The involvement of sensory neuropeptides in toluene diisocyanate-induced tracheal hyperreactivity in the mouse airways.
1. Recently, we developed a murine model to investigate toluene diisocyanate (%DI)-induced occupational asthma. After skin-sensitization and intranasal challenge with TDI (1%) mice exhibited tracheal hyperreactivity 24 h after the challenge. 2. The aim of the present study was to investigate the possible role for sensory neuropeptides in the development of this tracheal hyperreactivity. 3. First, we demonstrated that direct application of TDI in vitro induced the release of tachykinins from the sensory nerves in the mouse isolated trachea. Second, capsaicin pretreatment, resulting in the depletion of sensory neuropeptides, completely abolished the TDI-induced tracheal hyperreactivity 24 h after the challenge. Third, the selective neurokinin1 (NK1)-receptor antagonist RP 67580 (0.2 mumol kg-1) also inhibited tracheal hyperreactivity when it was administered before the challenge. However, administration of RP 67580 during the sensitization phase did not result in a suppression of the TDI-induced tracheal hyperreactivity 24 after the challenge. 4. When TDI-sensitized mice were topically challenged with TDI a marked ear swelling response was observed. The cutaneous response after TDI application was not affected by capsaicin pretreatment or RP 67580 administration. 5. These results clearly show that sensory neuropeptides, particularly tachykinins, are essential for the development of TDI-induced tracheal hyperreactivity during the effector phase. The differences between the airways and skin with respect to the sensory neuropeptides is intriguing and could suggest a local action for the tachykinins in the airways.
Scheerens
H
H
Department of Pharmacology and Pathophysiology, Utrech Institute for Pharmaceutical Sciences, Utrech University, The Netherlands.
Buckley
T L
TL
Muis
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Van Loveren
H
H
Nijkamp
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FP
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000503:physiopathology; D012867:Skin / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000502:physiology; D014051:Toluene 2,4-Diisocyanate; D014133:Tracheal Diseases / Q000139:chemically induced / Q000503:physiopathology*
D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides; D015320:Tachykinins; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D014051:Toluene 2,4-Diisocyanate; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin