The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK<sub>1</sub> receptor

Watson, J. W.; Gonsalves, Susan F.; Fossa, Anthony A.; McLean, Stafford; Seeger, Thomas; Obach, Scott R.; Andrews, Paul

doi:10.1111/j.1476-5381.1995.tb16324.x

Cited by 205 publications

(143 citation statements)

References 54 publications

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“…Rectal temperature was measured 0, 1, 2, 5 min and every 5 min during the first 30 min after apomorphine with an automatic electrical thermometer (HP 5316 Philips). The number of vomitings and retchings elicited by apomorphine was counted by a 'blind' uninformed observer (Watson et al,1995). When vomiting or retching occurred during measurement of blood pressure or heart rate values, a lapse of at least 60 s after the end of the last vomiting or retching was allowed until the cardiovascular parameters returned to preretching values.…”

Section: Methodsmentioning

confidence: 99%

A study of tolerance to apomorphine

Montastruc

Llau

Senard

et al. 1996

British J Pharmacology

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1 The present study was designed to investigate tolerance to several pharmacological effects of apomorphine. 2 Changes in blood pressure, heart rate, plasma noradrenaline levels, rectal temperature, respiratory rate and retching plus vomiting were compared after administration of apomorphine (200 jig kg-', i.v. as a bolus) or saline at different time intervals (30, 120 and 720 min) in four groups of chloraloseanaesthetized dogs. 3 The first administration of apomorphine induced a significant decrease in blood pressure and rectal temperature, a marked rise in heart rate with no change in noradrenaline plasma levels or respiratory rate. Emesis occurred in 71% of the animals. 4 A second administration of apomorphine 30 min later failed to modify blood pressure or heart rate. In contrast, the magnitude of apomorphine-induced changes in blood pressure and heart rate was similar to that observed after the first administration when apomorphine was given 120 or 720 min later. 5 The apomorphine-induced decrease in rectal temperature evoked by a second dose of apomorphine was less marked when given 30 and 120 min after the first dose and unchanged when given 720 min later. 6 The number of animals exhibiting retching and vomiting was lower when apomorphine was reinjected after 30 min than when the time between two successive injections of apomorphine was 120 or 720 min. 7 These results show that tolerance to apomorphine involves its cardiovascular, hypothermic and emetic effects. The time course of tolerance to repeated injections of apomorphine is longer for its hypothermic than for its hypotensive or emetic effects. This suggests a tissue-specific regulation of D2 dopamine receptors to repeated injections of apomorphine.

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Section: Methodsmentioning

confidence: 99%

A study of tolerance to apomorphine

Montastruc

Llau

Senard

et al. 1996

British J Pharmacology

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“…These disparate findings suggest a peripheral component in addition to the proposed central action. Indeed, centrally-and/or peripherally-acting NK 1 receptor antagonists can both prevent emesis produced by systemic administration of cisplatin [1,37,60], and reduce vagal afferent discharge produced peripherally [37,38].…”

Section: Introductionmentioning

confidence: 99%

Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

et al. 2008

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Substance P (SP) is thought to play a cardinal role in emesis via the activation of central tachykinin NK 1 receptors during the delayed phase of vomiting produced by chemotherapeutics. Although the existing supportive evidence is significant, due to lack of an appropriate animal model, the evidence is indirect. As yet, no study has confirmed that emesis produced by SP or a selective NK 1 receptor agonist is sensitive to brain penetrating antagonists of either NK 1 , NK 2 , or NK 3 receptors. The goals of this investigation were to demonstrate: 1) whether intraperitoneal (i.p.) administration of either SP, a brain penetrating (GR73632) or non-penetrating (e.g. SarMet -SP) NK 1 receptor agonist, an NK 2 receptor agonist (GR64349), or an NK 3 receptor agonist (Pro 7 -NKB), would induce vomiting and/or scratching in the least shrew (Cryptotis parva) in a dose-dependent manner; and whether these effects are sensitive to the above selective receptor antagonists; 2) whether an exogenous emetic dose of SP (50 mg/kg, i.p.) can penetrate into the shrew brain stem and frontal cortex; 3) whether GR73632 (2.5 mg/kg, i.p.)-induced activation of NK 1 receptors increases Fos-measured neuronal activity in the neurons of both brain stem emetic nuclei and the enteric nervous system of the gut; and 4) whether selective ablation of peripheral NK 1 receptors can affect emesis produced by GR73632. The results clearly demonstrated that while SP produced vomiting only, GR73632 caused both emesis and scratching behavior dose-dependently in shrews, and these effects were sensitive to NK 1 -, but not NK 2 -or NK 3 -receptor antagonists. Neither the selective, non-penetrating NK 1 receptor agonists, nor the selective NK 2 -or NK 3 -receptor agonists, caused a significant dose-dependent behavioral effect. An emetic dose of SP selectively and rapidly penetrated the brain stem but not the frontal cortex. Systemic GR73632 increased Fos expression in the enteric nerve plexi, the medial subnucleus of nucleus tractus solitarius, and the dorsal motor nucleus of the vagus, but not the area postrema. Ablation of peripheral NK 1 receptors attenuated the ability of GR73632 to induce a maximal frequency of emesis and shifted its percent animals vomiting dose-response curve to the right. The NK 1 -ablated shrews exhibited scratching behavior after systemic GR73632-injection. These results, for the first time, affirm a cardinal role for central NK 1 receptors in SP-induced vomiting, and a Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. facilitatory role for gastrointestinal NK 1 receptors. In addition, the...

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“…(Papka et al, 1981) and also in vagal afferents impinging on NTS neurons (Sykes et al, 1994) by NK1 receptors (Nilsson et al, 1991;Regoli et al, 1991;Rusin et al, 1993). In fact, high densities of NK1 receptors have been identified in the NTS (McRitchie & Tork, 1994;Watson et al 1995;Maubach and Jones, 1997). Other data indicate that the peptide attenuate the cardiac baroreceptor reflex mediated by NK1-GABA receptor mechanism in the NTS (Boscan et al, 2002;Pickering et al, 2003).…”

Section: Discussionmentioning

confidence: 94%

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

Endoh

2006

Brain Research

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The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK₁ receptor

Cited by 205 publications

References 54 publications

A study of tolerance to apomorphine

A study of tolerance to apomorphine

Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

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The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK1 receptor

Cited by 205 publications

References 54 publications

A study of tolerance to apomorphine

A study of tolerance to apomorphine

Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

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The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK₁ receptor