Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain

Jose Vicente Torres-Pérez,Gábor Jancsó,Istvan Nagy,Anna P Andreou,Bence Nagy,Péter Sántha,Miklós Sivadó,Peter Szucs,Angelika Varga,Joao Sousa-Valente,Botond Gaal,J Simon C Arthur,Sara Beattie,Klara Matesz

doi:10.1038/srep41221

Abstract

Transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) are essential in the development and maintenance of prolonged pain. Epigenetic mechanisms including post-translational modifications in histones are pivotal in regulating transcription. Here, we report that phosphorylation of serine 10 (S10) in histone 3 (H3) specifically occurs in a group of rat SSDHN following the activation of nociceptive primary sensory neurons by burn injury, capsaicin application or sustained electrical activation of nociceptive primary sensory nerve fibres. In contrast, brief thermal or mechanical nociceptive stimuli, which fail to induce tissue injury or inflammation, do not produce the same effect. Blocking N-methyl-D-aspartate receptors or activation of extracellular signal-regulated kinases 1 and 2, or blocking or deleting the mitogen- and stress-activated kinases 1 and 2 (MSK1/2), which phosphorylate S10 in H3, inhibit up-regulation in phosphorylated S10 in H3 (p-S10H3) as well as fos transcription, a down-stream effect of p-S10H3. Deleting MSK1/2 also inhibits the development of carrageenan-induced inflammatory heat hyperalgesia in mice. We propose that p-S10H3 is a novel marker for nociceptive processing in SSDHN with high relevance to transcriptional changes and the development of prolonged pain.

Highlights

The development of prolonged pain depends on long-term increase in the efficacy of nociceptive signal transduction, which includes activity-dependent increase in the excitability and activity of, and altered synaptic strength between, neurons involved in nociceptive processing[2,3]
In addition to neurons involved in nociceptive processing, neurons involved in other functions of the nervous system, including the formation of memory in the hippocampus exhibit activity-dependent increase in the efficacy of signal transduction, which is referred to as long term potentiation (LTP)[2]
We report that tissue injury, inflammation and persistent, but not brief non-tissue-damaging noxious stimuli phosphorylate serine 10 (S10) in Histone 3 (H3), in a group of superficial spinal dorsal horn neurons (SSDHN) and that the phosphorylation is mediated through the N-methyl-D-aspartate (NMDA) receptor – extracellular signal-regulated kinases 1 and 2 (ERK1/2) – mitogen and stress activated kinases 1 and 2 (MSK1/2) pathways

Summary

Introduction

The development of prolonged pain depends on long-term increase in the efficacy of nociceptive signal transduction, which includes activity-dependent increase in the excitability and activity (sensitisation) of, and altered synaptic strength between, neurons involved in nociceptive processing[2,3]. Epigenetic mechanisms including post-translational modifications (PTM) in histones, which occur as specific responses to various changes in the cellular environment, regulate transcription through the alteration of access to the DNA for proteins involved in gene expression[7]. Phosphorylation of serine 10 (S10) in H3 in the hippocampus has recently been associated with chromatin re-modelling and subsequent changes in gene transcription and synaptic connections as well as alterations in behaviour following environmental challenges[9,10,11,12]. We studied whether phosphorylated (p) S10 in H3 (p-S10H3) is associated with transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) and subsequent alterations in behaviour. During the revision of this manuscript Tochiki and co-workers have reported that p-S10H3 contributes to the development of formalin injection-evoked pain-related behaviour[19]

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