Inhibition of neurokinin‐1–substance P receptor and prostanoid activity prevents and reverses the development of morphine tolerance <i>in vivo</i> and the morphine‐induced increase in CGRP expression in cultured dorsal root ganglion neurons
Bibliographic record
Abstract
Chronic treatment with opioid drugs such as morphine leads to the development of tolerance, which manifests as a loss of drug potency. The mechanisms underlying this phenomenon are poorly understood, but recent evidence suggests that increased activity of nociceptive sensory transmitters [calcitonin gene-related peptide (CGRP) and substance P] and other signalling messengers (prostaglandins) contribute to its development. Chronic intrathecal morphine administration to rats for 7 days produced analgesic tolerance. Co-administration of SR140333, a selective substance P receptor (neurokinin-1) antagonist, or nimesulide, a cyclooxygenase-2-selective inhibitor, augmented the acute effects of morphine, prevented morphine tolerance and reversed established tolerance. In cultured adult dorsal root ganglion neurons, exposure to morphine for 5 days increased the number of neurons expressing CGRP immunoreactivity. Co-exposure with the peptide CGRP receptor antagonist CGRP8-37, SR140333 or nimesulide prevented the morphine-induced increase in the expression of CGRP immunoreactivity. Additionally, BIBN4096BS, a nonpeptide CGRP receptor antagonist, stereoselectively produced similar effects. In summary, this investigation demonstrates that activity of CGRP and substance P contributes to both the induction and expression of opioid analgesic tolerance. Additionally, it highlights the involvement of prostaglandins generated by spinal cyclooxygenase-2 activity in the genesis of opioid tolerance. The neuropeptide and prostanoid activity contributing to tolerance is expressed at the level of the primary afferents terminating in the spinal cord. The combination of opioids with agents that block this activity may represent a useful strategy for the prevention as well as the reversal of clinical opioid tolerance.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".