Effects of tachykinin NK1 receptor antagonists on vagal hyperreactivity and neuronal M2 muscarinic receptor function in antigen challenged guinea-pigs

Richard W. Costello, Allison Fryer, Kristen E. Belmonte, David Jacoby

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

1. The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2. In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1-100 μg kg-1, i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4 mg kg-1, i.p.), SR140333 (1 mg kg-1, s.c.) or CP96345 (15 mg kg-1, i.p.) before antigen challenge, prevented M2 receptor dysfunction. 3. Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 μmol kg-1 i.p.), before antigen challenge, prevented M2 receptor dysfunction. 4. Electrical stimulation of the vagus nerves caused a frequency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. 5. Histamine (1-20 nmol kg-1, i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity. 6. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7. These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.

Original languageEnglish (US)
Pages (from-to)267-276
Number of pages10
JournalBritish Journal of Pharmacology
Volume124
Issue number2
DOIs
StatePublished - 1998
Externally publishedYes

Fingerprint

Muscarinic M2 Receptors
Tachykinin Receptors
Guinea Pigs
Antigens
Bronchoconstriction
Eosinophils
Histamine
Muscarinic Agonists
Pilocarpine
Vagus Nerve
Eosinophilia
Bronchoalveolar Lavage
Electric Stimulation

Keywords

  • Eosinophils
  • Inflammation
  • Parasympathetic nerves

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{c4cd1a0643f547a1a741b63a15da23bc,
title = "Effects of tachykinin NK1 receptor antagonists on vagal hyperreactivity and neuronal M2 muscarinic receptor function in antigen challenged guinea-pigs",
abstract = "1. The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2. In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1-100 μg kg-1, i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4 mg kg-1, i.p.), SR140333 (1 mg kg-1, s.c.) or CP96345 (15 mg kg-1, i.p.) before antigen challenge, prevented M2 receptor dysfunction. 3. Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 μmol kg-1 i.p.), before antigen challenge, prevented M2 receptor dysfunction. 4. Electrical stimulation of the vagus nerves caused a frequency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. 5. Histamine (1-20 nmol kg-1, i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity. 6. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7. These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.",
keywords = "Eosinophils, Inflammation, Parasympathetic nerves",
author = "Costello, {Richard W.} and Allison Fryer and Belmonte, {Kristen E.} and David Jacoby",
year = "1998",
doi = "10.1038/sj.bjp.0701822",
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T1 - Effects of tachykinin NK1 receptor antagonists on vagal hyperreactivity and neuronal M2 muscarinic receptor function in antigen challenged guinea-pigs

AU - Costello, Richard W.

AU - Fryer, Allison

AU - Belmonte, Kristen E.

AU - Jacoby, David

PY - 1998

Y1 - 1998

N2 - 1. The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2. In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1-100 μg kg-1, i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4 mg kg-1, i.p.), SR140333 (1 mg kg-1, s.c.) or CP96345 (15 mg kg-1, i.p.) before antigen challenge, prevented M2 receptor dysfunction. 3. Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 μmol kg-1 i.p.), before antigen challenge, prevented M2 receptor dysfunction. 4. Electrical stimulation of the vagus nerves caused a frequency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. 5. Histamine (1-20 nmol kg-1, i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity. 6. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7. These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.

AB - 1. The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2. In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1-100 μg kg-1, i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4 mg kg-1, i.p.), SR140333 (1 mg kg-1, s.c.) or CP96345 (15 mg kg-1, i.p.) before antigen challenge, prevented M2 receptor dysfunction. 3. Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 μmol kg-1 i.p.), before antigen challenge, prevented M2 receptor dysfunction. 4. Electrical stimulation of the vagus nerves caused a frequency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. 5. Histamine (1-20 nmol kg-1, i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity. 6. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7. These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.

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