Pflügers Archiv : European journal of physiology
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Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. ⋯ Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.
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In the past years, several hereditary diseases caused by defects in transient receptor potential channels (TRP) genes have been described. This review summarizes our current knowledge about TRP channelopathies and their possible pathomechanisms. Based on available genetic indications, we will also describe several putative pathological conditions in which (mal)function of TRP channels could be anticipated.
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Review
Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases.
Mammalian airways are protected from infection by a thin film of airway surface liquid (ASL) which covers airway epithelial surfaces and acts as a lubricant to keep mucus from adhering to the epithelial surface. Precise regulation of ASL volume is essential for efficient mucus clearance and too great a reduction in ASL volume causes mucus dehydration and mucus stasis which contributes to chronic airway infection. The epithelial Na(+) channel (ENaC) is the rate-limiting step that governs Na(+) absorption in the airways. ⋯ ENaC can be regulated by multiple pathways, and once proteolytically cleaved ENaC may then be inhibited by intracellular second messengers such as cAMP and PIP(2). In the airways, however, regulation of ENaC by proteases seems to be the predominant mode of regulation since knockdown of either endogenous serine proteases such as prostasin, or inhibitors of ENaC proteolysis such as SPLUNC1, has large effects on ENaC activity in airway epithelia. In this review, we shall discuss how ENaC is proteolytically cleaved, how this process can regulate ASL volume, and how its failure to operate correctly may contribute to chronic airway disease.
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The rostral ventrolateral medulla (RVLM) plays a pivotal role in regulating sympathetic vasomotor activity. The cardiac sympathetic afferent reflex (CSAR) contributes to the enhanced sympathetic outflow in chronic heart failure and hypertension. The aim of the present study was to determine whether angiotensin (Ang) II and Ang-(1-7) in the RVLM modulate the CSAR and sympathetic activity. ⋯ These results indicate that Ang-(1-7) is as effective as Ang II in sensitizing the CSAR and increasing sympathetic outflow. In contrast to Ang II, the effects of Ang-(1-7) are not mediated by AT(1) receptors but by Mas receptors. Mas receptors, but not the AT(1) receptors, in the RVLM are involved in the tonic control of the CSAR.
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The generation of action potentials in nociceptive neurons is accomplished by the tetrodotoxin-resistant (TTXr) Na+ channel Na(v)1.8. Following nerve injury, a redistribution of Na(v)1.8 from dorsal root ganglion (DRG) neurons into peripheral axons contributes to hyperexcitability and possibly to neuropathic pain. Na(v)1.8 has been reported to display a lower sensitivity to block by Na+ channel blockers as compared to TTX-sensitive (TTXs) Na(v) subunits. ⋯ The efficacy of lidocaine on neurons lacking Na(v)1.8 was further increased by cold temperatures, due to a synergistic hyperpolarizing shift of the slow inactivation of TTXs Na+ channels by lidocaine and cooling. Finally, the approximately 90% reduction of TTXr Na+ currents in injured neurons from mice with a peripheral nerve injury was accompanied with an enhanced tonic block by lidocaine. In conclusion, our data demonstrate that the expression of Na(v)1.8 in sensory neurons can confine the antinociceptive efficacy of lidocaine and other Na+ channel blockers employed for pain treatment.