Ampakines Alleviate Respiratory Depression in Rats
Why this work is in the frame
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Bibliographic record
Abstract
RATIONALE: There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the pre-Bötzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. OBJECTIVE: We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid- and barbiturate-induced respiratory depression. METHODS: Respiratory frequency and amplitude were measured in the following rat models: (1) perinatal in vitro brainstem-spinal cord, (2) neonatal in vitro medullary slice, (3) juvenile in situ perfused, working heart-brainstem preparation, and (4) newborn and adult in vivo. RESULTS: Administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not in older animals (greater than Postnatal Day 0). Furthermore, pharmacologic depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ, and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus. CONCLUSIONS: CX546 effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify the potential of ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| 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 it