Abstract
Activation of airway nociceptive C‐fibers evokes cough and parasympathetic reflexes. Nociceptor excitability is increased by inflammation, worsening symptoms in asthma. Airway C‐fiber terminals are packed with mitochondria. Inflammatory signaling modulates mitochondrial function, causing reactive oxygen species (ROS) production. We hypothesize that these ROS increase nociceptor excitability. We recorded action potentials in single C‐fibers using an ex vivo mouse lung‐ganglia preparation. “Nociceptors” are slow fibers, sensitive to capsaicin (via TRPV1). Antimycin A, a mitochondrial complex III inhibitor that evokes ROS, had no effect on the excitability of non‐nociceptive nerves. Ten minutes after antimycin A, nociceptive nerves developed hyperexcitability to chemical and mechanical stimuli. Antimycin‐induced hyperexcitability was blocked by N‐acetyl cysteine and dithiothreitol but not by TRPV1 knockout. ROS can activate protein kinase C independently of Ca2+. Here, the PKC inhibitor bisindolylmaleimide I (BIM I), but not the inactive analogue BIM V, abolished antimycin‐induced hyperexcitability. Antimycin A also caused PKC translocation via ROS. Lastly, exogenous H2O2 induced nociceptor hyperexcitability, which was blocked by BIM I. We conclude that acute modulation of nerve terminal mitochondria can induce airway nociceptor hyperexcitability via ROS‐activated PKC pathways.Grant Funding Source: Supported by R01HL119802‐01
Published Version
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