Tac1‐expressing cells in the pre‐Bötzinger complex are potential targets to prevent opioid‐induced respiratory depression
Bibliographic record
Abstract
Rational Opioids are extensively used for their analgesic properties but present a variety of unwanted side effects, including tolerance, dependence and respiratory depression. The analgesic effect of opioids is due to activation of µ‐opioid receptors (MOR) in the central nervous system and no treatments are currently available to prevent respiratory depression without reducing their analgesic properties. The neural circuits and mechanisms regulating respiratory depression, sedation, and analgesia by opioids often overlap, therefore making challenging the identification of the mechanisms regulating respiratory depression. Neurons expressing tachykinin precursor 1 peptide (Tac1) located in the pre‐Bötzinger complex (preBötC) also co‐express neurokinin‐1 receptors (NK1R) and MORs. NK1R neurons are preferentially inhibited by opioids and play an essential role in mediating opioid‐induced respiratory depression. Objective Here, we tested the hypothesis that optogenetic activation of Tac1‐expressing preBötC cells in freely behaving mice will modulate breathing and prevent respiratory depression by opioids. Methods Using a Cre‐loxP recombination approach, we injected in Tac1 Cre recombinase mice the adeno‐associated virus containing the gene cassette of the excitatory channelrhodopsin‐2 ChETA flanked between loxP sites. A 200 µm optical fiber was then fixed above the preBötC for laser stimulation with blue light (wavelength: 480 nm). After a four weeks period to allow ChETA expression in targeted cells, the mouse was placed in a plethysmographic chamber and breathing was measured while laser stimulations were performed under baseline conditions (30 Hz). Following baseline measurements, the clinically relevant µ‐opioid drug fentanyl was administered by intraperitoneal injection (0.3 mg/Kg). About 5 minutes after fentanyl injection, targeted preBötC cells were activated using laser stimulations (30 Hz). Results Data show that stimulation of Tac1‐expressing cells increased respiratory frequency under baseline conditions. Fentanyl depressed breathing in 5 minutes and stimulation of Tac1 cells prevented opioid‐induced respiratory depression; an effect that was reversible. Conclusion Tac1‐expressing preBötC cells may constitute a target to prevent depression of breathing by opioids. These results will help identify the cells mediating opioid‐induced respiratory depression, an essential step toward the development of therapeutic targets to reduce the risk of opioids overdose and associated mortality.
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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".