A54 DELTA OPIOID RECEPTOR SIGNALING MEDIATES OPIOID INDUCED TOLERANCE AND HYPERALGESIA IN COLONIC SENSORY NERVES
Bibliographic record
Abstract
Abstract Background While opioid drugs are widely used for treating abdominal pain, prolonged exposure to opioids can induce tolerance and paradoxically increase pain. We previously showed in colonic afferent nerves that chronic morphine treatment causes tolerance and paradoxical hyperalgesia, however the mechanisms are unknown. Aims To evaluate the role of delta opioid receptor (DOR) signaling in opioid induced tolerance and hyperalgesia in colonic nerves during chronic morphine exposure. Methods C57BL/6 mice were injected (i.p.) 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); a subset of mice were also injected with 2.5 mg/kg naltrindole (NTI), a DOR antagonist. The analgesic response in vivo was monitored daily using the tail-flick test. To assess the effect of chronic morphine exposure, mice were euthanized on day 8, and the dorsal root ganglia (DRGs) and colons were harvested. Isolated DRG neurons were incubated with 1μM morphine (30 min) and neuronal excitability was determined by measuring the rheobase (amount of current required to elicit an action potential) using perforated patch clamp. To assess changes in colonic afferent nerve excitability, ex vivo afferent nerve recordings were obtained from flat-sheet colon preparations to determine the effects of 1μM morphine (10 min perfusion) on mechanosensitivity by probing with 1g von Frey hair. Results The tail flick test showed that the DOR antagonist NTI inhibited (30%) the maximal antinociceptive effect of morphine and reduced morphine tolerance. In patch clamp recordings, 1μM morphine paradoxically increased the excitability of small DRG neurons from morphine mice (rheobase decreased 28%; p<0.05, 2-way ANOVA), whereas this excitatory effect was absent on neurons from NTI+morphine mice. Acute application of 1μM morphine had no effect on afferent nerve responses to probing in morphine mice (14.9 vs 16.7 Hz; p=ns, paired t test, n=15) whereas it inhibited the afferent nerve response to probing in NTI+morphine mice (15.2 vs 9.9 Hz; p<0.001, paired t test, n=16). Furthermore, most single units from morphine mice had an increased response to probing following acute morphine application (7/15 vs 2/16 units excited), whereas most units form NTI-morphine mice were inhibited (14/16 vs. 3/15 units inhibited, P<0.001, Chi-square). Conclusions These findings suggest that DOR signaling plays a significant role in the development of opioid tolerance and hyperalgesia in colonic afferent nerves induced by chronic morphine treatment. Thus, antagonists of DOR may help to mitigate these side effects induced by opioids. Funding Agencies 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) | 0.000 | 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) | 0.003 | 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".