No abstract

An excessive, irritable, productive or non-productive coughing associated with airway inflammation belongs to pathological cough. Increased activation of airway vagal nociceptors in pathological conditions results from dysregulation of the neural pathway that controls cough. A variety of mediators associated with airway inflammation overstimulate these vagal airway fibers including C-fibers leading to hypersensitivity and hyperreactivity. Because current antitussives have limited efficacy and unwanted side effects there is a continual demand for the development of a novel more effective antitussives for a new efficacious and safe cough treatment. Therefore, inhibiting the activity of these vagal C-fibers represents a rational approach to the development of effective antitussive drugs. This may be achieved by blocking inflammatory mediator receptors or by blocking the generator potential associated with the specific ion channels. Because voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs become a promising neural target. There is evidence that NaV1.7, 1.8 and 1.9 subtypes are predominantly expressed in airway cough-triggering nerves. The advantage of blocking these NaVs is suppressing C-fiber irrespective to stimuli, but the disadvantage is that by suppressing the nerves is may also block beneficial sensations and neuronal reflex behavior. The concept is that new antitussive drugs would have the benefit of targeting peripheral airway nociceptors without inhibiting the protective cough reflex.

No abstract

We investigated voltage-gated sodium channels (NaV1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers with mechanically-sensitive nerve terminals in the isolated innervated guinea pig esophagus. NaV1 inhibitors were selectively delivered to the tissue containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The NaV1.7 inhibitor PF-05089771 nearly abolished action potential initiation in response to low levels of esophageal distention, but only partially inhibited the response to higher levels of esophageal distention. The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). In addition to NaV1.7, nodose C-fiber (TRPV1-positive) neurons retrogradely labeled from the esophagus expressed mRNA for multiple TTX-sensitive NaV1s. The group NaV1.1, NaV1.2 and NaV1.3 inhibitor ICA-121431 inhibited but did not abolish the PF-05089771-insensitive component of the response to high level of esophageal distention. However, combination of ICA-121431 with Compound 801, which also inhibits NaV1.7 and NaV1.6, nearly abolished the response to high level of esophageal distention. Our data indicate that the action potential initiation in esophageal nodose C-fibers evoked by low (innocuous) levels of esophageal distention is mediated by NaV1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing NaV1.7-independent component that involves multiple TTX-sensitive NaV1s. The stimulus intensity-dependent recruitment of NaV1s may offer novel opportunities for strategic targeting of NaV1 subunits for inhibition of nociceptive signaling in visceral C-fibers