Descending serotonergic modulation from rostral ventromedial medulla to spinal trigeminal nucleus is involved in experimental occlusal interference-induced chronic orofacial hyperalgesia

Si-Yi Mo; Yang Xue; Yuan Li; Yao-Jun Zhang; Xiao-Xiang Xu; Kai-Yuan Fu; Barry J Sessle; Qiu-Fei Xie; Ye Cao

doi:10.1186/s10194-023-01584-3

Descending serotonergic modulation from rostral ventromedial medulla to spinal trigeminal nucleus is involved in experimental occlusal interference-induced chronic orofacial hyperalgesia

J Headache Pain. 2023 May 10;24(1):50. doi: 10.1186/s10194-023-01584-3.

Authors

Si-Yi Mo^{1

2}, Yang Xue^{1

2}, Yuan Li^{1

2}, Yao-Jun Zhang^{1

2}, Xiao-Xiang Xu^{3

4}, Kai-Yuan Fu^{2

5}, Barry J Sessle⁶, Qiu-Fei Xie^{1

2}, Ye Cao^{7

8

9}

Affiliations

¹ Department of Prosthodontics, Center for Oral and Jaw Functional Diagnosis, Treatment and Research, School and Hospital of Stomatology, Peking University, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China.
² National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, 100081, PR China.
³ Department of Prosthodontics, Center for Oral and Jaw Functional Diagnosis, Treatment and Research, School and Hospital of Stomatology, Peking University, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. xiaoxiang86@bjmu.edu.cn.
⁴ National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, 100081, PR China. xiaoxiang86@bjmu.edu.cn.
⁵ Center for Temporomandibular Disorders and Orofacial Pain, School and Hospital of Stomatology, Peking University, Beijing, 100081, PR China.
⁶ Faculty of Dentistry & Department of Physiology, Temerty Faculty of Medicine & Centre for the Study of Pain, University of Toronto, Toronto, ON, M5G 1G6, Canada.
⁷ Department of Prosthodontics, Center for Oral and Jaw Functional Diagnosis, Treatment and Research, School and Hospital of Stomatology, Peking University, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. ye.cao@bjmu.edu.cn.
⁸ National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, 100081, PR China. ye.cao@bjmu.edu.cn.
⁹ Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of the People's Republic of China, Peking University, Beijing, 100083, PR China. ye.cao@bjmu.edu.cn.

Abstract

Background: Dental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI).

Methods: Expressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM.

Results: Upregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats.

Conclusions: These results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI.

Keywords: Chronic primary myofascial orofacial pain; Experimental occlusal interference; Hyperalgesia; Pain modulation; Rostral ventromedial medulla; Serotonin.

MeSH terms

Animals
Chronic Pain* / etiology
Facial Pain / etiology
Hyperalgesia* / chemically induced
Rats
Rats, Sprague-Dawley
Receptors, Serotonin, 5-HT3 / metabolism
Receptors, Serotonin, 5-HT3 / therapeutic use
Serotonin / metabolism
Trigeminal Nucleus, Spinal / metabolism

Substances

Receptors, Serotonin, 5-HT3
Serotonin

Abstract

MeSH terms

Substances

Grants and funding