EFFECTS OF TACHYKININ NK1 RECEPTOR ANTAGONISTS ON VAGAL HYPERREACTIVITY AND NEURONAL M-2 MUSCARINIC RECEPTOR FUNCTION IN ANTIGEN CHALLENGEDGUINEA-PIGS

1 The role of tachykinin NK, receptors in the recruitment of eosinophi ls to airway nerves, loss of inhibitory neuronal M-2 muscarinic recept or function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2 In anaesthetized guinea-pigs, the m uscarinic agonist, pilocarpine (1-100 mu g kg(-1), i.v), inhibited vag ally induced bronchoconstriction, in control, but not in antigen-chall enged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M-2 muscarinic receptors in controls and loss of neuronal M-2 receptor function in challenged guinea-pigs. :Pretreatmen t 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 M-2 receptor dysfuncti on. 3 Neither administration of the NK1 antagonists after antigen chal lenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 m u mol kg(-1), i.p.), before antigen challenge, prevented M-2 receptor dysfunction. 4 Electrical stimulation of the vagus nerves caused a fre quency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction t hat was significantly increased following antigen challenge. Pretreatm ent with the NK1 receptor antagonists CP99994 or SR140333 before chall enge prevented this increase. 5 Histamine (1-20 nmol kg(-1), i.v.) cau sed a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs comp ared to controls. Pretreatment of sensitized animals with CP99994 befo re challenge prevented the increase in histamine-induced reactivity. 6 Bronchoalveolar lavage and histological studies showed that after ant igen challenge significant numbers of eosinophils accumulated in the a irways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7 These data in dicate that pretreatment of antigen-sensitized guinea-pigs with NK1, b ut not with NK2 receptor antagonists before antigen challenge prevente d the development of hyperreactivity by protecting neuronal M-2 recept or function. NK1 receptor antagonists do not inhibit eosinophil accumu lation around airway nerves.