Towards a Better Understanding of Temporomandibular Disorder

Results from the OPPERA study provided evidence that risk factors such as neck muscle tension, prolonged jaw opening, and female gender increase the likelihood of developing temporomandibular joint disorders (TMJD), which are prevalent, debilitating orofacial pain conditions. Peripheral and central sensitization, which mediate a lowering of the stimulus required for pain signaling, are implicated in the underlying pathology of chronic TMJD. The goal of my study was to investigate cellular changes in the expression of proteins associated with the development of central sensitization. Female Sprague-Dawley rats were injected with complete Freund’s adjuvant in the upper trapezius muscles to promote trigeminal sensitization. After 8 days, animals were subjected to near maximal jaw opening for 20 minutes, and spinal cord tissues were collected at several time points until day 28 post jaw opening. Changes in proteins associated with neuronal and glial cell activation were investigated in the medullary dorsal horn using immunohistochemistry. Somewhat surprisingly, consistently increased protein expression was not observed in second-order nociceptive neurons, astrocytes, or microglia in the dorsal horn. Thus, my results are suggestive that this novel model for inducing chronic TMJD pathology is mechanistically different from other reported inflammatory-induced TMJD models. Based on my results, I propose that this model that involves pain signaling in response to prolonged jaw opening in sensitized animals involves dysfunction of descending inhibitory signaling and likely involves changes in the expression of cytokines and miRNAs

Evolution of mirror-image pain in temporomandibular joint osteoarthritis mouse model

Mirror-image pain is a kind of pain that occurs on the contralateral side, but its pathogenesis remains unclear.  Objective: To develop an osteoarthritis mouse model for investigating mirror-image pain through observing nocifensive behaviors, histological changes, and nociceptive activity at days 3, 7, 14, 21, and 28 after the chemical induction of unilateral temporomandibular joint (TMJ) osteoarthritis. Methodology: We randomly divided 6-week-old mice into sham and complete Freund adjuvant groups. To induce nocifensive behaviors, we applied 0.04 g of von Frey filament, 10 psi of air puff, and cold acetone on both sides of whisker pads at different days. The histology of TMJ on both sides was observed by hematoxylin/eosin staining and microcomputed tomography scanning. Furthermore, the nociceptive activity was evaluated using the phosphorylated cyclic AMP response element binding protein (pCREB) and a microglia marker at different days in the trigeminal subnucleus caudalis. Results: Nocifensive behaviors against mechanical and temperature stimuli on the contralateral side became stronger than the baseline on day 28, in agreement with the elevation of the pCREB and the microglia marker in the trigeminal subnucleus caudalis. Thus, hypernociception on the contralateral side occurred at day 28. Conclusions: Clearly, the TMJ model with unilateral osteoarthritis exhibited mirror-image pain. Therefore, this model is useful in investigating the pathogenesis of pain and in developing treatments

Calcitonin Gene-Related Peptide Promotes Peripheral and Central Trigeminal Sensitization

Temporomandibular joint disorder is characterized by peripheral and central sensitization of trigeminal nociceptive neurons. Although CGRP is implicated in the development of central sensitization by stimulating glial activation via its receptor, the mechanism by which CGRP promotes and maintains sensitization of trigeminal nociceptive neurons is not well understood. The goal of my study was to investigate the role of calcitonin gene-related peptide (CGRP) on the initiation and maintenance of a nocifensive withdrawal response to mechanical stimulation following activation of primary trigeminal sensory neurons. For my studies, I used adult male Sprague Dawley rats that were injected with CGRP alone or co-injected with inhibitors and determined changes in nocifensive behavior and inflammatory proteins. Intrathecal injection of CGRP increased nocifensive responses to mechanical stimulation up to 48 hours and this stimulatory effect was blocked by the antagonist peptide CGRP8-37 and a protein kinase A inhibitor. Results from my cellular studies provide evidence that elevated levels of CGRP in the spinal cord can promote bidirectional signaling within the trigeminal system, a novel finding that helps to explain how central sensitization can lower the activation threshold of primary nociceptors in TMD patients

