Advances in the Study of Microglia in Neuropathic Pain
Keywords:
neuropathic pain, microglia, neuroinflammation, activation mechanisms, receptor-mediated pathways, pro-inflammatory factors, signaling pathways, neuron-glia interactions, synaptic plasticity, therapeutic strategies
Abstract
Neuropathic pain is a kind of chronic pain triggered by nervous system injury or dysfunction, whose mechanism is complex and lacks effective treatment. Recent studies have shown that microglia, as core immune cells in the central nervous system, play a central by role in the development and maintenance of pain ). play a central role in the onset and maintenance of pain. In this paper, we systematically reviewed the activation mechanism of microglia and their multi-receptor regulatory network (including in neuropathic painreleasing pro-inflammatory factors (e.g., IL-1β, TNF-α), regulating key signaling pathways (e.g., TLR/NF-κB, NLRP3 inflammatory vesicles, JAK/STAT), and mediating neuron-glia interactions (e.g., BDNF-TrkB, ATP-P2X4P2X4, TLR4, RAGE, GLP-1R, CCR2, KOR, and GPR84) , and elucidated their amplification of pain signals through inflammatory factor release, synaptic plasticity regulation, and neuronal excitability enhancement. Meanwhile, this paper explores the potential value of therapeutic strategies targeting microglia receptors (e.g., antagonists, genetic interventions and electroacupuncture therapy), and looks forward to emerging research directions such as metabolic reprogramming, epigenetic regulation and gender differences, which will provide a theoretical basis for the development of precision analgesic therapies.
References
[1] Finnerup, N. B., Kuner, R., & Jensen, T. S. (2021). Neuropathic pain: From mechanisms to treatment. Physiological Reviews, 101(1), 259–301. https://doi.org/10.1152/physrev.00045.2019
[2] Scholz, J., Finnerup, N. B., Attal, N., et al. (2019). The IASP classification of chronic pain for ICD-11: Chronic neuropathic pain. Pain, 160(1), 53–59. https://doi.org/10.1097/j.pain.0000000000001365
[3] Binder, A., & Baron, R. (2016). The pharmacological therapy of chronic neuropathic pain. Deutsches Ärzteblatt International, 113(37), 616–625. https://doi.org/10.3238/arztebl.2016.0616
[4] Salter, M. W., & Beggs, S. (2014). Sublime microglia: Expanding roles for the guardians of the CNS. Cell, 158(1), 15–24. https://doi.org/10.1016/j.cell.2014.06.008
[5] Grace, P. M., Hutchinson, M. R., Maier, S. F., et al. (2014). Pathological pain and the neuroimmune interface. Nature Reviews Immunology, 14(4), 217–231. https://doi.org/10.1038/nri3621
[6] Inoue, K., & Tsuda, M. (2018). Microglia in neuropathic pain: Cellular and molecular mechanisms and therapeutic potential. Nature Reviews Neuroscience, 19(3), 138–152. https://doi.org/10.1038/nrn.2018.2
[7] Tay, T. L., Mai, D., Dautzenberg, J., et al. (2017). A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nature Neuroscience, 20(6), 793–803. https://doi.org/10.1038/nn.4547
[8] Kettenmann, H., Hanisch, U. K., Noda, M., et al. (2011). Physiology of microglia. Physiological Reviews, 91(2), 461–553. https://doi.org/10.1152/physrev.00011.2010
[9] Kwon, H. S., & Koh, S. H. (2020). Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Translational Neurodegeneration, 9(1), 42. https://doi.org/10.1186/s40035-020-00221-2
[10] Jurga, A. M., Paleczna, M., & Kuter, K. Z. (2020). Overview of general and discriminating markers of differential microglia phenotypes. Frontiers in Cellular Neuroscience, 14, 198. https://doi.org/10.3389/fncel.2020.00198
[11] Lan, X., Han, X., Li, Q., et al. (2017). Modulators of microglial activation and polarization after intracerebral haemorrhage. Nature Reviews Neurology, 13(7), 420–433. https://doi.org/10.1038/nrneurol.2017.69
[12] Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., et al. (2004). Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia, 45(1), 89–95. https://doi.org/10.1002/glia.10319
[13] Chu, J., Yang, J., Zhou, Y., et al. (2023). ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain. Science Advances, 9(13), eade9931. https://doi.org/10.1126/sciadv.ade9931
[14] Li, J., Wei, Y., Zhou, J., et al. (2022). Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn. Journal of Neuroinflammation, 19(1), 123. https://doi.org/10.1186/s12974-022-02444-2
