Contribution of adrenomedullin to the switch of G protein‐coupled μ‐opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats
Bibliographic record
Abstract
BACKGROUND AND PURPOSE: Chronic exposure to morphine increases spinal adrenomedullin (AM) bioactivity resulting in the development and maintenance of morphine tolerance. This study investigated the possible involvement of AM in morphine-evoked alteration in μ-opioid receptor-coupled G proteins. EXPERIMENTAL APPROACH: Agents were administered intrathecally (i.t.) in rats. Nociceptive behaviours and cumulative dose-response of morphine analgesia were assessed. Neurochemicals in the spinal dorsal horn were assayed by immunoprecipitation, Western blot analysis and ELISA. KEY RESULTS: Intrathecal injection of AM (8 μg) for 9 days decreased and increased the levels of μ receptor-coupled Gi and Gs proteins respectively. Morphine stimulation (5 μg) after chronic treatment with AM also induced an increase in cAMP production in the spinal dorsal horn. Co-administration of the selective AM receptor antagonist AM22-52 inhibited chronic morphine-evoked switch of G protein-coupled μ receptor from Gi to Gs. Chronic exposure to AM increased the phosphorylation of cAMP-responsive element-binding protein (CREB) and ERK. Co-administration of the PKA inhibitor H-89 (5 μg) or MEK1 inhibitor PD98059 (1 μg) reversed the AM-induced thermal/mechanical hypersensitivity, decline in morphine analgesic potency, switch of G protein-coupled μ receptor and increase in cAMP. CONCLUSIONS AND IMPLICATIONS: The present study supports the hypothesis that an increase in AM activity in the spinal dorsal horn contributes to the switch of the μ receptor-coupled G protein from Gi to Gs protein via the activation of cAMP/PKA/CREB and ERK signalling pathways in chronic morphine use.
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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".