title: Chronic stress mediators act synergistically on colonic nociceptive mouse dorsal root ganglia neurons to increase excitability.
abstract: BACKGROUND
  Stress hormones can signal to colonic dorsal root ganglia (DRG) neurons and may play a role in sustained hyperexcitability of nociceptors.
  
  
  METHODS
  Mouse DRG neurons were exposed overnight to epinephrine (Epi) 5 nM and/or corticosterone (Cort) 1 μM or prior water-avoidance stress. Patch clamp recordings, visceromotor reflexes (VMRs) and molecular studies were conducted.
  
  
  RESULTS
  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 β2 adrenoreceptor (butoxamine, But) and Cort receptor (mifepristone) in combination or alone. Stress hormones enhanced voltage-gated Nav 1.7 currents (p < 0.05) and suppressed IA (p < 0.0001) and IK+ (p < 0.05) currents. Furthermore, stress hormones increased DRG β2 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 β2 and glucocorticoid receptors (GCR) but together they paradoxically increased VMRs to colorectal balloon distension.
  
  
  CONCLUSIONS
  Stress mediators Epi and Cort activate β2 and GCR on DRG neurons which synergistically induce hyperexcitability of nociceptive DRG neurons and cause corresponding changes in voltage-gated Na(+) and K(+) currents. Furthermore, they increase the expression of β2 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.
authors.affiliation: Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University School of Medicine, Kingston, ON, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Ochoa-Cortes
authors.forename: R
authors.initials: R
authors.lastname: Guerrero-Alba
authors.forename: E E
authors.initials: EE
authors.lastname: Valdez-Morales
authors.forename: I
authors.initials: I
authors.lastname: Spreadbury
authors.forename: C
authors.initials: C
authors.lastname: Barajas-Lopez
authors.forename: M
authors.initials: M
authors.lastname: Castro
authors.forename: J
authors.initials: J
authors.lastname: Bertrand
authors.forename: N
authors.initials: N
authors.lastname: Cenac
authors.forename: N
authors.initials: N
authors.lastname: Vergnolle
authors.forename: S J
authors.initials: SJ
authors.lastname: Vanner
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002908:Chronic Disease; D003106:Colon / Q000294:innervation*; D003345:Corticosterone / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D011965:Receptors, Glucocorticoid; D003345:Corticosterone; D004837:Epinephrine
keywords: corticosteroids; dorsal root ganglia; epinephrine; hyperalgesia; psychological stress