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Tachykinins pp 359–440Cite as

The Role of Tachykinins and the Tachykinin NK1 Receptor in Nausea and Emesis

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 164))

Abstract

Nausea and vomiting are both components of the body’s defensive system to protect against the effects of accidentally ingested toxins. Whilst these responses have survival value in the wild, they can also be induced by diseases and disease treatments with one of the most unpleasant examples being the treatment of cancer using cytotoxic drugs and radiation. Understanding the mechanisms by which this occurs has been a major impetus to the identification of novel anti-emetic agents. The recent licensing of an NK1 receptor antagonist for the treatment of chemotherapy-induced emesis provides the first example of a drug acting to block the effects of substance P. Whilst the blockade of emesis by selective NK1 receptor antagonists provides the most powerful evidence implicating substance P in emesis there is a considerable body of supporting evidence including: presence of substance P (usually by immunohistochemistry) in relevant sites (e.g. vagal afferents, nucleus tractus solitarius, gastrointestinal mucosa); presence of NK1, receptors in relevant sites (e.g. nucleus tractus solitarius); induction of emesis by administration of NK1 receptor agonists. Pre-clinical studies in a variety of species revealed the broad-spectrum anti-emetic effects of NK1 receptor antagonists against stimuli including the anti-cancer agent cisplatin (acute and delayed phases), radiation, opioids, copper sulphate, apomorphine, motion and electrical stimulation of abdominal vagal afferents. Species differences in response to NK1 receptor antagonists and species-specific iso-forms of the receptor are discussed and the potential implications for transfer of data from these animal models to humans reviewed. The spectrum of antiemetic effects against stimuli acting via both peripheral and centrally acting emetic stimuli, a requirement for brain penetration and blockade of emesis by microinjection of antagonists into the brain stem all support a central site of action with the nucleus tractus solitarius and the vicinity of the Botzinger complex being the favoured locations although definitive studies are awaited. Evidence for a contribution from a peripheral site in the delayed phase of cytotoxic druginduced emesis is reviewed. The unique pre-clinical profile and especially the observation that NK1, receptor antagonists could block both the acute and delayed phase of cisplatin-induced emesis prompted clinical trials of a number of agents [CJ11974 (ezlopitant), GR205171 (vofopitant), MK869/L754030 (aprepi-tant)] in patients undergoing chemotherapy. These studies and others in motion and post-operative nausea and vomiting are reviewed in detail. In general the trials in chemotherapy show NK1 receptor antagonists have demonstrable efficacy against acute (first 24 h after therapy) emesis when given alone and enhance the efficacy of 5-hydroxytryptamine3 receptor antagonists and dexamethasone when given in combination. Of particular clinical significance is the efficacy of NK1 receptor antagonists given in combination with dexamethasone to reduce emesis in the delayed phase (days 2–5) as this phase of emesis is poorly con trolled using current treatments. Efficacy against nausea has been reported but to date the effects appear less clear than against emesis and further studies are required. The availability of NK1 receptor antagonists in the clinic will provide a useful tool to further investigate the involvement of NK1 receptors in emesis and to explore the roles of central and peripheral substance P in health and disease.

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Authors and Affiliations

  1. Department of Basic Medical Sciences, St George’s Hospital Medical School, Cranmer Terrace, London, SW17 ORE, UK

    P. L. R. Andrews

  2. Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin N.T., Hong Kong

    J. A. Rudd

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  1. Department of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria

    Peter Holzer (Professor) (Professor)

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Andrews, P.L.R., Rudd, J.A. (2004). The Role of Tachykinins and the Tachykinin NK1 Receptor in Nausea and Emesis. In: Holzer, P. (eds) Tachykinins. Handbook of Experimental Pharmacology, vol 164. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18891-6_12

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