Important roles of tachykinins in the development of allergic nasal hyperresponsiveness in guinea-pigs


Takeshi Nabe, Department of Pharmacology, Kyoto Pharmaceutical University, 5 Nakauchi, Misasagi, Yamashina, Kyoto 607-8414, Japan.


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 D4 was assessed 2 days after an antigen challenge. We also evaluated whether intranasal dosing with a tachykinin causes NHR. NK1 and NK2 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 NK1 and NK2 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 NK1 or NK2 receptor antagonists revealed that NK2 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 NK2 receptor antagonists and partially inhibited by NK1 receptor antagonists.

Conclusions SP and NKA, which are released early after the challenge, mediate the development of NHR by preferentially activating NK2 receptors. Therefore, NK2 receptor antagonists might prove to be effective treatment of AR.