Development of a Rat Model of Mechanically Induced Tunable Pain and Associated Temporomandibular Joint Responses

Kartha, Sonia; Zhou, Timothy C.; Granquist, Eric J.; Winkelstein, Beth A.

doi:10.1016/j.joms.2015.09.005

Cited by 26 publications

(55 citation statements)

References 32 publications

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“…Abnormal TMJ loading and the associated orofacial pain have been simulated by repeated mouth-opening in the rodent [13,86]. TMJ loading reorganizes cartilage and is associated with upregulation of biochemicals involved in OA, such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1a (HIF-1a) [13,86,87]. Application of different loading magnitudes to the jaw, for 1 h per day for 7 days, induces distinct pain responses in the rat, suggesting a correlation between the loading magnitude and pain ( Fig.…”

Section: Osteoarthritic Pathology Of the Temporomandibular Jointmentioning

confidence: 99%

“…2(a)). Evaluating mechanical hyperalgesia, an increased response to stimulation, demonstrates that a 2 N load to the jaw produces acute TMJ hyperalgesia that resolves to baseline (BL) levels by day 14, while a 3.5 N load induces chronic TMJ hyperalgesia, with sustained pain for up to 28 days [13,86]. However, mechanical hyperalgesia does not measure spontaneous pain, which is an important clinical outcome and is influenced by both sensory and affective components [88].…”

Section: Osteoarthritic Pathology Of the Temporomandibular Jointmentioning

confidence: 99%

“…Despite the association between certain magnitudes of TMJ loading and chronic pain, the mechanisms by which abnormal mechanics disrupts pain signaling remain unclear. Recent evidence from the same model suggests that hypoxia and inflammation increase in the TMJ after joint loading, with upregulation of HIF-1a, VEGF, matrix metalloproteinases (MMPs) [13]. These outcomes are associated with degenerative pathologies in humans [90] and in other animal models [91][92][93], suggesting that TMJ nociceptors may be sensitized by degenerative molecules and enzymes as a result of TMJ loading.…”

Section: Osteoarthritic Pathology Of the Temporomandibular Jointmentioning

confidence: 99%

“…Synovial joints permit complex motion and often sustain loads several times greater than the weight of the human body; yet, in some cases, repeated and mechanical loading above the normal physiological conditions contribute to the initiation of acute tissue damage and degeneration [10]. Further, the local mechanical environment of joints can be substantially altered after injury or degeneration, which, in some cases, produces dysfunctional nociceptive signaling [11][12][13][14]. Neck pain is among the most prevalent chronic joint pathologies, with 30-50% of the adult population reporting pain over a 12 month period [6].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, mechanical injury can disrupt the normal microenvironment of joint tissues in several distinct ways, including via acute traumatic loading and/or stretching of the capsular ligaments of the joint or by repeated, nontraumatic loading to the tissues in the joint. Both traumatic and repeated mechanical disruption can induce structural changes to joint tissues and inflammatory cascades, which separately activate pain fibers via a modified biomechanical and biochemical environment [13,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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The Interface of Mechanics and Nociception in Joint Pathophysiology: Insights From the Facet and Temporomandibular Joints

Sperry

Ita

Kartha

et al. 2017

Journal of Biomechanical Engineering

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Chronic joint pain is a widespread problem that frequently occurs with aging and trauma. Pain occurs most often in synovial joints, the body's load bearing joints. The mechanical and molecular mechanisms contributing to synovial joint pain are reviewed using two examples, the cervical spinal facet joints and the temporomandibular joint (TMJ). Although much work has focused on the macroscale mechanics of joints in health and disease, the combined influence of tissue mechanics, molecular processes, and nociception in joint pain has only recently become a focus. Trauma and repeated loading can induce structural and biochemical changes in joints, altering their microenvironment and modifying the biomechanics of their constitutive tissues, which themselves are innervated. Peripheral pain sensors can become activated in response to changes in the joint microenvironment and relay pain signals to the spinal cord and brain where pain is processed and perceived. In some cases, pain circuitry is permanently changed, which may be a potential mechanism for sustained joint pain. However, it is most likely that alterations in both the joint microenvironment and the central nervous system (CNS) contribute to chronic pain. As such, the challenge of treating joint pain and degeneration is temporally and spatially complicated. This review summarizes anatomy, physiology, and pathophysiology of these joints and the sensory pain relays. Pain pathways are postulated to be sensitized by many factors, including degeneration and biochemical priming, with effects on thresholds for mechanical injury and/or dysfunction. Initiators of joint pain are discussed in the context of clinical challenges including the diagnosis and treatment of pain.

