capsazepine and Apnea

Inhalation of capsaicin-based sprays can cause central respiratory depression and lethal apneas. There are contradictory reports regarding the sites of capsaicin action. Furthermore, an understanding of the neurochemical mechanisms underlying capsaicin-induced apneas and the development of pharmacological interventions is lacking. The main objectives of this study were to perform a systematic study of the mechanisms of action of capsaicin-induced apneas and to provide insights relevant to pharmacological intervention. In vitro and in vivo rat and transient receptor potential vanilloid superfamily member 1 (TRPV1)-null mouse models were used to measure respiratory parameters and seizure-like activity in the presence of capsaicin and compounds that modulate glutamatergic neurotransmission. Administration of capsaicin to in vitro and in vivo rat and wild-type mouse models induced dose-dependent apneas and the production of seizure-like activity. No significant changes were observed in TRPV1-null mice or rat medullary slice preparations. The capsaicin-induced effects were inhibited by the TRPV1 antagonist capsazepine, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists CNQX, NBQX, perampanel, and riluzole, a drug that inhibits glutamate release and increases glutamate uptake. The capsaicin-induced effects on breathing and seizure-like activity were accentuated by positive allosteric modulators of the AMPA receptors, CX717 and cyclothiazide. To summarize, capsaicin-induced apneas and seizure-like behaviors are mediated via TRPV1 activation acting at lung afferents, spinal cord-ascending tracts, and medullary structures (including nucleus tractus solitarius). AMPA receptor-mediated conductances play an important role in capsaicin-induced apneas and seizure-like activity. A pharmaceutical strategy targeted at reducing AMPA receptor-mediated glutamatergic signaling may reduce capsaicin-induced deleterious effects.

Topics: Animals; Animals, Newborn; Apnea; Brain Stem; Capsaicin; Mice, Inbred C57BL; Plethysmography; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spinal Cord; TRPV Cation Channels

Laryngeal exposure to cigarette smoke (CS) evokes sensory irritation, but the mechanisms are largely unclear. The TRPA1 and TRPV1 receptors are two types of Ca(2+)-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.. 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.. 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 Ca(2+) chelator) and BAPTA-AM (intracellular Ca(2+) chelator), indicating the importance of reactive oxygen species (ROS) and Ca(2+). 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.. 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.

Topics: Acetanilides; Acetylcysteine; Animals; Antioxidants; Apnea; Calcium Channels; Capsaicin; Chelating Agents; Dose-Response Relationship, Drug; Egtazic Acid; Indomethacin; Laryngeal Nerves; Larynx; Neurons, Afferent; Purines; Rats; Reactive Oxygen Species; Smoking; TRPA1 Cation Channel; TRPC Cation Channels; TRPV Cation Channels