Role of TRPA1 and TRPV1 in the ROS-dependent sensory irritation of superior laryngeal capsaicin-sensitive afferents by cigarette smoke in anesthetized rats

• Published in: Pulmonary pharmacology & therapeutics Vol. 26; no. 3; pp. 364 - 372
• Main Authors: Liu, Bi-Yu, Tsai, Tung-Lung, Ho, Ching-Yin, Lu, Shing-Hwa, Lai, Ching Jung, Kou, Yu Ru
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2013
• Subjects: Acetanilides - pharmacology; Acetylcysteine - pharmacology; Animals; Antioxidants - pharmacology; Apnea - chemically induced; Apnea - physiopathology; Calcium Channels - metabolism; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Chelating Agents - pharmacology; Cigarette smoke; Dose-Response Relationship, Drug; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Indomethacin - pharmacology; Laryngeal capsaicin-sensitive afferents; Laryngeal Nerves; Laryngeal sensory irritation; Larynx - drug effects; Medical Education; Neurons, Afferent - drug effects; Pulmonary/Respiratory; Purines - pharmacology; Rats; Reactive oxygen species; Reactive Oxygen Species - pharmacology; Smoking - physiopathology; TRPA1; TRPA1 Cation Channel; TRPC Cation Channels - drug effects; TRPV Cation Channels - drug effects; TRPV1; Reactive oxygen species; transient receptor potential ankyrin 1; TRPA1; transient receptor potential vanilloid 1; AITC; TRPV1; ethylene glycol-bis(β-aminoethyl ether)-N,N,N,N,-tetraacetic acid; CPZ; nordihydroguaiaretic acid; Laryngeal capsaicin-sensitive afferents; allyl isothiocyanate; EGTA; CS; α,β-methylene-ATP; NAC; superior laryngeal nerves; Laryngeal sensory irritation; NDGA; ROS; capsazepine; SLNs; Cigarette smoke; N-acetyl- l-cysteine; α,β-meATP
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2013.01.010

Abstract Background Laryngeal exposure to cigarette smoke (CS) evokes sensory irritation, but the mechanisms are largely unclear. The TRPA1 and TRPV1 receptors are two types of Ca2+ -permeant channels located at the terminals of airway capsaicin-sensitive afferents. We investigated the mechanisms underlying the airway reflex evoked by laryngeal CS exposure in anesthetized rats. Methods CS (7 ml) was delivered into a functionally isolated larynx, while the animals ( n  = 201) breathed spontaneously. Respiratory parameters were measured. All use of pharmacological agents involved pretreatment by laryngeal application. Results Laryngeal CS exposure immediately evoked a concentration-dependant apneic response that was unrelated to the nicotine content of the CS. This inhibition of breathing was abolished by bilateral sectioning of the superior laryngeal nerves (SLNs) or by perineural capsaicin treatment of the SLNs (selective blocking of capsaicin-sensitive afferent neural conduction), suggesting the involvement of superior laryngeal capsaicin-sensitive afferents in the reflex. The reflex apnea was significantly attenuated by N-acetyl- l -cysteine (antioxidant), EGTA (extracellular Ca2+ chelator) and BAPTA-AM (intracellular Ca2+ chelator), indicating the importance of reactive oxygen species (ROS) and Ca2+ . This reflex apnea was also partially reduced by HC030031 (TRPA1 receptor antagonist) and capsazepine (TRPV1 receptor antagonist), and was nearly abolished by a combination of these two antagonists, suggesting a central role for the TRPA1 and TRPV1 receptors. Furthermore, the reflex apnea was attenuated by indomethacin (cyclooxygenase inhibitor); however, the attenuation by indomethacin was not increased by pretreatment with HC030031 or capsazepine, indicating that TRPA1 and TRPV1 receptor functionality is, at least in part, linked to cyclooxygenase metabolites. Conclusions The reflex apnea evoked by laryngeal CS requires activation of both TRPA1 and TRPV1 receptors, which are likely to be located at the terminals of superior laryngeal capsaicin-sensitive afferents. Laryngeal sensory irritation by CS seems to depend on the actions of ROS and cyclooxygenase metabolites on these two types of receptors.