Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons
Sensory neurons embedded in muscle tissue that initiate pain sensations, i.e., nociceptors, are temporarily sensitized by inflammatory mediators during musculoskeletal trauma. These neurons transduce peripheral noxious stimuli into an electrical signal [i.e., an action potential (AP)] and, when sens...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2023.1147437/full |
| _version_ | 1797829016870191104 |
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| author | Sridevi Nagaraja Sridevi Nagaraja Shivendra G. Tewari Shivendra G. Tewari Jaques Reifman |
| author_facet | Sridevi Nagaraja Sridevi Nagaraja Shivendra G. Tewari Shivendra G. Tewari Jaques Reifman |
| author_sort | Sridevi Nagaraja |
| collection | DOAJ |
| description | Sensory neurons embedded in muscle tissue that initiate pain sensations, i.e., nociceptors, are temporarily sensitized by inflammatory mediators during musculoskeletal trauma. These neurons transduce peripheral noxious stimuli into an electrical signal [i.e., an action potential (AP)] and, when sensitized, demonstrate lower activation thresholds and a heightened AP response. We still do not understand the relative contributions of the various transmembrane proteins and intracellular signaling processes that drive the inflammation-induced hyperexcitability of nociceptors. In this study, we used computational analysis to identify key proteins that could regulate the inflammation-induced increase in the magnitude of AP firing in mechanosensitive muscle nociceptors. First, we extended a previously validated model of a mechanosensitive mouse muscle nociceptor to incorporate two inflammation-activated G protein-coupled receptor (GPCR) signaling pathways and validated the model simulations of inflammation-induced nociceptor sensitization using literature data. Then, by performing global sensitivity analyses that simulated thousands of inflammation-induced nociceptor sensitization scenarios, we identified three ion channels and four molecular processes (from the 17 modeled transmembrane proteins and 28 intracellular signaling components) as potential regulators of the inflammation-induced increase in AP firing in response to mechanical forces. Moreover, we found that simulating single knockouts of transient receptor potential ankyrin 1 (TRPA1) and reducing the rates of Gαq-coupled receptor phosphorylation and Gαq subunit activation considerably altered the excitability of nociceptors (i.e., each modification increased or decreased the inflammation-induced fold change in the number of triggered APs compared to when all channels were present). These results suggest that altering the expression of TRPA1 or the concentration of intracellular Gαq might regulate the inflammation-induced increase in AP response of mechanosensitive muscle nociceptors. |
| first_indexed | 2024-04-09T13:13:39Z |
| format | Article |
| id | doaj.art-941864d804ff4b73a98d991909b3d082 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-09T13:13:39Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-941864d804ff4b73a98d991909b3d0822023-05-12T05:55:35ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-05-011710.3389/fnins.2023.11474371147437Identification of key factors driving inflammation-induced sensitization of muscle sensory neuronsSridevi Nagaraja0Sridevi Nagaraja1Shivendra G. Tewari2Shivendra G. Tewari3Jaques Reifman4Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United StatesThe Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesDepartment of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United StatesThe Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesDepartment of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United StatesSensory neurons embedded in muscle tissue that initiate pain sensations, i.e., nociceptors, are temporarily sensitized by inflammatory mediators during musculoskeletal trauma. These neurons transduce peripheral noxious stimuli into an electrical signal [i.e., an action potential (AP)] and, when sensitized, demonstrate lower activation thresholds and a heightened AP response. We still do not understand the relative contributions of the various transmembrane proteins and intracellular signaling processes that drive the inflammation-induced hyperexcitability of nociceptors. In this study, we used computational analysis to identify key proteins that could regulate the inflammation-induced increase in the magnitude of AP firing in mechanosensitive muscle nociceptors. First, we extended a previously validated model of a mechanosensitive mouse muscle nociceptor to incorporate two inflammation-activated G protein-coupled receptor (GPCR) signaling pathways and validated the model simulations of inflammation-induced nociceptor sensitization using literature data. Then, by performing global sensitivity analyses that simulated thousands of inflammation-induced nociceptor sensitization scenarios, we identified three ion channels and four molecular processes (from the 17 modeled transmembrane proteins and 28 intracellular signaling components) as potential regulators of the inflammation-induced increase in AP firing in response to mechanical forces. Moreover, we found that simulating single knockouts of transient receptor potential ankyrin 1 (TRPA1) and reducing the rates of Gαq-coupled receptor phosphorylation and Gαq subunit activation considerably altered the excitability of nociceptors (i.e., each modification increased or decreased the inflammation-induced fold change in the number of triggered APs compared to when all channels were present). These results suggest that altering the expression of TRPA1 or the concentration of intracellular Gαq might regulate the inflammation-induced increase in AP response of mechanosensitive muscle nociceptors.https://www.frontiersin.org/articles/10.3389/fnins.2023.1147437/fullmusculoskeletal painnociceptorion channelscomputational analysisaction potentialsensitization |
| spellingShingle | Sridevi Nagaraja Sridevi Nagaraja Shivendra G. Tewari Shivendra G. Tewari Jaques Reifman Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons Frontiers in Neuroscience musculoskeletal pain nociceptor ion channels computational analysis action potential sensitization |
| title | Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons |
| title_full | Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons |
| title_fullStr | Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons |
| title_full_unstemmed | Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons |
| title_short | Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons |
| title_sort | identification of key factors driving inflammation induced sensitization of muscle sensory neurons |
| topic | musculoskeletal pain nociceptor ion channels computational analysis action potential sensitization |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2023.1147437/full |
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