The Prospect for Potent Sodium Voltage-Gated Channel Blockers to Relieve an Excessive Cough

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.

The Changes in Expression of NaV1.7 and NaV1.8 and the Effects of the Inhalation of Their Blockers in Healthy and Ovalbumin-Sensitized Guinea Pig Airways

“…Na V 1.7 and Na V 1.8 have been shown to be expressed in lung-specific vagal sensory neurons in human and animal models that display cough reflexes, e.g., guinea pigs [ 12 ], or on jugular and nodose ganglia [ 21 ]. These channels are upregulated in response to inflammatory mediators that are known to increase cough sensitivity [ 22 ]. Moreover, former and recent studies have already shown that cultured bronchial smooth muscle cells, including those from human airways, express Na + currents [ 23 ].…”

From bench to bedside: The role of cough hypersensitivity in chronic cough

“…Neuronally expressed ion channels and receptors are implicated in the development of cough hypersensitivity, including those involved in peripheral stimulation of cough (e.g., transient receptor potential [TRP] ankyrin-1 [TRPA1], TRP villanoid-1 [TRPV1], TRPV4, TRP melastatin-8 [TRPM8], P2 × 3 receptors and NaV 1.7 and 1.8) and those involved in the transmission of signals in the central nervous system (CNS; e.g., neurokinin-1 [NK-1] receptors, nicotinic acetylcholine receptors). 33,[57][58][59][60] The TRPA1 and TRPV1 channels regulate tussive responses in murine and guinea pig models, 61 and sodium channel blockers reduce capsaicin-invoked cough in guinea pigs, 62 thus demonstrating these peripheral channels play a role in irritant-induced cough. Additionally, preclinical studies have shown that central administration of nicotine reduces cough in cats, and the α7 nicotinicreceptor agonist ATA-101 dose dependently inhibits cough in guinea pigs.…”

“Prostaglandin E2 Sensitizes the Cough Reflex Centrally via EP3 Receptor-dependent Activation of NaV 1.8 Channels”

“…In particular, transient resistant potential (TRP) channels such as TRPV1 and TRPA1 have been reported to play key roles in sensitizing the cough re ex both peripherally and centrally (12,13,18,19). More recently, voltage-gated sodium channels (NaVs), mainly NaV 1.7, 1.8 and 1.9, which are expressed in airway sensory neurons, have been reported to be involved in the regulation of peripheral cough (20)(21)(22).…”