Spinal CCK1 Receptors Contribute to Somatic Pain Hypersensitivity Induced by Malocclusion via a Reciprocal Neuron-Glial Signaling Cascade |
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| Affiliation: | 2. Department of Orthodontics, Xi''an Jiaotong University College of Stomatology, Xi''an, Shaanxi, China;3. Department of Neural and Pain Sciences, School of Dentistry; Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, Maryland;2. Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland;3. Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, Maryland;4. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri;5. Department of Mechanical Engineering, Xian Jiaotong University, Xi''an, Shaanxi, China;2. Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina;3. Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, North Carolina;4. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina;5. Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, New York;6. Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, Florida;2. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;3. Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;4. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;5. Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, New York;6. Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, Florida |
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| Abstract: | Recent studies have shown that the incidence of chronic primary pain including temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently reported that central sensitization and descending facilitation system contributed to the development of somatic pain hypersensitivity induced by orofacial inflammation combined with stress. The purpose of this study was to explore whether TMD caused by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and whether the cholecystokinin (CCK) receptor-mediated descending facilitation system promotes hypersensitivity through neuron-glia cell signaling cascade. UAC evoked thermal and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked at week 4 post UAC. The expression levels of CCK1 receptors, interleukin-18 (IL-18) and IL-18 receptors (IL-18R) were significantly up-regulated in the L4 to L5 spinal dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent with neurons. These findings indicate that the signaling transduction between neurons and glia at the spinal cord level contributes to the descending pain facilitation through CCK1 receptors during the development of the comorbidity of TMD and FMS.PerspectiveCCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade, providing novel therapeutic targets for the clinical treatment of TMD and FMS comorbidities. |
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