The role of vascular dysfunction in neuropathic pain
Bibliographic record
Abstract
Neuropathic pain is a debilitating condition of which current treatment options are few and ineffective.In order to improve the treatment of neuropathic pain, we must advance our understanding of neuropathic pain mechanisms.Statins, drugs for control of hypercholesterolemia, were found to have analgesic effects and these effects were characterized.The mechanism of statin analgesia was attributed to their pleiotropic effects, such as anti-inflammation and neuroprotection.Statins also have beneficial effects on the microvascular system, however it was not known whether the vascular system contributes to neuropathic pain.Blood-nerve barrier dysfunction was found to be a contributing factor to the development and maintenance of neuropathic pain.After nerve injury, pro-nociceptive molecules from the blood may enter into the nerve to contribute to pain.The breakdown of the blood-nerve barrier can also be exploited to develop novel analgesics which can access injured nerves, without affecting healthy nerves.Further investigations on the vascular system revealed that persistent endoneurial hypoxia was observed in injured nerves.Hypoxia was due to microvascular disturbance, endoneurial fibrosis, and increased metabolic requirements of injured nerves.Hypoxia produces functional effects on both the immune and nervous system, contributing to neuropathic pain, making hypoxia a novel mechanistic target.Ongoing hypoxia in injured nerves suggests novel analgesics which are activated by hypoxia may be created to localize drugs to injured nerves.This work is an original contribution to the understanding of novel peripheral neuroimmune mechanisms of neuropathic pain.~ 3 ~ RésuméLa douleur neuropathique est une condition invalidante qui n'a que peu d'options thérapeutiques modérement efficaces.Afin d'améliorer la prise en charge de la douleur neuropathique, nous devons faire avancer notre connaissance de ses mécanismes sous-jacents.Les statines, qui sont des médicaments utilisés pour l'hypercholestérolémie, ont été démontrés avoir un effet antalgique dont le mécanisme a été caractérisé.Le rôle antalgique des stastines a été attribué à leurs effets pléiotropiques anti-inflamatoires et neuroprotecteurs.Les statines ont également un effet bénéfique sur le système microvasculaire, mais il n'a jamais été démontré que le système microvasculaire pouvait contribuer à la douleur neuropathique.Un disfonctionnement de la barrière hématho-nerveuse a cependant été démonstré et contribue au développement et à la maintenance de la douleur neuropahtique.Suite à la lésion d'un nerf, les molécules pro-inflammatoires sanguines peuvent pénétrer dans le nerf et contribuent ainsi à la douleur.La rupture de la barrière hématho-nerveuse pourrait également être exploité pour developper de nouveaux traitements analgésiques qui auraient un accès direct au nerf endommagé, sans affecter les nerfs sains.Des études plus poussées du système vasculaire ont révélé une hypoxie persistante endoneuriale dans les nerfs endommagés.Cette hypoxie proviendrait de perturbations microvasculaires, de fibrose endoneuriale et d'une augmentation des besoins métabolique des nerfs endommagés.L'hypoxie impacte également fonctionnellement sur les système immunitaires et nerveux, contribuant ainsi à la douleur neuropathique, et faisant ainsi de l'hypoxie une nouvelle cible thérapeutique.La présence d'hypoxie dans les nerfs abimés suggère que de nouveaux antalgiques qui seraient activés par l'hypoxie elle-même pourrait être developpés afin de cibler localement les nerfs endommagés. ~ 4 ~Ce travail est une contribution nouvelle à la compréhension de nouveaux mécannismes periphériques neuro-immunitaires de la douleur neuropathique. ~ 5 ~ 2 AcknowledgementsThis thesis is a milestone of six years of work.It began as an idea -an idea that after spending one year of studying -turned out to be incorrect.Humbled and dejected, it was only through the continued support of the great people around me that allowed me to return to my path.To go where no person has gone before!To search for the truth!To embetter the world!Let us all hold this candle proudly, so that we may continue the fight against darkness.First and foremost, I would like to thank my advisor, Professor Ji Zhang, for her patience, support and guidance throughout these years.This thesis would not have been possible without your resourcefulness, insight and knowledge.From the bottom of my heart, thank you.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".