[15] Wu, J., Han, Y., Xu, H., et al. (2023). Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-kappaB/NLRP3 pathway. Science Advances, 9(40), eadi8343. https://doi.org/10.1126/sciadv.adi8343
[16] Malko, P., Jia, X., Wood, I., et al. (2023). Piezo1 channel-mediated Ca(2+) signaling inhibits lipopolysaccharide-induced activation of the NF-κB inflammatory signaling pathway and generation of TNF-α and IL-6 in microglial cells. Glia, 71(4), 848–865. https://doi.org/10.1002/glia.24354
[17] Jia, D., Liu, G., Sun, Y., et al. (2023). Trifluoro-icaritin ameliorates spared nerve injury-induced neuropathic pain by inhibiting microglial activation through α7nAChR-mediated blockade of BDNF/TrkB/KCC2 signaling in the spinal cord of rats. Biomedicine & Pharmacotherapy, 157, 114001. https://doi.org/10.1016/j.biopha.2023.114001
[18] Huang, L., Jin, J., Chen, K., et al. (2021). BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury. PLoS Biology, 19(7), e3001337. https://doi.org/10.1371/journal.pbio.3001337
[19] Hernandez-Echeagaray, E. (2020). The role of the TrkB-T1 receptor in the neurotrophin-4/5 antagonism of brain-derived neurotrophic factor on corticostriatal synaptic transmission. Neural Regeneration Research, 15(11), 1973–1976. https://doi.org/10.4103/1673-5374.282230
[20] Gilabert, D., Duveau, A., Carracedo, S., et al. (2023). Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice. iScience, 26(11), 108110. https://doi.org/10.1016/j.isci.2023.108110
[21] Dave, K. M., Ali, L., & Manickam, D. S. (2020). Characterization of the SIM-A9 cell line as a model of activated microglia in the context of neuropathic pain. PLOS ONE, 15(4), e0231597. https://doi.org/10.1371/journal.pone.0231597
[22] Widerström-Noga, E. (2023). Neuropathic pain and spinal cord injury: Management, phenotypes, and biomarkers. Drugs, 83(11), 1001–1025. https://doi.org/10.1007/s40265-023-01888-x
[23] Haruwaka, K., Ying, Y., Liang, Y., et al. (2024). Microglia enhance post-anesthesia neuronal activity by shielding inhibitory synapses. Nature Neuroscience, 27(3), 449–461. https://doi.org/10.1038/s41593-024-01594-w
[24] Ahmad, K. A., Shoaib, R. M., Ahsan, M. Z., et al. (2021). Microglial IL-10 and β-endorphin expression mediates gabapentinoids' antineuropathic pain. Brain, Behavior, and Immunity, 95, 344–361. https://doi.org/10.1016/j.bbi.2021.04.017
[25] Moraes, T. R., Veras, F. P., Barchuk, A. R., et al. (2024). Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation. Frontiers in Immunology, 15, 1303937. https://doi.org/10.3389/fimmu.2024.1303937
[26] Deng, M. Y., Cheng, J., Gao, N., et al. (2024). Dexamethasone attenuates neuropathic pain through spinal microglial expression of dynorphin A via the cAMP/PKA/p38 MAPK/CREB signaling pathway. Brain, Behavior, and Immunity, 119, 36–50. https://doi.org/10.1016/j.bbi.2024.03.005
[27] Dansereau, M. A., Midavaine, É., Bégin-Lavallée, V., et al. (2021). Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity. Journal of Neuroinflammation, 18(1), 79. https://doi.org/10.1186/s12974-021-02126-7
[28] Li, Y., Yin, C., Li, X., et al. (2019). Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. International Journal of Molecular Sciences, 20(23), 6085. https://doi.org/10.3390/ijms20236085
[29] Nicol, L. S., Dawes, J. M., La Russa, F., et al. (2015). The role of G-protein receptor 84 in experimental neuropathic pain. The Journal of Neuroscience, 35(23), 8959–8969. https://doi.org/10.1523/JNEUROSCI.3948-14.2015
[30] Joshi, H. P., Jo, H. J., Kim, Y. H., et al. (2021). Stem cell therapy for modulating neuroinflammation in neuropathic pain. International Journal of Molecular Sciences, 22(9), 4669. https://doi.org/10.3390/ijms22094669
[31] Attal, N., & Bouhassira, D. (2021). Advances in the treatment of neuropathic pain. Current Opinion in Neurology, 34(5), 631–637. https://doi.org/10.1097/WCO.0000000000000972
[32] Shen, C. L., Castro, L., Fang, C. Y., et al. (2022). Bioactive compounds for neuropathic pain: An update on preclinical studies and future perspectives. The Journal of Nutritional Biochemistry, 104, 108979. https://doi.org/10.1016/j.jnutbio.2022.108979
