Role of Cation-Chloride-Cotransporters (CCC) in Pain and Hyperalgesia
Bibliographic record
Abstract
The importance of the GABAergic system in spinal nociceptive processing has long been appreciated but we have only recently begun to understand how this system is modulated by the regulation of anion gradients. In neuronal tissues, cation-chloride cotransporters regulate Cl- homeostasis and the activity and/or expression of these transporters has important implications for the direction and magnitude of anion flow through GABA-A channels. Here we review recent evidence that two cation-chloride cotransporters, NKCC1 and KCC2 are involved in pain and enhanced nociception. On the one hand, NKCC1 activity is upregulated in primary afferents following an inflammatory insult and this produces excessive GABAergic depolarization in primary afferents leading to cross excitation between low and high threshold afferents. On the other hand, KCC2 expression is reduced in dorsal horn neurons following peripheral nerve injury resulting in a loss of GABA-/glycinergic inhibitory tone and, in some cases, inverting its action into net excitation. Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".