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.
- MeSH
- akční potenciály účinky léků fyziologie MeSH
- antitusika farmakologie terapeutické užití MeSH
- blokátory sodíkových kanálů řízených napětím farmakologie terapeutické užití MeSH
- kašel farmakoterapie patofyziologie MeSH
- lidé MeSH
- nociceptory účinky léků metabolismus MeSH
- sodíkové kanálky řízené napětím fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antitusika MeSH
- blokátory sodíkových kanálů řízených napětím MeSH
- sodíkové kanálky řízené napětím MeSH
UNLABELLED: Controlling pain in burn-injured patients poses a major clinical challenge. Recent findings suggest that reducing the activity of the voltage-gated sodium channel Nav1.7 in primary sensory neurons could provide improved pain control in burn-injured patients. Here, we report that partial thickness scalding-type burn injury on the rat paw upregulates Nav1.7 expression in primary sensory neurons 3 h following injury. The injury also induces upregulation in phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), a marker for nociceptive activation in primary sensory neurons. The upregulation in p-CREB occurs mainly in Nav1.7-immunopositive neurons and exhibits a peak at 5 min and, following a decline at 30 min, a gradual increase from 1 h post-injury. The Nav1.7 blocker protoxin II (ProTxII) or morphine injected intraperitoneally 15 min before or after the injury significantly reduces burn injury-induced spinal upregulation in phosphorylated serine 10 in histone H3 and phosphorylated extracellular signal-regulated kinase 1/2, which are both markers for spinal nociceptive processing. Further, ProTxII significantly reduces the frequency of spontaneous excitatory post-synaptic currents in spinal dorsal horn neurons following burn injury. Together, these findings indicate that using Nav1.7 blockers should be considered to control pain in burn injury. KEY MESSAGES: • Burn injury upregulates Nav1.7 expression in primary sensory neurons. • Burn injury results in increased activity of Nav1.7-expressing primary sensory neurons. • Inhibiting Nav1.7 by protoxin II reduces spinal nociceptive processing. • Nav1.7 represents a potential target to reduce pain in burn injury.
- Klíčová slova
- Pain, Primary sensory neuron, Spinal cord, p-ERK1/2, p-S10H3,
- MeSH
- analgetika terapeutické užití MeSH
- blokátory sodíkových kanálů řízených napětím terapeutické užití MeSH
- bolest farmakoterapie MeSH
- mícha cytologie fyziologie MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- napěťově řízený sodíkový kanál, typ 9 fyziologie MeSH
- nervové receptory fyziologie MeSH
- pavoučí jedy terapeutické užití MeSH
- peptidy terapeutické užití MeSH
- popálení farmakoterapie MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- protein vázající element responzivní pro cyklický AMP metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- analgetika MeSH
- blokátory sodíkových kanálů řízených napětím MeSH
- napěťově řízený sodíkový kanál, typ 9 MeSH
- pavoučí jedy MeSH
- peptidy MeSH
- protein vázající element responzivní pro cyklický AMP MeSH
- protoxin II, Thrixopelma pruriens MeSH Prohlížeč
