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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.