The Role of the Immune System in Nociception Development: A Neuroimmune Perspective
##plugins.themes.bootstrap3.article.main##
##plugins.themes.bootstrap3.article.sidebar##
Published
Apr 30, 2025
Abstract
Nociception, the neural process responsible for detecting and transmitting pain signals, was historically perceived as a purely neuronal phenomenon. It primarily involved nociceptors—specialized sensory neurons located in peripheral tissues—that detect potentially harmful stimuli and convey this information to the central nervous system. However, a growing body of evidence over the past two decades has illuminated the pivotal role of the immune system in modulating nociception at both peripheral and central levels. This neuroimmune interplay has profound implications for understanding the pathophysiology of acute and chronic pain and opens novel therapeutic avenues for managing complex pain conditions.
##plugins.themes.bootstrap3.article.details##
Keywords
Nociception, Immune System, Neuronal Connection, Endocrinology, Pain
References
Bhave, G., & Gereau, R. W. (2004). Posttranslational mechanisms of peripheral sensitization. Journal of Neurobiology, 61(1), 88–106. https://doi.org/10.1002/neu.20083
Chen, G., Zhang, Y., Qadri, Y. J., Serhan, C. N., & Ji, R. (2018). Microglia in Pain: Detrimental and protective roles in pathogenesis and resolution of pain. Neuron, 100(6), 1292–1311. https://doi.org/10.1016/j.neuron.2018.11.009
Cheng, J., & Ji, R. (2008). Intracellular signaling in primary sensory neurons and persistent pain. Neurochemical Research, 33(10), 1970–1978. https://doi.org/10.1007/s11064-008-9711-z
Fiore, N. T., Debs, S. R., Hayes, J. P., Duffy, S. S., & Moalem-Taylor, G. (2023). Pain-resolving immune mechanisms in neuropathic pain. Nature Reviews Neurology. https://doi.org/10.1038/s41582-023-00777-3
Grace, P. M., Hutchinson, M. R., Maier, S. F., & Watkins, L. R. (2014). Pathological pain and the neuroimmune interface. Nature Reviews. Immunology, 14(4), 217–231. https://doi.org/10.1038/nri3621
Gu, D., Xia, Y., Ding, Z., Qian, J., Gu, X., Bai, H., Jiang, M., & Yao, D. (2024). Inflammation in the Peripheral Nervous System after Injury. Biomedicines, 12(6), 1256. https://doi.org/10.3390/biomedicines12061256
Jang, K., & Garraway, S. M. (2024). A review of dorsal root ganglia and primary sensory neuron plasticity mediating inflammatory and chronic neuropathic pain. Neurobiology of Pain, 15, 100151. https://doi.org/10.1016/j.ynpai.2024.100151
Jayathilake, N. J., Phan, T. T., Kim, J., Lee, K. P., & Park, J. M. (2025). Modulating neuroplasticity for chronic pain relief: noninvasive neuromodulation as a promising approach. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-025-01409-0
Karavis, M. Y., Siafaka, I., Vadalouca, A., & Georgoudis, G. (2023). Role of microglia in neuropathic pain. Cureus. https://doi.org/10.7759/cureus.43555
Karcz, M., Abd-Elsayed, A., Chakravarthy, K., Aman, M. M., Strand, N., Malinowski, M. N., Latif, U., Dickerson, D., Suvar, T., Lubenow, T., Peskin, E., D’Souza, R., Cornidez, E., Dudas, A., Lam, C., Farrell, M., II, Sim, G. Y., Sebai, M., Garcia, R., . . . Deer, T. (2024). Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project). Journal of Pain Research, Volume 17, 3757–3790. https://doi.org/10.2147/jpr.s475351
