The Role of Somatostatin‐Expressing Cells in Opioid‐Induced Respiratory Depression
Bibliographic record
Abstract
Introduction Opioids have the ability to cause respiratory depression, a severe decline in respiratory rate that can be lethal with overdose. While key brainstem respiratory regions have been shown to play a role in respiratory depression by opioids, the cells involved remain unknown. One region of interest is the preBötzinger Complex, a site that mediates respiratory depression and contains a subgroup of somatostatin (SST)‐expressing cells that are required to maintain normal breathing. We aimed to determine the role of SST‐expressing cells in respiratory depression by opioids. We hypothesized that deletion of mu‐opioid receptors (MORs) in SST‐expressing cells will prevent opioid‐induced respiratory depression. Methods We developed transgenic knockout mice that lack MORs in SST‐expressing cells (SST‐MOR ‐/‐ ) using Cre‐lox recombination. SST‐Cre +/+ mice (Ssttm2.1(cre)Zjh/J) were bred with Oprm1 fl/fl mice (Oprm1tm1.1Cgrf/KffJ) to produce SST‐MOR ‐/‐ mice. We used in situ hybridization to determine whether MOR mRNAs are co‐expressed with SST mRNA in the brainstem of control (wild‐type, SST‐MOR +/+ ) and SST‐MOR ‐/‐ mice. To determine the effect of removing MORs from SST‐expressing cells, respiratory depression by intraperitoneal injection of fentanyl (0.3mg/kg) was quantified in control (wild‐type, SST‐MOR +/+ ) and SST‐MOR ‐/‐ mice. Respiratory rate was recorded using whole‐body plethysmography. Results MORs were expressed in several brainstem regions regulating breathing such as the preBötzinger Complex, the Bötzinger Complex, the nucleus ambiguus, the Kölliker‐Fuse nucleus, the locus coeruleus and the nucleus tractus solitarius, while SST and MORs were co‐expressed primarily in the preBötzinger Complex. Knockout of MORs in SST‐expressing cells was confirmed by microscopy. Intraperitoneal injection of fentanyl (0.3mg/kg) induced a similar, significant respiratory rate depression in both wild‐type (p<0.001, n=14) and SST‐MOR ‐/‐ (p<0.001, n=12) mice. Conclusions SST and MORs are co‐expressed in the preBötzinger Complex while MORs are expressed in other key brainstem respiratory sites. Preliminary data suggests that MORs in SST‐expressing cells are not required for fentanyl‐induced respiratory depression. Our previous work showed that arousal state can affect the severity of respiratory depression by opioids. For this reason, we are currently investigating the impact of arousal state (active versus inactive) on opioid‐induced respiratory depression in control and SST‐MOR ‐/‐ mice. We are also looking at the role of SST‐expressing cells in respiratory depression by other opioid drugs such as morphine.
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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 | 0.000 |
| 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".