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SAHA Inhibits Somatic Hyperalgesia Induced by Stress Combined with Orofacial Inflammation Through Targeting Different Spinal 5-HT Receptor Subtypes

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Abstract

Epigenetic regulation of gene expression has been implicated in the development of chronic pain. However, little is known about whether this regulation is involved in the development and treatment of chronic pain comorbidities such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), a comorbidity predominantly occurring among women. Here we explored the impact of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on somatic hyperalgesia induced by stress or stress combined with orofacial inflammation, which mimicked the comorbidity of FMS and TMD in rats. Our data showed that somatic thermal hyperalgesia and mechanical allodynia induced by both conditions were completely prevented by intrathecal injection of SAHA, which upregulated 5-HT2C receptors but downregulated 5-HT3 receptors in the spinal dorsal horn. Subsequent spinal administration of RS102221 to inhibit 5-HT2C receptors or SR57227 to activate 5-HT3 receptors reversed the analgesic effect of SAHA under both conditions. These results indicate that SAHA attenuates the pro-nociceptive effects of stress combined with orofacial inflammation and the effects of stress alone. This likely occurs through epigenetic regulation of spinal 5-HT2C and 5-HT3 receptor expression, suggesting that SAHA has potential therapeutic value in FMS or comorbid FMS-TMD patients with somatic hyperalgesia.

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Acknowledgements

The authors wish to thank Ms. Holly Ross (Department of Neural and Pain Sciences, University of Maryland School of Dentistry) for English reading and editing.

Funding

This work was supported by the National Natural Science Foundation of China (81971049, 81671097) and the Social Development Program of Shaanxi Province, China (2020SF-018).

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Authors and Affiliations

  1. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Research Center of Stomatology, Xi’an Jiaotong University College of Stomatology, 98 West 5th Road, Xi’an, 710004, Shaanxi, China

    Zhuo-Ying Tao, Xin-Yi Qiu, Si-Qi Wei, Jin-Feng Li & Dong-Yuan Cao

  2. Department of Cleft Palate-Craniofacial Surgery, Xi’an Jiaotong University College of Stomatology, 98 West 5th Road, Xi’an, 710004, Shaanxi, China

    Zhuo-Ying Tao & Jin-Feng Li

  3. Department of Neural and Pain Sciences, UM Center to Advance Chronic Pain Research, University of Maryland School of Dentistry, 650 West Baltimore Street, Baltimore, MD, 21201, USA

    Guang Bai & Dong-Yuan Cao

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  1. Zhuo-Ying Tao
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  2. Xin-Yi Qiu
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Contributions

DYC designed the study, ZYT, XYQ, and SQW performed the experiments. GB analyzed the data and edited the paper. ZYT, JFL, and DYC analyzed the data and wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Jin-Feng Li or Dong-Yuan Cao.

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Experimental protocols were approved by the Institutional Animal Care and Use Committees of Xi’an Jiaotong University, China (No. 2016-006).

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11064_2022_3540_MOESM1_ESM.eps

Supplementary material 1 SAHA did not affect the thermal withdrawal latency and mechanical withdrawal threshold in rats in the E2 + non-FS group and the E2 + saline + non-FS group (EPS 47.1 kb)

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Tao, ZY., Qiu, XY., Wei, SQ. et al. SAHA Inhibits Somatic Hyperalgesia Induced by Stress Combined with Orofacial Inflammation Through Targeting Different Spinal 5-HT Receptor Subtypes. Neurochem Res 47, 1405–1418 (2022). https://doi.org/10.1007/s11064-022-03540-0

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