Roles of Substance P and NK1 Receptor in the Brainstem in the Development of Emesis

Saito, Ryo; Takáno, Yukio; Kamiya, Hiro-o

doi:10.1254/jphs.91.87

Cited by 112 publications

(68 citation statements)

References 82 publications

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“…3 H]substance P bindings in the solitary nucleus, a part of the vomiting center (4,5). T-2328 is a potent and selective NK 1 -receptor antagonist that penetrates into the central nervous system upon i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have suggested the involvement of substance P and NK 1 receptors in the generation of delayed emesis following the treatment with chemotherapeutic agents (4). Substance P-containing fibers and tackykinin NK 1 receptors are present in the solitary nucleus, a part of the emetic center (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…Substance P-containing fibers and tackykinin NK 1 receptors are present in the solitary nucleus, a part of the emetic center (4,5). Administration of substance P produced emesis in ferrets (6).…”

Section: Introductionmentioning

confidence: 99%

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Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Watanabe¹,

Okamoto

Ishii³

et al. 2008

J Pharmacol Sci

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Abstract. The effect of T-2328 {2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl] amino]methyl]-[1,1'-biphenyl]-4-carbonitrile dihydrochloride}, a novel tachykinin NK 1 -receptor antagonist, was examined on cisplatin-induced emesis in ferrets. Cisplatin induced acute emesis in 24 h and delayed emesis during 24 and 72 h, respectively. Ondansetron, a 5-HT 3 antagonist, almost completely blocked the acute emesis and transiently reduced the delayed emesis. In contrast, T-2328 elicited long-lasting anti-emetic effects on both acute and delayed phases by a single intravenous administration. Suppression of delayed emesis was not due to elimination of the acute phase because the delayed emesis was also suppressed by administration after the onset of delayed emesis. Persistent blockade of NK 1 receptors in the brain was demonstrated by inhibition of the NK 1 agonist-induced foot tapping response for over 24 h. An appreciable amount of T-2328 was present in the brain 32 and 72 h after the injection. The NK 1 agonistinduced contractions of isolated ileum in guinea pigs was antagonized with IC 50 values of 1.4 nM in an insurmountable manner. It is likely that T-2328 exerts the long-lasting anti-emetic effect by not only long-term presence in the brain but also its insurmountable inhibition of NK 1 receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Watanabe¹,

Okamoto

Ishii³

et al. 2008

J Pharmacol Sci

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“…Neuroanatomical regions of the area postrema and nucleus of the tractus solitarius (NTS) in the brainstem underlie emetic responding. Vagal afferents from the gastrointestinal tract innervate these areas, which lie outside the blood-brain barrier, to mediate the emetic response (Hornby, 2001;Saito et al, 2003). Using pharmacological magnetic resonance imaging in live rats, Chin et al (2006) found that apomorphine activated the area postrema and NTS at plasma concentrations of drug known to induce emesis.…”

Section: Introductionmentioning

confidence: 99%

Acute Oxycodone Induces the Pro-Emetic Pica Response in Rats

Batra¹,

Schrott²

2011

J Pharmacol Exp Ther

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Oxycodone, a semisynthetic opioid analgesic, is frequently prescribed for the management of pain. Side effects of nausea and emesis affect patient compliance and limit its therapeutic use. The present study established that an antinociceptive dose of oxycodone (15 mg/kg; oral) induces the pica response. We found sex differences in the temporal course of pica, with females having a longer duration. Opioid receptors mediated the pica response, as 1.0 mg/kg naloxone transiently attenuated and 2.0 mg/kg naloxone blocked pica. A -selective antagonist failed to block the response, suggesting mediation by opioid receptor. For further validation, we used the well established kaolin intake model to assess pica with the chemotherapeutic drug cisplatin as a positive control. Oxycodone and cisplatin significantly increased kaolin intake 4-to 7-fold, and the wet weight of stomach was elevated 2-to 3-fold. To examine the underlying neural circuitry, we investigated c-fos activation in the area postrema and nucleus of solitary tract (NTS). Oxycodone treatment significantly increased the number of c-fos-positive neurons in the area postrema and NTS compared with water controls. As expected, cisplatin also increased the number of c-fos-positive cells in these regions. In the area postrema, the oxycodone effect was greater than cisplatin, especially at 2 h. These results indicate that an antinociceptive dose of oxycodone is associated with the expression of pica, a pro-emetic response.

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“…While the acute phase emesis responds to 5-HT 3 antagonists, the delayed phase remains difficult to control (19). Involvement of substance P and NK 1 has been suggested in the generation of delayed emesis following the treatment with chemotherapeutic agents (20). Recent studies further demonstrated the suppression of delayed emesis by aprepitant in both humans and animals (4,5,10), although brain-nonpenetrating NK 1 antagonists are ineffective (21).…”

Section: Gr73632-induced Foot Tapping In Gerbilsmentioning

confidence: 99%

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

Watanabe¹,

Asai²,

Ishii³

et al. 2008

J Pharmacol Sci

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Abstract. The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK 1 ) receptor. T-2328 inhibited the specific binding of [ 3 H][Sar 9 ,Met(O 2 ) 11 ]substance P to tachykinin NK 1 receptors in human lymphoblastic IM9 cells with K i of 0.08 nM. In the same assay, K i for aprepitant, a brain-penetrating NK 1 antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK 1 receptors since the affinities for human NK 2 , NK 3 receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK 1 receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK 1 receptor. T-2328 (0.03 -0.1 mg / kg, i.v.) and aprepitant (1 -3 mg / kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1 -0.3 mg/ kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg / kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK 1 antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapyinduced emesis.

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Roles of Substance P and NK1 Receptor in the Brainstem in the Development of Emesis

Cited by 112 publications

References 82 publications

Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Long-Lasting Anti-emetic Effect of T-2328, a Novel NK1 Antagonist

Acute Oxycodone Induces the Pro-Emetic Pica Response in Rats

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

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