Featured Article| Volume 23, ISSUE 10, P1629-1645, October 2022

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Spinal CCK1 Receptors Contribute to Somatic Pain Hypersensitivity Induced by Malocclusion via a Reciprocal Neuron-Glial Signaling Cascade

  • Ting Xiang
    Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China

    Department of Orthodontics, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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  • Jia-Heng Li
    Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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  • Han-Yu Su
    Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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  • Kun-Hong Bai
    Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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  • Shuang Wang
    Department of Orthodontics, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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  • Richard J. Traub
    Address reprint requests to Dong-Yuan Cao, PhD, Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi 710004, China.
    Department of Neural and Pain Sciences, School of Dentistry; Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, Maryland
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  • Dong-Yuan Cao
    Address reprint requests to Richard J. Traub, PhD, Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, 650 W Baltimore St, Baltimore, MD 21201.
    Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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      • Malocclusion induces widespread somatic pain hypersensitivity, a typical characteristic of fibromyalgia syndrome.
      • Cholecystokinin -dependent descending facilitation contributes to the development of temporomandibular disorders and fibromyalgia syndrome comorbidity.
      • IL-18 in the spinal cord is important for the development of somatic pain hypersensitivity.
      • Cholecystokinin /IL-18-mediated neuronal and glial cascades are involved in the somatic pain hypersensitivity.


      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.


      CCK1 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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