ADRB2, pain and opioids in mice and man
Bibliographic record
Abstract
Abstract Aims We aim to characterize the effects of variation within ADRB2 -gene on pain and opioid requirements in human patients. We will assess ADRB2-OPRM1-6TM heterodimer as a molecular mechanism, potentially explaining pronociceptive and antianalgetic effects, using preclinical in vitro and in vivo models. We will further assess clinical significance via its genetic proxy, rs563649 in humans Methods In humans, experimental and postoperative pain and opioid responses were assessed in 1000 breast cancer surgery patients. Association of ADRB2 (n = 40) and OPRM1 (n = 1) polymorphisms was assessed using linear regression and analysis of variances (ANOVA). In vitro methods involved immunofluorescence microscopy (IF), cellular localization and translocation of 6TM/β2AR-heterodimers and Ca 2+ -measurements. Behavioral in vivo characterization was performed in mice using formalin, von Frey, hot plate and cold plate tests after administration of morphine, specific OPRM1-6TM agonist IBNtxA and ADRB2-antagonist ICI118,551. Results In humans, several ADRB2 SNPs were associated with pain and opioid phenotypes. The strongest associations were seen between cold pain phenotypes and rs17108817 & rs11957757 (p < 0.0001). In vitro , coexpression with β 2 -Ars increased translocation of 6TM-MOR to plasma membrane and Ca 2+ responses after treatment with selective 6TM-agonist, IBNtxA, compared with the cells expressing OPRM1-6TM alone. In vivo , co-administration of P2AR selective antagonist ICI 118,551 increased analgesic efficacy of opioids in a synergistic manner and reduced opioid-induced hyperalgesia. Conclusions Our findings suggest that ADRB2 and genetic variation in ADRB2 -gene are involved in the modulation of human pain and opioid responses. 6TM-MOR/P2-AR heterodimerization represents a molecular mechanism causing excitatory cellular effects and sufficient explanatory potential to explain pronociceptive and antianalgesic effects. Our animal findings further confirmed the concept of β 2 -AR and 6TM-MOR interaction in vivo . We suggest that co-administration of β-blockers with opioids might increase efficacy and safety of OPRM1 agonists.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 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) | 0.000 | 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 teacher head, 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".