisplatin were randomized to group T (administration of tropisetron before and 4 days after cisplatin treatment) and group P (administration of tropisetron before cisplatin treatment and followed by placebo for 4 days). The rate of complete protection from delayed emesis in the groups T and P was 46.3 and 36.5%. All scales, except social wellbeing changed immediately in both groups and reached a nadir on days 2-3, after that returning to the control levels during 2 weeks after cisplatin treatment. Group T was significantly better than group P in physical wellbeing, mental wellbeing, functional wellbeing and global QOL scores summarized by area under the curve and Difmax (maximum differences of QOL scales' score from the best score throughout the entire period). These results indicate that continuous administration of tropisetron could contribute to preventing patient QOL influenced by cisplatin treatment, and the combined use of summary measures may be useful for the evaluation of QOL in cancer clinical trial.
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Affiliation(s)
- K Kobayashi
- Fourth Department of Internal Medicine, Nippon Medical School, Tokyo Women's Medical University, Japan
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Sann H, Hoppe S, Baldwin L, Grundy D, Schemann M. Presence of putative neurotransmitters in the myenteric plexus of the gastrointestinal tract and in the musculature of the urinary bladder of the ferret. Neurogastroenterol Motil 1998; 10:35-47. [PMID: 9507249 DOI: 10.1046/j.1365-2982.1998.00083.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The innervation of the musculature in the ferret stomach, ileum, colon and urinary bladder was investigated using immunohistochemistry in noncolchicin-treated tissues. In the gastrointestinal tract two main subpopulations of myenteric neurones were found: cholinergic neurones expressing choline acetyltransferase (ChAT), which made up 68, 67 and 67% of the neurones in the stomach, ileum and colon, respectively, and nitrergic neurones containing nitric oxide synthase and NADPH-diaphorase (stomach: 23%, ileum: 21%, colon: 26%). In the stomach, cholinergic neurones expressed substance P (SP, 2% of all neurones), dopamine-beta-hydroxylase (DBH, 19%) but not tyrosine hydroxylase (TH) or vasoactive intestinal polypeptide (VIP), while nitrergic neurones contained VIP and neuropeptide Y (NPY). TH- but not DBH-immunoreactivity was observed in 4% of gastric neurones. Intense immunoreactivity in the musculature suggests that part of ChAT/SP- and NOS/NPY/VIP-positive neurones function as motorneurones. In the ileum, a high number (32%) of DBH-positive neurones was demonstrated. About half of the SP-positive neurones in the ileum also contained calcitonin gene-related peptide (CGRP). In the urinary bladder, only few intramural ganglia were observed. The smooth muscle was densely innervated by ChAT, NPY and DBH immunoreactive fibres. The data showed that the innervation of the ferret viscera exhibited similarities but also differences as compared with other mammalian species. Some of the chemical coding of myenteric neurones is remarkably similar to that observed in other mammals.
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Affiliation(s)
- H Sann
- Physiologisches Institut, Tierärztliche Hochschule, Hannover, Germany
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Abstract
The development of antiemetic drugs has been one of the most rewarding areas of oncologic research, since therapeutic advances in this area can result in immediate improvement in the quality of life for patients undergoing chemotherapy. Antiemetic therapy has progressed dramatically during the past decade and a half. Fifteen years ago, patients receiving cisplatin for the first time had a median of 12 vomiting episodes within the first 24 hours, whereas now more than 50 percent of such patients have no vomiting episodes at all. Theoretical and clinical challenges remain, however, in the effort to control chemotherapy-induced emesis. The mechanisms of anticipatory vomiting and delayed vomiting are still not understood, and consistently effective therapeutic approaches to these problems have yet to be developed.
