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Important roles of tachykinins in the development of allergic nasal hyperresponsiveness in guinea‐pigs
Author(s) -
Nabe T.,
Tsuzuike N.,
Ohtani Y.,
Mizutani N.,
Watanabe S.,
Fujii M.,
Yoshimura M.,
Nagasawa M.,
Kohno S.
Publication year - 2009
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2008.03097.x
Subject(s) - nasal administration , neurokinin a , substance p , tachykinin receptor , medicine , receptor , immunology , pharmacology , tachykinin receptor 1 , guinea pig , receptor antagonist , antagonist , neuropeptide
Summary Background Although it has been suggested that the use of tachykinin receptor antagonists might prove to be an effective treatment for allergic rhinitis (AR), they are not used clinically. Therefore, we decided to examine the effects of tachykinin receptor antagonists on AR symptoms in an appropriate experimental model. Objective To evaluate newly developed tachykinin receptor antagonists in a Japanese cedar pollen‐induced AR model and to determine their effect on allergen‐induced sneezing, nasal blockage, and nasal hyperresponsiveness (NHR). Methods Sensitized guinea‐pigs were challenged by forced inhalation of pollen once every week. Sneezing and nasal blockage were observed after pollen challenges. NHR (nasal blockage) to an intranasal application of leukotriene D 4 was assessed 2 days after an antigen challenge. We also evaluated whether intranasal dosing with a tachykinin causes NHR. NK 1 and NK 2 receptor antagonists were administered before an intranasal treatment with antigen or tachykinin. Amounts of tachykinins present in nasal cavity lavage fluid were measured by an enzyme immunoassay. Results Although an NK 1 and NK 2 receptor dual antagonist showed no effect on pollen‐induced sneezing and biphasic nasal blockage, it did completely suppress the development of NHR. Experiments using specific NK 1 or NK 2 receptor antagonists revealed that NK 2 receptor activation was preferentially involved in the development of hyperresponsiveness. Increases in the levels of substance P (SP) and neurokinin A (NKA) in the nasal tissue were noted 20 min–1 h after the challenge. Intranasal instillation of either SP or NKA‐induced NHR, which was almost completely inhibited by NK 2 receptor antagonists and partially inhibited by NK 1 receptor antagonists. Conclusions SP and NKA, which are released early after the challenge, mediate the development of NHR by preferentially activating NK 2 receptors. Therefore, NK 2 receptor antagonists might prove to be effective treatment of AR.