[33] Di Stefano, G., Di Lionardo, A., Di Pietro, G., et al. (2021). Pharmacotherapeutic options for managing neuropathic pain: A systematic review and meta-analysis. Pain Research & Management, 2021, 6656863. https://doi.org/10.1155/2021/6656863
[34] Thouaye, M., & Yalcin, I. (2023). Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons. Pharmacology & Therapeutics, 251, 108546. https://doi.org/10.1016/j.pharmthera.2023.108546
[35] Wei, X. Y., Wang, X., Shi, G. X., et al. (2024). Acupuncture modulation of chronic neuropathic pain and its association with brain functional properties. Journal of Pain, 25(11), 104645. https://doi.org/10.1016/j.jpain.2024.01.009
[36] Petzke, F., Tölle, T., Fitzcharles, M. A., et al. (2022). Cannabis-based medicines and medical cannabis for chronic neuropathic pain. CNS Drugs, 36(1), 31–44. https://doi.org/10.1007/s40263-021-00864-3
[2] Scholz, J., Finnerup, N. B., Attal, N., et al. (2019). The IASP classification of chronic pain for ICD-11: Chronic neuropathic pain. Pain, 160(1), 53–59. https://doi.org/10.1097/j.pain.0000000000001365
[3] Binder, A., & Baron, R. (2016). The pharmacological therapy of chronic neuropathic pain. Deutsches Ärzteblatt International, 113(37), 616–625. https://doi.org/10.3238/arztebl.2016.0616
[4] Salter, M. W., & Beggs, S. (2014). Sublime microglia: Expanding roles for the guardians of the CNS. Cell, 158(1), 15–24. https://doi.org/10.1016/j.cell.2014.06.008
[5] Grace, P. M., Hutchinson, M. R., Maier, S. F., et al. (2014). Pathological pain and the neuroimmune interface. Nature Reviews Immunology, 14(4), 217–231. https://doi.org/10.1038/nri3621
[6] Inoue, K., & Tsuda, M. (2018). Microglia in neuropathic pain: Cellular and molecular mechanisms and therapeutic potential. Nature Reviews Neuroscience, 19(3), 138–152. https://doi.org/10.1038/nrn.2018.2
[7] Tay, T. L., Mai, D., Dautzenberg, J., et al. (2017). A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nature Neuroscience, 20(6), 793–803. https://doi.org/10.1038/nn.4547
[8] Kettenmann, H., Hanisch, U. K., Noda, M., et al. (2011). Physiology of microglia. Physiological Reviews, 91(2), 461–553. https://doi.org/10.1152/physrev.00011.2010
[9] Kwon, H. S., & Koh, S. H. (2020). Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Translational Neurodegeneration, 9(1), 42. https://doi.org/10.1186/s40035-020-00221-2
[10] Jurga, A. M., Paleczna, M., & Kuter, K. Z. (2020). Overview of general and discriminating markers of differential microglia phenotypes. Frontiers in Cellular Neuroscience, 14, 198. https://doi.org/10.3389/fncel.2020.00198
[11] Lan, X., Han, X., Li, Q., et al. (2017). Modulators of microglial activation and polarization after intracerebral haemorrhage. Nature Reviews Neurology, 13(7), 420–433. https://doi.org/10.1038/nrneurol.2017.69
[12] Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., et al. (2004). Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia, 45(1), 89–95. https://doi.org/10.1002/glia.10319
[13] Chu, J., Yang, J., Zhou, Y., et al. (2023). ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain. Science Advances, 9(13), eade9931. https://doi.org/10.1126/sciadv.ade9931
[14] Li, J., Wei, Y., Zhou, J., et al. (2022). Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn. Journal of Neuroinflammation, 19(1), 123. https://doi.org/10.1186/s12974-022-02444-2
[15] Wu, J., Han, Y., Xu, H., et al. (2023). Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-kappaB/NLRP3 pathway. Science Advances, 9(40), eadi8343. https://doi.org/10.1126/sciadv.adi8343
[16] Malko, P., Jia, X., Wood, I., et al. (2023). Piezo1 channel-mediated Ca(2+) signaling inhibits lipopolysaccharide-induced activation of the NF-κB inflammatory signaling pathway and generation of TNF-α and IL-6 in microglial cells. Glia, 71(4), 848–865. https://doi.org/10.1002/glia.24354
[17] Jia, D., Liu, G., Sun, Y., et al. (2023). Trifluoro-icaritin ameliorates spared nerve injury-induced neuropathic pain by inhibiting microglial activation through α7nAChR-mediated blockade of BDNF/TrkB/KCC2 signaling in the spinal cord of rats. Biomedicine & Pharmacotherapy, 157, 114001. https://doi.org/10.1016/j.biopha.2023.114001
