Chronic stress mediators act synergistically on colonic nociceptive mouse dorsal root ganglia neurons to increase excitability
Bibliographic record
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. KEY 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 & INFERENCES: 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".