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.
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.
J Pain. 2022 Oct;23(10):1629-1645. doi: 10.1016/j.jpain.2022.05.009. Epub 2022 Jun 10.
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. PERSPECTIVE: 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.
最近的研究表明，慢性原发性疼痛（包括颞下颌关节紊乱症和纤维肌痛综合征）的发病率通常表现出共病现象。我们最近报道称，中枢敏化和下行易化系统有助于解释口腔炎症和应激引起的躯体疼痛过敏现象。本研究旨在探讨单侧前牙反（UAC）引起的 TMD 是否会导致躯体疼痛过敏，以及胆囊收缩素（CCK）受体介导的下行易化系统是否通过神经元-神经胶质细胞信号级联促进过敏反应。UAC 可引起后肢热和机械性痛觉过敏，从第 5 天到第 70 天逐渐加重，在 UAC 后第 4 周达到高峰。UAC 后 4 周，L4 至 L5 脊髓背角的 CCK1 受体、白细胞介素-18（IL-18）和 IL-18 受体（IL-18R）的表达水平显著上调。鞘内注射 CCK1 和 IL-18 受体拮抗剂可阻断躯体疼痛过敏。IL-18 主要与小胶质细胞共定位，而 IL-18R 主要与星形胶质细胞共定位，且与神经元的共定位程度较低。这些发现表明，脊髓水平神经元与神经胶质细胞之间的信号转导有助于 CCK1 受体在 TMD 和 FMS 共病发展过程中诱导下行性疼痛易化。观点：CCK1 受体依赖性下行易化可能通过神经元-神经胶质细胞的相互信号级联，介导广泛躯体疼痛的中枢机制，为 TMD 和 FMS 共病的临床治疗提供新的治疗靶点。
