The role of mitogen- and stress-activated kinase 1 (MSK1) in nociceptive processing in primary sensory neurons
File(s)
Author(s)
Febrianto, Muhammad Rizki
Type
Thesis
Abstract
Pain following tissue injury is a part of inflammatory reaction to restore tissue integrity, thus serves a biological purpose. However, in the event of prolonged pain, the inflammatory reaction persists and is no longer physiologically beneficial. The development of prolonged pain is due to a series of adaptive changes in molecular regulation, causing an increased response of neuronal activity in nervous system, termed as sensitisation, which consists of three mechanistically and temporarily distinct phases. Immediate events occur instantly after injury and are due to self-amplification of currents carried by ion channels. Early changes occur within seconds to minutes and are mediated by a post-translational modification (PTM). Finally, the third phase, which happens in tens of minutes after injury, are the most pivotal phase and due to transcriptional changes. While several of the molecules have been identified, the molecular processes in which physiological sensitivity turns into prolonged hypersensitivity are largely unknown.
Here I show mitogen and stress activated kinase-1 (MSK1), through regulating transcriptional changes, is needed for the development of prolonged inflammatory heat hypersensitivity. Through global deletion of MSK1, I provide evidence that MSK1-/- mice fail to develop prolonged inflammatory heat hypersensitivity, but not mechanical hypersensitivity, while still preserving their basal noxious heat detection. In the naïve state, through immunohistochemistry analysis, I provide evidence that MSK1 expressing cells are in majority peptidergic C-neurons, a subpopulation in sensory neurons associated with the development of noxious heat nociception. Using complete Freund’s adjuvant (CFA) model of inflammation, I show that MSK1 is the major kinase for cyclic-adenosine monophosphate (cAMP) response element-binding protein (CREB) phosphorylation, a transcription factor that regulates many genes implicated in nociception. I conclude that MSK1 serves as a nuclear check point for the development of inflammatory heat hyperalgesia, and controlling MSK1 signalling provides opportunity in the development of novel analgesic drug.
Here I show mitogen and stress activated kinase-1 (MSK1), through regulating transcriptional changes, is needed for the development of prolonged inflammatory heat hypersensitivity. Through global deletion of MSK1, I provide evidence that MSK1-/- mice fail to develop prolonged inflammatory heat hypersensitivity, but not mechanical hypersensitivity, while still preserving their basal noxious heat detection. In the naïve state, through immunohistochemistry analysis, I provide evidence that MSK1 expressing cells are in majority peptidergic C-neurons, a subpopulation in sensory neurons associated with the development of noxious heat nociception. Using complete Freund’s adjuvant (CFA) model of inflammation, I show that MSK1 is the major kinase for cyclic-adenosine monophosphate (cAMP) response element-binding protein (CREB) phosphorylation, a transcription factor that regulates many genes implicated in nociception. I conclude that MSK1 serves as a nuclear check point for the development of inflammatory heat hyperalgesia, and controlling MSK1 signalling provides opportunity in the development of novel analgesic drug.
Version
Open Access
Date Issued
2023-05-01
Date Awarded
01/02/2024
License URL
Advisor
Nagy, Istvan
Vizcaychipi, Marcela
Sponsor
Indonesia Endowment Fund for Education
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)