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

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.

The NAv1.7 blocker protoxin II reduces burn injury-induced spinal nociceptive processing

“…Burn or sham injury was induced as described previously [ 11 , 12 ]. Briefly, animals were anaesthetised by intraperitoneal urethane (0.02 mg/g) or isoflurane (3%, for spinal cord slice preparation) and one of the hind paws (both paws for spinal cord slices) was immersed into 60 or 37 °C water up to the knee for 2 min.…”

“…Ten-micrometre sections were cut and incubated in PBS containing 0.3% Triton-X 100 (PBST) for 10 min, then in 10% normal donkey serum (NDS) for 1 h followed by the primary antibody (Supplementary Table 1 ). For visualisation of the phosphorylated serine 10 in histone H3 (p-S10H3) staining, the tyramide signal amplification procedure was used [ 12 ]. Other immunoreactions were visualised by Alexa Fluor-conjugated secondary antibodies (Supplementary Table 1 ).…”

“…Data were analysed as previously reported [ 12 ]. In brief, power calculations were used to estimate sufficient sample size using an online-based software ( http://homepage.stat.uiowa.edu/~rlenth/Power/ ) and statistical analyses were carried out using the SPSS program (IBM SPSS statistics 22.0 for Windows).…”

Intracerebroventricular Coadministration of Protoxin-II and Trace Elements in Rats Enhances the Analgesic Effect of the 1.7 Voltage-Gate Sodium Channel Blocker

“…Pharmacologically, compounds discovered in the past two decades from spider venoms have been recognized as valuable agents for their neuroprotective, antimicrobial, anticancer, and analgesic properties. Current research studies have specified that these toxins may function as antinociceptive agents by acting on ion channels [11,13]. erefore, in the current report, we studied whether ProTx-II coupled with common trace elements represents a reasonable target to minimize the nociceptive processing in central pain modulation following intracerebroventricular administration, increase efficacy, and reduce side effects of selective Nav1.7 blocker.…”

La epigenética en el tratamiento del dolor

“…demostraron en animales de experimentación que la fosforilación de la serina 10 (S10) en la histona 3 (H3) produce activación de fibras nerviosas sensitivas primarias nociceptivas, específicamente en un grupo de neuronas superficiales del cuerno dorsal espinal (SSDHN), después de la activación de neuronas sensoriales primarias nociceptivas por lesión tipo quemadura o aplicación de capsaicina (9).…”