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Mitogen- and stress-activated kinase 1 in primary sensory neurons contributes to formalin-induced tonic pain

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机构: [1]Nociception Group, APMIC, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom. [2]Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. [3]Austria Division of Neuroscience, Department of Physiology and Biomedical Physics, Institute of Physiology, Medical University of Innsbruck, Innsbruck, Austria. [4]Department of Physiology, University of Debrecen, Debrecen, Hungary. [5]Department of Anaesthesia, Prince Sultan Military College of Health Sceince, Dhahran, Saudi Arabia. [6]Department of Pain Management, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, PR China.
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关键词: MSK1 Formalin test Nociceptors Calcitonin gene–related peptide Dorsal root ganglion

摘要:
The nuclear mitogen- and stress-activated kinases (MSKs) play a critical role in the development and persistence of pain after tissue injury.Here, we ascertained the MSK isoform, the cells and mechanisms, which mediate MSKs' pronociceptive function.Nocifensive behaviour evoked by subcutaneous formalin injection into the paw was quantified in wild type (WT), MSK1 and MSK2 global knock out (MSK1-/- and MSK2-/-) mice, and a month after injecting adeno-associated viral vector carrying short-hairpin (sh) RNA directed towards the MSK1-encoding gene Rps6ka5 mRNA or scrambled shRNA into the sciatic nerve of WT mice. Rps6ka5 expression in nociceptors was ascertained by analysing publicly available single cell and single nucleus RNA sequencing datasets on primary sensory neurons and reverse transcription polymerase chain reaction on dorsal root ganglia (DRG). Mitogen- and stress-activated kinase 1 expression was verified by immunofluorescent staining on DRG sections.MSK1-/- but not MSK2-/- mice exhibited significantly attenuated evoked nocifensive behaviour specifically in the second but not the first phase of the formalin test. Downregulating Rps6ka5 in nociceptors by the viral vector tool attenuated formalin-induced pain behaviour to the same extent as observed in MSK1-/- animals. Rps6ka5 expression was found in DRG and various transcriptionally defined groups of nociceptive primary sensory neurons (nociceptors). Immunofluorescence confirmed the presence of MSK1 predominantly in peptidergic nociceptors.MSK1 constitutes the principal MSK isoform, which is critically important for regulating cellular components that enable the transient activation of a specific subpopulation of nociceptors by formalin.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

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出版当年[2025]版:
大类 | 3 区 医学
小类 | 3 区 神经科学
最新[2025]版:
大类 | 3 区 医学
小类 | 3 区 神经科学
第一作者:
第一作者机构: [1]Nociception Group, APMIC, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom.
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通讯机构: [1]Nociception Group, APMIC, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom. [4]Department of Physiology, University of Debrecen, Debrecen, Hungary.
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