Investigating Neuroinflammation and Opioid Receptor Signaling Mechanisms in Chronic Pain Pathology
Bibliographic record
Abstract
Chronic pain represents a substantial burden to society and is difficult to manage for both physicians and patients due to lack of effective therapies. There are multiple dimensions of chronic pain, with symptoms such as anxiety, depression, fatigue, anhedonia, etc. Collectively known as negative affect, these symptoms exacerbate the pain experience and results in decreased efficacy of opioid analgesics. Endotoxins known to induce neuroinflammation produce anhedonia and depression in humans. Similarly, activation of kappa opioid receptors produces dysphoric and depressive symptoms in humans. This work investigates the contribution of neuroinflammation and kappa opioid receptors in multiple rodent models of chronic pain and the manifestation of negative affect in these models. We identified that kappa opioid receptors are upregulated within limbic brain regions of neuropathic pain animals and upregulation within ventral tegmental area dopamine neurons is responsible for the tonic-aversive component of pain. This effect was sex dependent where blocking or elimination of kappa opioid receptors in male but not female mice prevented pain-induced aversion. Our lab previously identified that neuroinflammation within the ventral tegmental area in a model of neuropathic pain was responsible for altered reward signaling and dopamine release. We show that peripheral nerve injury model of neuropathic pain causes microglial activation in many brain structures but is not ubiquitous, and neuroinflammation is primarily restricted to limbic brain structures. Because neuroinflammation is a hallmark of traumatic brain injury, we asked whether neuroinflammation is also causative to chronic pain following head injury. Using a model of repeated mild traumatic brain injury (rmTBI), we show that blocking microglial activation one month after injury reverses cold hypersensitivity and affective-like behaviors but has no effect on rmTBI-induced hyper-locomotion or risk-taking behavior. Together, we provide insight to the complexity and importance of a global neuroinflammatory response and kappa opioid receptors to pain.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".