TNFα is a key mediator of the pronociceptive effects of mucosal supernatant from human ulcerative colitis on colonic DRG neurons
Bibliographic record
Abstract
OBJECTIVES: Abdominal pain is a serious cause of morbidity in patients with inflammatory bowel disease. To better understand the mechanisms and potentially identify new targets for treatment, the effects of inflammatory supernatant from colonic biopsies of patients with active ulcerative colitis (UC) on mouse colonic nociceptive dorsal root ganglia neurons were examined. METHODS: Acutely dissociated dorsal root ganglia neurons innervating the mouse colon were incubated in supernatants obtained from colonic biopsies from patients with UC. Whole-cell patch clamp recordings were obtained to examine the effects on neuronal excitability. The role of tumour necrosis factor alpha (TNFalpha) was studied using TNFalpha receptor (TNFR) knockout mice and comparing supernatant and TNFalpha actions. RESULTS: UC supernatants significantly decreased the rheobase and increased action potential discharge, indicating increased neuronal excitability. Human biopsies exhibited high levels of TNFalpha, and mouse colonic neurons only exhibited TNFR1 mRNA. Incubation with TNFalpha recapitulated the supernatant effects on neuronal excitability, and supernatant and TNFalpha actions were almost completely blocked in TNFR knockout mice. In voltage clamp studies, transient I(A) and I(K) currents were suppressed and Na(v) 1.8 currents were enhanced by TNFalpha and UC supernatant, suggesting that multiple underlying mechanisms contributed to the enhanced excitability. CONCLUSIONS: UC supernatants enhance neuronal excitability of sensory dorsal root ganglia neurons innervating the colon. TNFalpha is a key mediator which acts at neuronal TNFR1 to modulate K(v) and Na(v) currents. Together these data provide a number of potential new targets for pain management in UC.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 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 | 0.000 |
| 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".