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.
Cough is one of the most important defensive reflexes. However,
extensive non- productive cough is a harmful mechanism leading
to the damage of human airways. Cough is initiated by activation
of vagal afferents in the airways. The site of their convergence is
particularly the nucleus of the solitary tract (nTS). The secondorder neurons terminate in the pons, medulla and spinal cord and
there is also the cortical and subcortical control of coughing. Upper
airway cough syndrome (UACS) – previously postnasal drip
syndrome - is one of the most common causes of chronic cough
together with asthma and gastroesophageal reflux. The main
mechanisms leading to cough in patients with nasal and sinus
diseases are postnasal drip, direct irritation of nasal mucosa,
inflammation in the lower airways, upper airway inflammation and
the cough reflex sensitization. The cough demonstrated by UACS
patients is probably due to hypersensitivity of the upper airways
sensory nerve or lower airways sensory nerve, or a combination of
both. Further studies are needed to clarify this mechanism.