title: The mitogen and stress-activated protein kinase 1 regulates the rapid epigenetic tagging of dorsal horn neurons and nocifensive behaviour.
abstract: Phosphorylation of histone H3 at serine 10 (p-H3S10) is a marker of active gene transcription. Using cognitive models of neural plasticity, p-H3S10 was shown to be downstream of extracellular signal-regulated kinase (ERK) signalling in the hippocampus. In this study, we show that nociceptive signalling after peripheral formalin injection increased p-H3S10 expression in the ipsilateral dorsal horn. This increase was maximal 30 minutes after formalin injection and occurred mainly within p-ERK-positive neurons. Spinal p-H3S10-enhanced expression was also observed in neurokinin 1 receptor (NK1R), c-Fos, and Zif268 positive neurons and was inhibited by ablation of serotonergic descending controls. The mitogen and stress-activated protein kinase 1 (MSK1) is downstream of ERK and can induce p-H3S10. We found that, after formalin injection, most phospho-MSK1 (p-MSK1)-positive cells (87% ± 3%) expressed p-ERK and the majority of p-H3S10-positive cells (85% ± 5%) expressed p-MSK1. Inhibition of ERK activity with the MEK inhibitor SL327 reduced formalin-induced p-ERK, p-MSK1, and p-H3S10, demonstrating that spinal p-MSK1 and p-H3S10 were at least partly downstream of ERK signalling. Crucially, pharmacological blockade of spinal MSK1 activity with the novel MSK1 inhibitor SB727651A inhibited formalin-induced spinal p-H3S10 and nocifensive behaviour. These findings are the first to establish the involvement of p-H3S10 and its main kinase, MSK1, in ERK regulation of nociception. Given the general importance of ERK signalling in pain processing, our results suggest that p-H3S10 could play a role in the response to injury.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Keri K
authors.initials: KK
authors.lastname: Tochiki
authors.forename: Maria
authors.initials: M
authors.lastname: Maiarú
authors.forename: Caspar
authors.initials: C
authors.lastname: Norris
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunt
authors.forename: Sandrine M
authors.initials: SM
authors.lastname: Géranton
mesh_terms: D015115:5,6-Dihydroxytryptamine / Q000494:pharmacology; D059787:Acute Pain / Q000139:chemically induced / Q000178:diet therapy / Q000473:pathology*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D005557:Formaldehyde / Q000633:toxicity; D006657:Histones / Q000378:metabolism*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D008934:Mitogens / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018689:Sensory System Agents / Q000633:toxicity; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D006657:Histones; D008934:Mitogens; D018689:Sensory System Agents; D005557:Formaldehyde; D012701:Serotonin; D048055:Mitogen-Activated Protein Kinase 8; D002211:Capsaicin; D003891:Desipramine; D015115:5,6-Dihydroxytryptamine