A313 MUCOSAL PROTEASES FROM IBS PATIENTS PRODUCE LONG TERM HYPEREXCITABILITY IN NOCICEPTIVE DRG NEURONS BY ACTIVATING NOVEL INTRACELLULAR SIGNALING PATHWAYS
Bibliographic record
Abstract
Patients suffering from the irritable bowel syndrome report exaggerated and sustained abdominal pain. We have shown that activation of protease activated receptor 2 (PAR2) on nociceptive (pain sensing) dorsal root ganglia (DRG) neurons evoke long term hyperexcitability but the mechanisms of this sustained pain signaling are unclear. Recent studies show that trypsin activates canonical PAR2 signaling causing endocytosis and this leads to sustained PAR2- endosomal signaling. Proteases such as elastase and cathepsin S, however, act at non-canonical sites and do not cause receptor endocytosis. We have shown that protease activity is increased in IBS tissues but it is unclear whether this leads to sustained neuronal excitation. To examine whether proteases in tissues from IBS patients lead to sustained nociceptive signaling and, if so, what intracellular mechanisms are involved. DRG neurons (T9-T13) from C57BL/6 mice were pre-incubated (10 min) with Trypsin (50nM) or supernatants (30 min) from colonic biopsies obtained from diarrhea predominant IBS patients or controls then washed with F12 media. We measured neuronal excitability by perforated patch-clamp, recording changes in rheobase (minimum current to fire action potential) and action potential discharged at twice rheobase immediately after washing with F12 media (time 0) or ~ 30 min later (time 30). PAR2 (10 μM I-343) and ERK1/2 (50 μM PD8059) inhibitors were applied 30 min before IBS supernatant or trypsin. Two way ANOVA and post hoc Tuckey’s tests were used to analyze the data. IBS supernatants increased DRG neuronal excitability acutely (time 0) as well as sustained hyperexcitability (time 30) (Table 1). This was blocked by the PAR2 antagonist I-343. This sustained excitability was also blocked by antagonist of ERK1/2. Sustained excitability evoked by trypsin was also inhibited by the ERK1/2 antagonist. Proteases in IBS tissues, acting through PAR2, evoke long term hyperexcitability of nociceptive signaling in DRG neurons that is ERK1/2 dependent. In addition, the sustained excitability evoked by the serine protease trypsin, which we previously have shown is mediated by PAR2-endosomal signaling, was also ERK1/2 dependent. Thus, serine proteases in IBS tissues may be signaling through similar pathways and these could provide a novel therapeutic target to treat pain in patients with IBS. CAGCONACYT
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.000 | 0.000 |
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".