Mackey, S., Aghaeepour, N., Gaudilliere, B., Kao, M., Kaptan, M., Lannon, E., Pfyffer, D., & Weber, K. (2025). Innovations in acute and chronic pain biomarkers: enhancing diagnosis and personalized therapy. Regional Anesthesia & Pain Medicine, 50(2), 110–120. https://doi.org/10.1136/rapm-2024-106030
Marty-Lombardi, S., Lu, S., Ambroziak, W., Schrenk-Siemens, K., Wang, J., DePaoli-Roach, A. A., Hagenston, A. M., Wende, H., Tappe-Theodor, A., Simonetti, M., Bading, H., Okun, J. G., Kuner, R., Fleming, T., & Siemens, J. (2024). Neuron–astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain. Nature Metabolism, 6(3), 494–513. https://doi.org/10.1038/s42255-024-01001-2
Nijs, J., George, S. Z., Clauw, D. J., Fernández-De-Las-Peñas, C., Kosek, E., Ickmans, K., Fernández-Carnero, J., Polli, A., Kapreli, E., Huysmans, E., Cuesta-Vargas, A. I., Mani, R., Lundberg, M., Leysen, L., Rice, D., Sterling, M., & Curatolo, M. (2021). Central sensitisation in chronic pain conditions: latest discoveries and their potential for precision medicine. The Lancet Rheumatology, 3(5), e383–e392. https://doi.org/10.1016/s2665-9913(21)00032-1
Pinho-Ribeiro, F. A., Verri, W. A., & Chiu, I. M. (2016). Nociceptor Sensory Neuron–Immune interactions in pain and inflammation. Trends in Immunology, 38(1), 5–19. https://doi.org/10.1016/j.it.2016.10.001
Sommer, C., Leinders, M., & Üçeyler, N. (2017). Inflammation in the pathophysiology of neuropathic pain. Pain, 159(3), 595–602. https://doi.org/10.1097/j.pain.0000000000001122
Uvnäs-Moberg, K., Gross, M. M., Calleja-Agius, J., & Turner, J. D. (2024). The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories. Frontiers in Endocrinology, 15. https://doi.org/10.3389/fendo.2024.1272270
Wu, M., Song, W., Zhang, M., Teng, L., Tang, Q., & Zhu, L. (2024). Potential mechanisms of exercise for relieving inflammatory pain: a literature review of animal studies. Frontiers in Aging Neuroscience, 16. https://doi.org/10.3389/fnagi.2024.1359455
Zou, Y., Liu, C., Wang, Z., Li, G., & Xiao, J. (2024). Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies. Journal of Orthopaedic Translation, 48, 123–132. https://doi.org/10.1016/j.jot.2024.07.010
Chen, G., Zhang, Y., Qadri, Y. J., Serhan, C. N., & Ji, R. (2018). Microglia in Pain: Detrimental and protective roles in pathogenesis and resolution of pain. Neuron, 100(6), 1292–1311. https://doi.org/10.1016/j.neuron.2018.11.009
Cheng, J., & Ji, R. (2008). Intracellular signaling in primary sensory neurons and persistent pain. Neurochemical Research, 33(10), 1970–1978. https://doi.org/10.1007/s11064-008-9711-z
Fiore, N. T., Debs, S. R., Hayes, J. P., Duffy, S. S., & Moalem-Taylor, G. (2023). Pain-resolving immune mechanisms in neuropathic pain. Nature Reviews Neurology. https://doi.org/10.1038/s41582-023-00777-3
Grace, P. M., Hutchinson, M. R., Maier, S. F., & Watkins, L. R. (2014). Pathological pain and the neuroimmune interface. Nature Reviews. Immunology, 14(4), 217–231. https://doi.org/10.1038/nri3621
Gu, D., Xia, Y., Ding, Z., Qian, J., Gu, X., Bai, H., Jiang, M., & Yao, D. (2024). Inflammation in the Peripheral Nervous System after Injury. Biomedicines, 12(6), 1256. https://doi.org/10.3390/biomedicines12061256
Jang, K., & Garraway, S. M. (2024). A review of dorsal root ganglia and primary sensory neuron plasticity mediating inflammatory and chronic neuropathic pain. Neurobiology of Pain, 15, 100151. https://doi.org/10.1016/j.ynpai.2024.100151
