Histone modification of pain-related gene expression in spinal cord neurons under a persistent postsurgical pain-like state by electrocautery

Yosuke Katsuda,Eiichi Inada,Keisuke Yamaguchi,Yusuke Hamada,Hideyuki Takeshima,Masako Iseki,Naoko Kuzumaki,Daisuke Sato,Kenichi Tanaka,Minoru Narita,Yoshiyuki Yamabe,Tomohisa Mori,Toshikazu Ushijima,Michiko Narita,Misa Matsufuji,Takashige Kondo

doi:10.1186/s13041-021-00854-y

Yosuke Katsuda, Eiichi Inada + Show 14 more

Open Access

https://doi.org/10.1186/s13041-021-00854-y

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Abstract

Chronic postsurgical pain (CPSP) is a serious problem. We developed a mouse model of CPSP induced by electrocautery and examined the mechanism of CPSP. In this mouse model, while both incision and electrocautery each produced acute allodynia, persistent allodynia was only observed after electrocautery. Under these conditions, we found that the mRNA levels of Small proline rich protein 1A (Sprr1a) and Annexin A10 (Anxa10), which are the key modulators of neuropathic pain, in the spinal cord were more potently and persistently increased by electrocautery than by incision. Furthermore, these genes were overexpressed almost exclusively in chronic postsurgical pain-activated neurons. This event was associated with decreased levels of tri-methylated histone H3 at Lys27 and increased levels of acetylated histone H3 at Lys27 at their promoter regions. On the other hand, persistent allodynia and overexpression of Sprr1a and Anxa10 after electrocautery were dramatically suppressed by systemic administration of GSK-J4, which is a selective H3K27 demethylase inhibitor. These results suggest that the effects of electrocautery contribute to CPSP along with synaptic plasticity and epigenetic modification.

Highlights

Pain, which is a common medical problem, is an unpleasant sensation caused by illness or injury
These experiments showed that the mRNA level of Small proline rich protein 1A (Sprr1a) was significantly increased at 3 to 11 days after surgery in electrocauterytreated mice (Fig. 1D, One-way ANOVA with post-hoc Bonferroni test, **p < 0.01, ***p < 0.001 vs. Sham group, ##p < 0.01, ###p < 0.001 vs. incision group), whereas it was significantly increased at 3 days (Fig. 1D, One-way ANOVA with post-hoc Bonferroni test, **p < 0.01 vs. Sham group), but not at 7 or 11 days, after surgery in incision-treated mice
We revealed that the mRNA levels of cholecystokinin (Cck) identified as “Glut 1, 2- and 3-types”, tachykinin 2 (Tac2) identified as “Glut 5- and 6-types”, neuromedin U (Nmu) identified as “Glut 6- and 7-types”, tachykinin 1 (Tac1) identified as “Glut 10-type”, and ELAV-like RNA binding protein 4 (Elavl4) and Ly6/Plaur domain containing 1 (Lypd1) identified as “Glut 15-type” in cFos-positive neurons were significantly higher than those in cFos-negative neurons (Fig. 2E, F, unpaired t-test, *p < 0.05, **p < 0.01 vs. cFos-negative neurons)

Summary

Introduction

Pain, which is a common medical problem, is an unpleasant sensation caused by illness or injury. Acute postsurgical pain, which is a form of nociceptive pain that is temporarily observed after surgery, can be controlled by analgesic medications and disappears with healing. Electrocautery is a well-known routine surgical procedure that enables faster surgeries, achieves better hemostasis, removes abnormal tissue growth and prevents infection. It generates heat and produces tissue and neuronal damage, which may result in CPSP [5, 6]. While some studies have compared postsurgical pain resulting from incision by scalpel to that caused by electrocautery, they focused on acute postsurgical pain

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