Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Beth A. Winkelstein

Second Advisor

Eric J. Granquist

Abstract

Temporomandibular joint (TMJ) pain is among the most prevalent musculoskeletal conditions and is initiated by atypical joint loading from parafunctional behaviors or disc dysfunction. For most patients, TMJ pain is self–resolving; however, 15% of patients develop chronic TMJ pain that is recalcitrant to therapy and may be attributed to changes in pain processing centers. Although TMJ overloading induces pain and osteoarthritis (OA) in the mandibular condyle, if and how modifications in brain networks, circuits, and neurons contribute to persistent TMJ pain is unknown. Studies in this thesis use a rat model of repeated jaw loading with tunable transient (2N–load) or persistent (3.5N–load) pain to define the intraarticular mechanisms that initiate TMJ pain and contribute to the inflammatory, catabolic, and hypoxic dysregulation of TMJ articular cartilage. Whether pain is sustained by functional remodeling of supraspinal networks and modifications in neurons, synapses, and microglia in the trigeminal sensory system is investigated using a combination of 18F–FDG PET imaging, complex network analysis, circuit modeling, and neural tissue assays. Findings show that 3.5N jaw loading induces affective pain, osteoarthritic cartilage, and reorganization of condylar trabecular bone, which parallel signs of TMJ OA in humans. Increased hypoxia and the catabolism–promoting protein HIF–2 occur transiently only after 3.5N jaw loading; hypoxia is also detected at day 7 in the TMJ by 18F–EF5 PET imaging. Cortical brain regions are functionally clustered and prefrontal–limbic circuits are activated only with persistent pain. The excitatory neuropeptide substance P and microglial activation are upregulated in the spinal trigeminal nucleus caudalis after loading. Inhibiting intraarticular TNF– before loading prevents the pain, joint hypoxia and HIF–2, and cellular and network modifications that otherwise occur. Blocking TMJ afferent inputs normalizes brain network organization. At a delayed time, enhanced network clustering in the limbic system and loss of inhibitory synapses in the ventroposteriomedial thalamus are identified with persistent, but not transient, pain, which implicates those supraspinal modifications in sustaining pain. Collectively, these findings suggest that augmented, but flexible, central pain processing is a feature of early TMJ OA and that brain modifications have a role in the maintenance of TMJ pain.

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