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Section: Osteoarthritic Pathology Of the Temporomandibular Jointmentioning

confidence: 99%

Section: Osteoarthritic Pathology Of the Temporomandibular Jointmentioning

confidence: 99%

Section: Osteoarthritic Pathology Of the Temporomandibular Jointmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Interface of Mechanics and Nociception in Joint Pathophysiology: Insights From the Facet and Temporomandibular Joints

Sperry

Ita

Kartha

et al. 2017

Journal of Biomechanical Engineering

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Intra‐articular etanercept attenuates pain and hypoxia from TMJ loading in the rat

Sperry

Kartha

et al. 2020

Journal Orthopaedic Research

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Mechanical overloading of the temporomandibular joint (TMJ) and biochemical changes, like inflammation and hypoxia, contribute to cartilage degeneration and pain associated with osteoarthritis (OA). Yet, how overloading contributes to early dysregulation of chondrocytes is not understood, limiting the development of diagnostics and treatments for TMJ OA. Hypoxia‐inducible factors (HIF)‐1α/2α in chondrocytes were evaluated at Days 8 and 15 in a rat TMJ pain model induced by jaw loading (1 h/day for 7 days) using immunohistochemistry and compared between cases that induce persistent (3.5 N), acute (2 N), or no (0 N) sensitivity. Hypoxia was measured on Day 8 by immunolabeling of the tracer EF5 and 18F‐EF5 PET imaging. To assess the role of tumor necrosis factor (TNF) in painful TMJ loading, intra‐articular etanercept was given before loading. Orofacial sensitivity was evaluated during and after loading. Facial grimace, TNF‐α, HIF‐2α, and hypoxia levels in the TMJ were measured after loading. HIF‐2α was elevated (P = .03) after 3.5 N loading at Day 8, but HIF‐1α was unchanged. EF5 uptake increased on Day 8 in the 3.5 N group (P < .048) by tissue assay and 18F‐EF5 PET. At Day 8, both HIF‐2α (P = .01) and EF5 uptake (P = .005) were correlated with loading magnitude. Etanercept attenuated sensitivity (P < .01) and the facial grimace on Day 7 (P = .01). It also reduced (P < .01) HIF‐2α and EF5 uptake on Day 8; but TNF‐α levels were not different from controls at that time. Findings suggest that TMJ loading that induces persistent sensitivity upregulates the catabolic factor HIF‐2α and reduces oxygen levels in the cartilage, which may be TNF‐driven.

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MMPs in tissues retrieved during surgery from patients with TMJ disorders relate to pain more than to radiological damage score

Ita

Ghimire

Granquist

et al. 2021

Journal Orthopaedic Research

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Orofacial pain is among the most common chronic pain conditions and can result from temporomandibular disorders (TMDs) of the temporomandibular joint (TMJ). Matrix metalloproteinases (MMPs) drive degeneration of TMJ tissues and likely mediate pain in TMJ disorders given their role in nociception. However, few studies have assessed MMPs in the TMJ innervated tissues nor in the context of pain. This study defined the extent of MMP‐1, MMP‐9, and MMP‐2 in TMJ tissues from patients undergoing total joint replacement (TJR) or arthroplasty discectomy for painful TMJ disorders. Protein expression was probed by Western blot in TMJ disc and capsular ligaments taken during TJR (n = 6) or discectomy (n = 3) for osteoarthritis or internal derangement in an IRB‐approved study. Pro‐ and active MMP‐1, active MMP‐9, and pro‐ and active MMP‐2 are detectable. MMP‐1 and MMP‐9 correlate positively to each other (Kendall's τ = 0.63; p = 0.01), strengthening the hypothesis that they are mechanistically related in regulatory cascades. Active MMP‐1 and active MMP‐9 correlate positively with self‐reported pain scores (τ ≥ 0.51; p ≤ 0.04), suggesting their involvement in peripheral nociception. Overall, neither MMPs nor pain correlate with the functional vertical opening of the jaw. MMP‐1 varies with the observed stage of degeneration during surgery (p = 0.04). Neither overall MMPs nor pain correlate with the overall magnetic resonance imaging scores, corroborating the longstanding, but confounding, clinical observation that pain and radiological evidence of joint damage are not always related. Clinical significance: These findings suggest that MMPs mediate pain in innervated soft tissues and may be targets for diagnosing disease stage and treatments in painful TMJ disorders.

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Development of a Rat Model of Mechanically Induced Tunable Pain and Associated Temporomandibular Joint Responses

Cited by 26 publications

References 32 publications

The Interface of Mechanics and Nociception in Joint Pathophysiology: Insights From the Facet and Temporomandibular Joints

The Interface of Mechanics and Nociception in Joint Pathophysiology: Insights From the Facet and Temporomandibular Joints

Intra‐articular etanercept attenuates pain and hypoxia from TMJ loading in the rat

MMPs in tissues retrieved during surgery from patients with TMJ disorders relate to pain more than to radiological damage score

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