title: Mechanistic Studies of Capsaicin-Induced Apnea in Rodents.
abstract: 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.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D001933:Brain Stem / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D010991:Plethysmography; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D050916:TRPV Cation Channels; C071423:capsazepine; D002211:Capsaicin
keywords: amino-3-hydroxy-5-methyl-4-isoxazolepropionate; apnea; capsaicin; glutamate; transient receptor potential vanilloid superfamily member 1