[18] Huang, L., Jin, J., Chen, K., et al. (2021). BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury. PLoS Biology, 19(7), e3001337. https://doi.org/10.1371/journal.pbio.3001337
[19] Hernandez-Echeagaray, E. (2020). The role of the TrkB-T1 receptor in the neurotrophin-4/5 antagonism of brain-derived neurotrophic factor on corticostriatal synaptic transmission. Neural Regeneration Research, 15(11), 1973–1976. https://doi.org/10.4103/1673-5374.282230
[20] Gilabert, D., Duveau, A., Carracedo, S., et al. (2023). Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice. iScience, 26(11), 108110. https://doi.org/10.1016/j.isci.2023.108110
[21] Dave, K. M., Ali, L., & Manickam, D. S. (2020). Characterization of the SIM-A9 cell line as a model of activated microglia in the context of neuropathic pain. PLOS ONE, 15(4), e0231597. https://doi.org/10.1371/journal.pone.0231597
[22] Widerström-Noga, E. (2023). Neuropathic pain and spinal cord injury: Management, phenotypes, and biomarkers. Drugs, 83(11), 1001–1025. https://doi.org/10.1007/s40265-023-01888-x
[23] Haruwaka, K., Ying, Y., Liang, Y., et al. (2024). Microglia enhance post-anesthesia neuronal activity by shielding inhibitory synapses. Nature Neuroscience, 27(3), 449–461. https://doi.org/10.1038/s41593-024-01594-w
[24] Ahmad, K. A., Shoaib, R. M., Ahsan, M. Z., et al. (2021). Microglial IL-10 and β-endorphin expression mediates gabapentinoids' antineuropathic pain. Brain, Behavior, and Immunity, 95, 344–361. https://doi.org/10.1016/j.bbi.2021.04.017
[25] Moraes, T. R., Veras, F. P., Barchuk, A. R., et al. (2024). Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation. Frontiers in Immunology, 15, 1303937. https://doi.org/10.3389/fimmu.2024.1303937
[26] Deng, M. Y., Cheng, J., Gao, N., et al. (2024). Dexamethasone attenuates neuropathic pain through spinal microglial expression of dynorphin A via the cAMP/PKA/p38 MAPK/CREB signaling pathway. Brain, Behavior, and Immunity, 119, 36–50. https://doi.org/10.1016/j.bbi.2024.03.005
[27] Dansereau, M. A., Midavaine, É., Bégin-Lavallée, V., et al. (2021). Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity. Journal of Neuroinflammation, 18(1), 79. https://doi.org/10.1186/s12974-021-02126-7
[28] Li, Y., Yin, C., Li, X., et al. (2019). Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. International Journal of Molecular Sciences, 20(23), 6085. https://doi.org/10.3390/ijms20236085
[29] Nicol, L. S., Dawes, J. M., La Russa, F., et al. (2015). The role of G-protein receptor 84 in experimental neuropathic pain. The Journal of Neuroscience, 35(23), 8959–8969. https://doi.org/10.1523/JNEUROSCI.3948-14.2015
[30] Joshi, H. P., Jo, H. J., Kim, Y. H., et al. (2021). Stem cell therapy for modulating neuroinflammation in neuropathic pain. International Journal of Molecular Sciences, 22(9), 4669. https://doi.org/10.3390/ijms22094669
[31] Attal, N., & Bouhassira, D. (2021). Advances in the treatment of neuropathic pain. Current Opinion in Neurology, 34(5), 631–637. https://doi.org/10.1097/WCO.0000000000000972
[32] Shen, C. L., Castro, L., Fang, C. Y., et al. (2022). Bioactive compounds for neuropathic pain: An update on preclinical studies and future perspectives. The Journal of Nutritional Biochemistry, 104, 108979. https://doi.org/10.1016/j.jnutbio.2022.108979
[33] Di Stefano, G., Di Lionardo, A., Di Pietro, G., et al. (2021). Pharmacotherapeutic options for managing neuropathic pain: A systematic review and meta-analysis. Pain Research & Management, 2021, 6656863. https://doi.org/10.1155/2021/6656863
[34] Thouaye, M., & Yalcin, I. (2023). Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons. Pharmacology & Therapeutics, 251, 108546. https://doi.org/10.1016/j.pharmthera.2023.108546
[35] Wei, X. Y., Wang, X., Shi, G. X., et al. (2024). Acupuncture modulation of chronic neuropathic pain and its association with brain functional properties. Journal of Pain, 25(11), 104645. https://doi.org/10.1016/j.jpain.2024.01.009
[36] Petzke, F., Tölle, T., Fitzcharles, M. A., et al. (2022). Cannabis-based medicines and medical cannabis for chronic neuropathic pain. CNS Drugs, 36(1), 31–44. https://doi.org/10.1007/s40263-021-00864-3
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2025-03-14
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