Targeting p38 Mitogen-activated Protein Kinase to Reduce the Impact of Neonatal Microglial Priming on Incision-induced Hyperalgesia in the Adult Rat
Bibliographic record
Abstract
AbstractAbstract In rats, incisional surgery in adulthood resulted in greater phosphorylation of the signaling enzyme, p38 mitogen-activated protein (MAP) kinase in spinal cord microglia of animals which had received incisional surgery in the neonatal period. A p38 MAP kinase inhibitor reduced pain behaviors after surgery in adults with previous neonatal surgery, suggesting this enzyme may be a target to reduce exaggerated pain responses after surgery in individuals with a history of neonatal surgery. Background: Neonatal surgical injury triggers developmentally regulated long-term changes that include enhanced hyperalgesia and spinal microglial reactivity after reinjury. To further evaluate priming of response by neonatal hindpaw incision, the authors investigated the functional role of spinal microglial p38 mitogen-activated protein kinase after reincision in adult rodents. Methods: Plantar hindpaw incision was performed in anesthetized adult rats, with or without previous incision on postnatal day 3. Numbers and distribution of phosphorylated-p38 (1, 3, 24 h) and phosphorylated extracellular signal-regulated kinase (15 min, 24 h) immunoreactive cells in the lumbar dorsal horn were compared after adult or neonatal plus adult incision. Withdrawal thresholds evaluated reversal of incision-induced hyperalgesia by p38 inhibition with intrathecal SB203850. Results: Neonatal injury significantly increased phosphorylated-p38 expression 3 h after adult incision (55 ± 4 vs. 35 ± 4 cells per section, mean ± SEM, n = 6 to 7, P < 0.01). Increased expression was restricted to microglia, maintained across lumbar segments, and also apparent at 1 and 24 h. Preincision intrathecal SB203850 prevented the enhanced mechanical hyperalgesia in adults with previous neonatal injury and was effective at a lower dose (0.2 vs. 1 mg/kg, n = 8, P < 0.05) and for a longer duration (10 vs. 3 days). Lumbar neuronal phosphorylated extracellular signal-regulated kinase expression reflected the distribution of hindpaw primary afferents, but was not significantly altered by previous incision. Conclusions: Neonatal incision primes spinal neuroglial signaling, and reincision in adult rats unmasks centrally mediated increases in functional microglial reactivity and persistent hyperalgesia. After early life injury, p38 inhibitors may have specific benefit as part of multimodal analgesic regimes to reduce the risk of persistent postsurgical pain.
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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".