A53 CHRONIC MORPHINE TREATMENT CAUSES TOLERANCE AND INCREASES PAIN SIGNALING FOLLOWING ACUTE MORPHINE APPLICATION TO MOUSE VISCERAL SENSORY NERVES
Bibliographic record
Abstract
Opioid drugs are efficacious for treating abdominal pain but prolonged exposure to opioids in patients induces tolerance, which in turn can lead to escalating doses to achieve an analgesic effect. Furthermore, these increasing doses can activate pronociceptive signaling but the mechanisms are unclear. To evaluate the short-term effect of morphine on the excitability of mouse colonic afferent nerve fibers and dorsal root ganglion (DRG) neurons, and determine whether chronic treatment with increasing doses of morphine modifies this effect. C57BL/6 mice were intraperitoneally injected twice daily for 7 days with escalating doses of morphine (10, 20, 30 mg/kg for the first 3 days, then 40mg/kg on 4th to 7th day) or saline. The analgesic response to morphine injections was monitored daily using the tail-flick test. At day 8, mice were euthanized and the DRGs and colons were removed. Isolated DRG neurons were cultured and overnight incubated with 1µM morphine or media alone. Neuronal excitability was recorded by measuring the rheobase using perforated patch clamp. In vitro afferent recordings were performed on flat-sheet colon preparations to determine the effects of 1µM morphine (10 min perfusion) on basal firing frequency and response to probing with 1g von Frey hair. The tail flick test demonstrated morphine tolerance in morphine treated mice; the antinociceptive effect reached a maximum on day 4 and declined on the following days despite high doses. In patch clamp recordings, overnight incubation with 1µM morphine reduced the excitability of small DRG neurons from saline treated mice (rheobase increased 48%; p<0.01, unpaired t test), whereas this inhibitory effect was absent on neurons from morphine treated mice. Acute application of 1µM morphine inhibited the colonic afferent response to probing in saline treated mice (14.2 vs 8.5 Hz; p<0.01, paired t test, n=14), but not in morphine treated mice. Consistently, acute morphine decreased the basal activity of afferent axons in saline treated mice (0.46 vs 0.22 Hz; p<0.05), whereas it increased firing in morphine treated mice (0.08 vs 0.39 Hz; p<0.05, n=18). Chronic treatment with morphine reduced the inhibitory effect of acute morphine application on mechanosensitivity (12/14 vs. 6/18 units inhibited, P<0.05), and switched the effect of acute morphine on basal afferent firing from inhibition to excitation (0/14 vs. 6/12 units excited, P<0.05). These findings suggest that chronic treatment with morphine impairs the antinociceptive effect of acute morphine application and increases firing in a subset of colonic afferents evoking a pronociceptive effect. This finding demonstrates a peripheral action of morphine underlying its ability to paradoxically increase pain signaling. CCC
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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) | 0.000 | 0.001 |
| 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".