Regulation of Peripheral Clock to Oscillation of Substance P Contributes to Circadian Inflammatory Pain
Bibliographic record
Abstract
BACKGROUND: The daily fluctuations of many physiologic and behavioral parameters are differentially influenced by either central or peripheral clocks in mammals. Since substance P (SP) oscillates in some brain tissues and plays an indispensable role in modulating inflammatory pain at the spinal level, we speculated that SP mediates circadian nociception transmission at the spinal level. METHODS: In the present study behavioral observation, real-time polymerase chain reaction, luciferase assay, chromatin immunoprecipitation, and immunohistochemistry stain methods were used to investigate the role of SP in the spinal circadian nociception transmission and its regulation mechanism. RESULTS: Our results showed that under transcriptional regulation of BMAL1:CLOCK heterodimers, SP's coding gene Tac1 expression oscillates in dorsal root ganglion (n = 36), but not in the spinal dorsal horn. Further, the expression of SP cycled in the spinal dorsal horn, and this rhythmicity was potentially determined by circadian expression of Tac1 in dorsal root ganglion. Furthermore, the variation of SP expression induced by formalin was fluctuated in a similar rhythm to behavioral nociceptive response induced by formalin (n = 48); and the nociceptive behavioral circadian rhythm could be abolished through blockade of the SP-Neurokinin 1 receptor pathway (n = 70). Lastly, the variations of spinal SP expression and behavioral nociceptive response were in step, and both were changed by the deletion mutation of clock gene. CONCLUSIONS: We conclude that spinal SP probably plays a pivotal role in modulating circadian inflammatory pain and suggest that peripheral circadian-regulated signaling is potentially an essential pathway for circadian nociceptive transmission.
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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 | 0.001 |
| 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".