Jayathilake, N. J., Phan, T. T., Kim, J., Lee, K. P., & Park, J. M. (2025). Modulating neuroplasticity for chronic pain relief: noninvasive neuromodulation as a promising approach. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-025-01409-0
Karavis, M. Y., Siafaka, I., Vadalouca, A., & Georgoudis, G. (2023). Role of microglia in neuropathic pain. Cureus. https://doi.org/10.7759/cureus.43555
Karcz, M., Abd-Elsayed, A., Chakravarthy, K., Aman, M. M., Strand, N., Malinowski, M. N., Latif, U., Dickerson, D., Suvar, T., Lubenow, T., Peskin, E., D’Souza, R., Cornidez, E., Dudas, A., Lam, C., Farrell, M., II, Sim, G. Y., Sebai, M., Garcia, R., . . . Deer, T. (2024). Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project). Journal of Pain Research, Volume 17, 3757–3790. https://doi.org/10.2147/jpr.s475351
Mackey, S., Aghaeepour, N., Gaudilliere, B., Kao, M., Kaptan, M., Lannon, E., Pfyffer, D., & Weber, K. (2025). Innovations in acute and chronic pain biomarkers: enhancing diagnosis and personalized therapy. Regional Anesthesia & Pain Medicine, 50(2), 110–120. https://doi.org/10.1136/rapm-2024-106030
Marty-Lombardi, S., Lu, S., Ambroziak, W., Schrenk-Siemens, K., Wang, J., DePaoli-Roach, A. A., Hagenston, A. M., Wende, H., Tappe-Theodor, A., Simonetti, M., Bading, H., Okun, J. G., Kuner, R., Fleming, T., & Siemens, J. (2024). Neuron–astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain. Nature Metabolism, 6(3), 494–513. https://doi.org/10.1038/s42255-024-01001-2
Nijs, J., George, S. Z., Clauw, D. J., Fernández-De-Las-Peñas, C., Kosek, E., Ickmans, K., Fernández-Carnero, J., Polli, A., Kapreli, E., Huysmans, E., Cuesta-Vargas, A. I., Mani, R., Lundberg, M., Leysen, L., Rice, D., Sterling, M., & Curatolo, M. (2021). Central sensitisation in chronic pain conditions: latest discoveries and their potential for precision medicine. The Lancet Rheumatology, 3(5), e383–e392. https://doi.org/10.1016/s2665-9913(21)00032-1
Pinho-Ribeiro, F. A., Verri, W. A., & Chiu, I. M. (2016). Nociceptor Sensory Neuron–Immune interactions in pain and inflammation. Trends in Immunology, 38(1), 5–19. https://doi.org/10.1016/j.it.2016.10.001
Sommer, C., Leinders, M., & Üçeyler, N. (2017). Inflammation in the pathophysiology of neuropathic pain. Pain, 159(3), 595–602. https://doi.org/10.1097/j.pain.0000000000001122
Uvnäs-Moberg, K., Gross, M. M., Calleja-Agius, J., & Turner, J. D. (2024). The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories. Frontiers in Endocrinology, 15. https://doi.org/10.3389/fendo.2024.1272270
Wu, M., Song, W., Zhang, M., Teng, L., Tang, Q., & Zhu, L. (2024). Potential mechanisms of exercise for relieving inflammatory pain: a literature review of animal studies. Frontiers in Aging Neuroscience, 16. https://doi.org/10.3389/fnagi.2024.1359455
Zou, Y., Liu, C., Wang, Z., Li, G., & Xiao, J. (2024). Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies. Journal of Orthopaedic Translation, 48, 123–132. https://doi.org/10.1016/j.jot.2024.07.010
How to Cite
Grimm, H. M. (2025). The Role of the Immune System in Nociception Development: A Neuroimmune Perspective. Science Insights, 46(4), 1795–1798. https://doi.org/10.15354/si.25.op269
Issue
Section
Opinion
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.