Stimulating <scp>TRPV</scp>1 externalization and synthesis in dorsal root ganglion neurons contributes to <scp>PGE</scp>2 potentiation of <scp>TRPV</scp>1 activity and nociceptor sensitization
Bibliographic record
Abstract
BACKGROUND: Persistent peripheral sensitization contributes to chronic pain. Plasticity of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) induced by pro-inflammatory mediators contributes to sensitization. Prostaglandin E2 (PGE2) enriched in injured tissues is known not only directly to sensitize DRG neurons, but also to potentiate sensitizing effects of other pain mediators such as capsaicin and its receptor transient receptor potential vanilloid-1 (TRPV1). It remains unknown whether PGE2 potentiates TRPV1 activity by stimulating its synthesis, cell surface and axonal trafficking in DRG neurons. METHODS: Combined biochemical, morphological, pharmacological and behavioral approaches have been used to address this issue in both in vitro and in vivo models. RESULTS: PGE2 increased TRPV1 externalization in cultured rat DRG neurons in a time- and concentration-dependent manner, an event blocked by an inhibitor of protein synthesis or anterograde export. EP1 and EP4, but not EP2 and EP3, mediated this event. EP1 agonist-induced TRPV1 externalization was suppressed by inhibitors of CaMKII, PLC, PKC and PKCε, while EP4 agonist-induced TRPV1 externalization by inhibitors of cAMP/PKA and ERK/MAPK. Pre-exposure to PGE2 potentiated release of calcitonin gene-related peptide from cultured DRG neurons evoked by subsequent capsaicin stimulation. This event was blocked by an inhibitor of protein synthesis or export, suggesting that PGE2-induced TRPV1 synthesis and externalization is coupled to enhanced TRPV1 activity. Pre-exposure to PGE2 not only prolonged tactile allodynia evoked by subsequent capsaicin challenge, but also increased TRPV1 levels in L4-6 DRG, sciatic nerves and plantar skin. CONCLUSIONS: Our data indicate that facilitating TRPV1 synthesis, cell surface and axonal trafficking is a novel mechanism underlying PGE2 potentiation of TRPV1 activity.
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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 | 0.004 | 0.013 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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".