Background & Aims
Chronic pain affects 30% of adults in the USA and is associated with suffering as well as high treatment costs and lost productivity. Despite its prevalence, the mechanisms of pain chronification remain elusive. While extensive studies focus on the cellular mechanisms, it is essential to give more emphasis to the relationship between the extracellular matrix (ECM) and neuron-glia interactions.
Our long-term goal is to develop novel approaches for preventing and treating the progression of chronic pain. Our central hypothesis is that maladaptive changes in ECM components are associated with alterations in neuron-glia crosstalk, thus contributing to the development of chronic pain. This objective aims to offer potential venues for mechanism-based treatments.
AIM1: Identify the key ECM components that are significantly altered during chronic pain.
AIM2: Identify changes in hippocampal glial activity as a function of ECM plasticity.
Methods
Animal subjects will be male mice, 12 weeks old at the time of tibial fracture. mice will be anesthetized with 1.5% isoflurane and will undergo a distal tibial fracture in the right leg. A hemostat will be used to make a closed fracture of the right tibia just distal to the middle of the tibia and the hindlimb will be wrapped in casting tape. The cast will be removed in 3 weeks under brief isoflurane anesthesia.
1. Behavioral analyses: Two timepoints will be studied to include the baseline test, the acute (4w), chronic (7w) phases following tibia fracture.
2. Imaging mass spectrometry analysis of the extracellular matrix: Marix-Assisted Laser Desorption Ionization (MALDI) will be followed by liquid chromatography–mass spectrometry (LC–MS) for the identification of spatially specific changes in ECM protein expression and modification in intact and decellularized brain section.
3. Single-cell western: Be used to quantify the microglial engulfment of distal neuronal dendrites.
Results
Mice displayed decreased mechanical thresholds in the injured hind paw coupled with working memory deficits, as observed in the Y maze. Our preliminary MALDI studies show biologically relevant localization of ECM proteins with specific and localized changes in ECM protein expression following tibia fracture. Our glial engulfment experiments are ongoing. Prior research indicates a rise in glial engulfment of neuronal dendrites during developmental stages and in specific pathological conditions characterized by observed neuronal reorganization[1]. We expect an increase in glial engulfment after injury.
Conclusions
Our study aims to highlight the role of the brain ECM in pain chronification, with particular emphasis on glia-neuron dynamics. This line of investigation not only advances our comprehension of the pathophysiology of chronic pain but also provides a novel therapeutic strategy targeting the maladaptive interactions between ECM constituents and glial cells.
References
[1] Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan W-B. ATP mediates rapid microglial response to local brain injury in vivo. Nature neuroscience 2005;8(6):752-758.
[2] Krishnaswamy VR, Benbenishty A, Blinder P, Sagi I. Demystifying the extracellular matrix and its proteolytic remodeling in the brain: structural and functional insights. Cellular and molecular life sciences 2019;76:3229-3248.
[3] Tajerian M, Clark JD. Spinal matrix metalloproteinase 8 regulates pain after peripheral trauma. J Pain Res 2019;12:1133-1138.
[4] Tajerian M, Hung V, Nguyen H, Lee G, Joubert LM, Malkovskiy AV, Zou B, Xie S, Huang TT, Clark JD. The hippocampal extracellular matrix regulates pain and memory after injury. Mol Psychiatry 2018;23(12):2302-2313.
Presenting Author
Chuang Ge
Poster Authors
Topics
- Models: Transition to Chronic Pain