A Trigeminoreticular Pathway: Implications in Pain

Neurons in the caudalmost ventrolateral medulla (cmVLM) respond to noxious stimulation. We previously have shown most efferent projections from this locus project to areas implicated either in the processing or modulation of pain. Here we show the cmVLM of the rat receives projections from superficial laminae of the medullary dorsal horn (MDH) and has neurons activated with capsaicin injections into the temporalis muscle. Injections of either biotinylated dextran amine (BDA) into the MDH or fluorogold (FG)/fluorescent microbeads into the cmVLM showed projections from lamina I and II of the MDH to the cmVLM. Morphometric analysis showed the retrogradely-labeled neurons were small (area 88.7 µm2±3.4) and mostly fusiform in shape. Injections (20–50 µl) of 0.5% capsaicin into the temporalis muscle and subsequent immunohistochemistry for c-Fos showed nuclei labeled in the dorsomedial trigeminocervical complex (TCC), the cmVLM, the lateral medulla, and the internal lateral subnucleus of the parabrachial complex (PBil). Additional labeling with c-Fos was seen in the subnucleus interpolaris of the spinal trigeminal nucleus, the rostral ventrolateral medulla, the superior salivatory nucleus, the rostral ventromedial medulla, and the A1, A5, A7 and subcoeruleus catecholamine areas. Injections of FG into the PBil produced robust label in the lateral medulla and cmVLM while injections of BDA into the lateral medulla showed projections to the PBil. Immunohistochemical experiments to antibodies against substance P, the substance P receptor (NK1), calcitonin gene regulating peptide, leucine enkephalin, VRL1 (TPRV2) receptors and neuropeptide Y showed that these peptides/receptors densely stained the cmVLM. We suggest the MDH- cmVLM projection is important for pain from head and neck areas. We offer a potential new pathway for regulating deep pain via the neurons of the TCC, the cmVLM, the lateral medulla, and the PBil and propose these areas compose a trigeminoreticular pathway, possibly the trigeminal homologue of the spinoreticulothalamic pathway

The Relationship Between the Stomatognathic System and Body Posture

In recent years, many researchers have investigated the various factors that can influence body posture: mood states, anxiety, head and neck positions, oral functions (respiration, swallowing), oculomotor and visual systems, and the inner ear. Recent studies indicate a role for trigeminal afferents on body posture, but this has not yet been demonstrated conclusively. The present study aims to review the papers that have shown a relationship between the stomatognathic system and body posture. These studies suggest that tension in the stomatognathic system can contribute to impaired neural control of posture. Numerous anatomical connections between the stomatognathic system’s proprioceptive inputs and nervous structures are implicated in posture (cerebellum, vestibular and oculomotor nuclei, superior colliculus). If the proprioceptive information of the stomatognathic system is inaccurate, then head control and body position may be affected. In addition, the present review discusses the role the myofascial system plays in posture. If confirmed by further research, these considerations can improve our understanding and treatment of muscular-skeletal disorders that are associated with temporomandibular joint disorders, occlusal changes, and tooth loss

Infra-slow oscillations in chronic orofacial neuropathic pain and the effects of palmitoylethanolamide

For centuries, chronic pain was denied as being real by physicians, mainly because there was no evidence of tissue damage. The lack of understanding of the neural mechanisms underlying chronic pain, particular that arising from nervous system damage, has hindered treatment development which has led to the over-prescription of opioids. Whilst the brain circuitry responsible for the perception of acute painful stimuli have been mapped in both animal studies and studies using brain imaging in awake humans, the circuitry responsible for the initiation and maintenance of chronic pain remain unknown. Over the past few decades, many human brain imaging investigations have shown that neuropathic pain is associated with altered brain rhythms and in particular thalamocortical dysrhythmia. In addition, animal studies have shown that neuropathic pain is associated with altered non-neural function including microglial and astrocyte activation at the level of the primary afferent synapse. These results have led to theories that non-neuronal cells may be crucial for the initiation and maintenance of chronic pain, particularly chronic neuropathic pain. It has been a long held view that astrocytes mainly play the role of neural support in the central nervous system, however, these cells are also capable of controlling neural function. In fact, astrocytes have access to every neural synapse and animal models of chronic neuropathic pain have shown that targeting astrocytes can control pain intensity. As such, the focus of this thesis is to identify the role of astrocytes in modulating neural function in chronic neuropathic pain and to determine whether reducing astrocyte activity can reduce pain intensity. There are three main investigations that make up this thesis, the first describes an experimental procedure whereby on-going patterns of neural activity were assessed in patients with orofacial neuropathic pain using resting state functional magnetic resonance imaging. The second attempts to measure an anatomical marker of astrocyte activation. And the final investigation describes an experimental procedure whereby patients with orofacial neuropathic pain were administered an astrocyte modulator, palmitoylethanolamide (PEA) and neural activity was compared before and after treatment