Bibliographic record
Abstract
Human CYP2D is a highly genetically variable enzyme that metabolizes numerous centrally-acting substrates such as opioids, psychostimulants and neurotoxins. CYP2D is expressed primarily in the liver but also in the brain. CYP2D in the liver is considered uninducible, regulated only by genetics. However, CYP2D in the brain may also be regulated by age, hormones and xenobiotics such as nicotine/cigarette smoke and ethanol. CYP2D metabolizes most oral opioids to more potent metabolites which may contribute to drug effects. In this thesis we investigated the impact of CYP2D in the brain on opioid concentrations and response as a potential contributing factor to the large interindividual differences in therapeutic response to oral opioids.Using an experimental paradigm which selectively inhibits CYP2D in the brain, but not the liver, we assessed a) the impact of CYP2D in the brain on acute and long-term opioid responses and b) hormonal regulation of CYP2D in the brain. In study 1, inhibition resulted in lower brain (leaving liver unchanged) CYP2D activity and higher analgesia from oral hydrocodone. Furthermore brain, but not peripheral, CYP2D activity correlated with analgesia response. In study 2, we showed that CYP2D in the brain cycled across the estrous cycle: males and females in estrus, compared to females in diestrus, had higher brain CYP2D activity, lower brain oxycodone concentrations and lower oxycodone-induced analgesia. Ovariectomized female rats had lower brain CYP2D activity which was restored with estradiol, but not progesterone, supplementation. In study 3, inhibition of CYP2D in the brain resulted in a trend for higher initial oxycodone-induced analgesia and faster loss in analgesia. Baseline novelty-induced locomotor activity was also associated with the induction and expression of behavioural sensitization to oral oxycodone.These data suggest that estradiol may regulate CYP2D in the brain which in turn may impact acute and longer-term opioid responses. This suggests that CYP2D in the brain could contribute to the wide interindividual differences in therapeutic response to opioid substrates, and potentially other centrally acting CYP2D substrates.
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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) | 0.000 | 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) | 0.002 | 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 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".