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 Implant Dentistry, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China.
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.
Eur J Pharmacol. 2021 Dec 15;913:174619. doi: 10.1016/j.ejphar.2021.174619. Epub 2021 Nov 5.
In some chronic primary pain conditions such as temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS), mild or chronic stress enhances pain. TMD and FMS often occur together, but the underlying mechanisms are unclear. The purpose of this study was to investigate the role of cholecystokinin (CCK) in the spinal cord in somatic hyperalgesia induced by orofacial inflammation combined with stress. Somatic hyperalgesia was detected by the thermal withdrawal latency and mechanical withdrawal threshold. The expression of CCK receptors, CCK receptors, ERK1/2 and p-ERK1/2 in the spinal cord was examined by Western blot. After the stimulation of orofacial inflammation combined with 3 day forced swim, the expression of CCK receptors and p-ERK1/2 protein in the L4-L5 spinal dorsal horn increased significantly, while the expression of CCK receptors and ERK1/2 protein remained unchanged. Intrathecal injection of the CCK receptor antagonist YM-022 or mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 blocked somatic hyperalgesia induced by orofacial inflammation combined with stress. Intrathecal administration of the MEK inhibitor blocked somatic sensitization caused by the CCK receptor agonist CCK8. The CCK receptor antagonist YM-022 significantly reduced the expression of p-ERK1/2. These data indicate that upregulation of CCK receptors through the MAPK pathway contributes to somatic hyperalgesia in this comorbid pain model. Thus, CCK receptors and MAPK pathway may be potential targets for the treatment of TMD comorbid with FMS.
在一些慢性原发性疼痛疾病中，如颞下颌关节紊乱症（TMD）和纤维肌痛综合征（FMS），轻度或慢性应激会加重疼痛。TMD 和 FMS 经常同时发生，但潜在的机制尚不清楚。本研究旨在探讨胆囊收缩素（CCK）在脊髓中在口腔炎症合并应激引起的躯体痛觉过敏中的作用。躯体痛觉过敏通过热退缩潜伏期和机械退缩阈值来检测。通过 Western blot 检测脊髓中 CCK 受体、CCK 受体、ERK1/2 和 p-ERK1/2 的表达。在口腔炎症合并 3 天强迫游泳刺激后，L4-L5 脊髓背角中的 CCK 受体和 p-ERK1/2 蛋白表达显著增加，而 CCK 受体和 ERK1/2 蛋白表达保持不变。鞘内注射 CCK 受体拮抗剂 YM-022 或丝裂原活化蛋白激酶（MAPK）激酶（MEK）抑制剂 PD98059 可阻断口腔炎症合并应激引起的躯体痛觉过敏。鞘内给予 MEK 抑制剂可阻断 CCK 受体激动剂 CCK8 引起的躯体敏化。CCK 受体拮抗剂 YM-022 显著降低了 p-ERK1/2 的表达。这些数据表明，通过 MAPK 途径上调 CCK 受体参与了这种共病疼痛模型中的躯体痛觉过敏。因此，CCK 受体和 MAPK 通路可能是治疗 TMD 合并 FMS 的潜在靶点。
