1. Academic Validation
  2. Spinal CCK contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress in adult female rats

Spinal CCK contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress in adult female rats

  • Eur J Pharmacol. 2021 Dec 15;913:174619. doi: 10.1016/j.ejphar.2021.174619.
Lu-Lu Duan 1 Xin-Yi Qiu 2 Si-Qi Wei 2 Han-Yu Su 2 Fu-Rong Bai 2 Richard J Traub 3 Qin Zhou 4 Dong-Yuan Cao 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Neural and Pain Sciences, UM Center to Advance Chronic Pain Research, University of Maryland School of Dentistry, Baltimore MD, 21201, USA.
  • 4 Department of Implant Dentistry, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China. Electronic address: zhouqin0529@126.com.
  • 5 Department of Implant Dentistry, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China. Electronic address: dongyuan_cao@hotmail.com.
Abstract

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 CCK1 receptors, CCK2 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 CCK2 receptors and p-ERK1/2 protein in the L4-L5 spinal dorsal horn increased significantly, while the expression of CCK1 receptors and ERK1/2 protein remained unchanged. Intrathecal injection of the CCK2 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 CCK2 receptor antagonist YM-022 significantly reduced the expression of p-ERK1/2. These data indicate that upregulation of CCK2 receptors through the MAPK pathway contributes to somatic hyperalgesia in this comorbid pain model. Thus, CCK2 receptors and MAPK pathway may be potential targets for the treatment of TMD comorbid with FMS.

Keywords

Cholecystokinin receptor; Comorbidity; ERK1/2; Fibromyalgia syndrome; Hyperalgesia; Temporomandibular disorder.

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