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Affiliation(s)
- S M Grunberg
- Section of Hematology/Oncology, Vermont Cancer Center, University of Vermont, Burlington 05402
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Fukui H, Yamamoto M, Sasaki S, Sato S. Emetic effects of anticancer drugs and involvement of visceral afferent fibers and 5-HT3 receptors in dogs. Eur J Pharmacol 1993; 250:281-7. [PMID: 8112385 DOI: 10.1016/0014-2999(93)90392-u] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The emetic effects of five anticancer drugs, cyclophosphamide, nitrogen mustard-N-oxide, actinomycin D, 5-fluorouracil and L-asparaginase, and the effects of bilateral abdominal vagotomy and bilateral greater splanchnic nerve section or a 5-HT3 receptor antagonist on the emesis induced by these drugs were investigated in dogs. Cyclophosphamide (20 mg/kg, i.v.), nitrogen mustard-N-oxide (5 mg/kg, i.v.) and actinomycin D (50 micrograms/kg, i.v.) caused vomiting in dogs with a long latency period. 5-Fluorouracil (5 mg/kg, i.v.) and L-asparaginase (2000 K.U./kg, i.v.) failed to induce vomiting. Bilateral abdominal vagotomy and bilateral greater splanchnic nerve section completely inhibited the vomiting induced by the former three anticancer drugs. Furthermore, the vomiting was inhibited completely by intravenous administration of ICS205930 (2 x 0.1 mg/kg), a 5-HT3 receptor antagonist. These results suggest that activation of visceral afferents through 5-HT3 receptors mediates the vomiting induced by cyclophosphamide, nitrogen mustard-N-oxide and actinomycin D.
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Affiliation(s)
- H Fukui
- Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan
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Fukui H, Yamamoto M, Sasaki S, Sato S. Involvement of 5-HT3 receptors and vagal afferents in copper sulfate- and cisplatin-induced emesis in monkeys. Eur J Pharmacol 1993; 249:13-8. [PMID: 8282015 DOI: 10.1016/0014-2999(93)90656-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The emetic effects of copper sulfate and cisplatin and the potential involvement of vagal afferent fibers and 5-HT3 receptors in the emesis were investigated in cynomolgus monkeys. Retching and vomiting induced by both oral (100 mg/kg) and intravenous (20 mg/kg) copper sulfate were inhibited markedly by abdominal vagotomy. Furthermore, the emetic response induced by oral copper sulfate was strongly inhibited by intravenous ICS 205-930 (0.1 mg/kg), a 5-HT3 receptor antagonist. Cisplatin (3 mg/kg, i.v.) caused severe retching and vomiting, and the number of emetic responses was much greater than that in other species. The emetic response induced by cisplatin was inhibited markedly by abdominal vagotomy or concurrent administration of ICS 205-930 (3 x 0.1 mg/kg, i.v.). These results suggest that the monkey is more sensitive to cisplatin than other species and that the vagal afferent terminals and 5-HT3 receptors play an important role in the emetic response induced by copper sulfate and cisplatin.
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Affiliation(s)
- H Fukui
- Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan
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Fukui H, Yamamoto M, Sato S. Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. JAPANESE JOURNAL OF PHARMACOLOGY 1992; 59:221-6. [PMID: 1434118 DOI: 10.1254/jjp.59.221] [Citation(s) in RCA: 64] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The involvement of visceral afferent fibers and 5-HT3 receptors in the emesis induced by cisplatin was studied in beagle dogs. The emesis induced by cisplatin (3 mg/kg, i.v.) was inhibited by the intravenous administration of ICS205930 (2 x 0.01 or 2 x 0.1 mg/kg) and MDL72222 (2 x 0.5 mg/kg), 5-HT3 receptor antagonists, but not by the intravenous administration of metoclopramide (2 x 0.5 mg/kg), a dopamine D2 receptor antagonist. The cisplatin-induced emesis was also suppressed by the intravenous administration of para-chlorophenylalanine (300 mg/kg/day for 3 days), an inhibitor of 5-HT synthesis. On the other hand, the administration of ICS205930 into the IVth ventricle (2 x 0.01 mg/animal) had no effects on the cisplatin-induced emesis. The cisplatin-induced emesis was completely inhibited by abdominal vagotomy and splanchnicectomy, but not by splanchnicectomy alone. On the contrary, the emesis induced by apomorphine was suppressed by the intravenous (0.1 mg/kg) or intracerebroventricular (0.05 mg/animal) administration of metoclopramide, but not by visceral nerve section. These results strongly suggest that cisplatin evokes emesis mainly by acting on the vagal afferent terminals through the release of 5-HT and that peripheral 5-HT3 receptors are involved in this action.
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Affiliation(s)
- H Fukui
- Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan
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