Chronic stress mediators act synergistically on colonic nociceptive mouse dorsal root ganglia neurons to increase excitability. Issue 3 (29th November 2013)

• Record Type: Journal Article
• Authors: Ochoa‐Cortes, F.; Guerrero–Alba, R.; Valdez‐Morales, E. E.; Spreadbury, I.; Barajas‐Lopez, C.; Castro, M.; Bertrand, J.; Cenac, N.; Vergnolle, N.; Vanner, S. J.
• Is Part Of: Neurogastroenterology & motility. Volume 26:Issue 3(2014:Mar.)
• Page Start: 334
• Page End: 345
• Publication Date: 2013-11-29
• Subjects: Gastrointestinal system -- Motility -- Periodicals; Gastrointestinal system -- Innervation -- Periodicals; 616.33
• DOI: 10.1111/nmo.12268
• Languages: English
• ISSNs: 1350-1925

Abstract

<abstract abstract-type="main" id="nmo12268-abs-0001"> <title>Abstract</title> <sec id="nmo12268-sec-0001" sec-type="section"> <title>Background</title> <p>Stress hormones can signal to colonic dorsal root ganglia (DRG) neurons and may play a role in sustained hyperexcitability of nociceptors.</p> </sec> <sec id="nmo12268-sec-0002" sec-type="section"> <title>Methods</title> <p>Mouse DRG neurons were exposed overnight to epinephrine (Epi) 5 nM and/or corticosterone (Cort) 1 <italic>μ</italic>M or prior water‐avoidance stress. Patch clamp recordings, visceromotor reflexes (VMRs) and molecular studies were conducted.</p> </sec> <sec id="nmo12268-sec-0003" sec-type="section"> <title>Key Results</title> <p>Water‐avoidance stress induced neuronal hyperexcitability. Incubation of DRG neurons in both Cort and Epi (but neither alone) induced hyperexcitability (rheobase decreased 51%, p < 0.05; action potential discharge increased 95%, p < 0.01); this was blocked by antagonists of the β<sub>2</sub> adrenoreceptor (butoxamine, But) and Cort receptor (mifepristone) in combination or alone. Stress hormones enhanced voltage‐gated Na<sub>v</sub>1.7 currents (p < 0.05) and suppressed I<sub><italic>A</italic></sub> (p < 0.0001) and I<sub>K+</sub> (p < 0.05) currents. Furthermore, stress hormones increased DRG β<sub>2</sub> adrenoreceptor mRNA (59%, p = 0.007) and protein (125%, p < 0.05), also Nav 1.7 transcript (45%, p = 0.004) and protein (114%, p = 0.002). In whole‐animal studies, the WAS hyperexcitability of DRG neurons was blocked by antagonists of the β<sub>2</sub> and glucocorticoid receptors (GCR) but together they paradoxically increased VMRs to colorectal balloon distension.</p> </sec> <sec id="nmo12268-sec-0004" sec-type="section"> <title>Conclusions & Inferences</title> <p>Stress mediators Epi and Cort activate β<sub>2</sub> and GCR on DRG neurons which synergistically induce hyperexcitability of nociceptive DRG neurons and cause corresponding changes in voltage‐gated Na<sup>+</sup> and K<sup>+</sup> currents. Furthermore, they increase the expression of β<sub>2</sub> adrenoreceptors and Nav1.7 channels, suggesting transcriptional changes could contribute to sustained signaling following stress. The paradoxical effects of But and mifepristone in electrophysiological compared to VMR testing may reflect different peripheral and central actions on sensory signaling.</p> </sec> </abstract>