Inhibition of Endoplasmic Reticulum Oxidoreductin 1 Modulates Neuronal Excitability and Nociceptive Sensitivity in Mice
Bibliographic record
Abstract
BACKGROUND: In the peripheral nervous system, nociceptors become hyperexcitable in both acute and chronic pain conditions. This phenotype can be mediated by dysregulated calcium, which occurs if the endoplasmic reticulum and mitochondria fail to buffer it appropriately. The redox enzyme endoplasmic reticulum oxidoreductin 1 (ERO1) regulates calcium transfer at endoplasmic reticulum-mitochondria contact sites (ERMCSs). This study hypothesized that inhibiting ERO1 and thereby dampening ERMCS calcium transfer might lower nociceptor hyperexcitability in sensory neurons and pain-like behaviors in mice. METHODS: C57BL/6 mice were used for histology, behavior, and cell culture experiments. Behavior included thermal tail flick, the formalin hind paw injection model of acute inflammatory pain, and hind paw incision postsurgical pain. Postmortem human dorsal root ganglia (DRGs) were used for immunohistochemistry and in vitro calcium imaging. RESULTS: This study demonstrates that the α isoform of ERO1 is expressed in mouse DRGs across multiple subtypes of mouse sensory neurons. This led us to peripherally administer an ERO1 inhibitor in mice, which acutely reversed nociception in acute inflammatory and postsurgical pain models. The hypothesis was that this may be due to reduced excitability of DRG neurons and tested ERO1 inhibition in vitro. In cultured DRGs, ERO1 inhibition dampened nociceptor excitability and mitochondrial function, suggesting that reduced calcium transfer through ERMCS could be responsible for the behavior observed in vivo . ERO1α expression was also found in human DRGs using immunohistochemistry and previously published single-cell RNA-sequencing data. Finally, the study showed that ERO1 inhibition modulates human sensory neuronal excitability in cultured post-mortem DRGs. CONCLUSIONS: This study found that ERO1 inhibition dampens mitochondrial function, sensory neuron excitability, and acute pain-like behavior in mice. Additionally, ERO1 inhibition decreases sensory neuron excitability in post-mortem human sensory neurons in vitro. The results indicate that targeting ERO1 may be a viable strategy for non-narcotic acute pain relief.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".