Microglia role in the pain phenomenon

A study published in the Journal of the Brazilian Medical Association examined the microglia role as the regulator of cognitive function¹. Authors¹ reviewed what makes microglia so interesting to be studied as a possible therapeutic target in different conditions, starting with the analysis of its origins, passing through different conditions/diseases, and then discussing the possible future directions in research and clinic¹. However, they¹ did not discuss the microglia role in the pain phenomenon as well as how it is related to cognitive function²–⁴. Therefore, as a contribution to the literature, we summarize the key findings on this topic (pain).

In neuropathic pain, microglia are morphologically and molecularly activated by opioids and contribute to opioid tolerance and dependence⁵. Activated microglia in the dorsal horn of the spinal cord are necessary for synaptic changes in this region and for pain hypersensitivity following nerve injury⁶,⁷. In addition, microglia are also activated in the brain and contribute to sensory and/or non-sensory (emotion, reward, and memory) aspects of neuropathic pain⁵.

In chronic visceral pain, the mechanisms of microglia and astrocytes regarding the release of cytokines, chemokines, and neuroactive substances and the alteration of intracellular signaling pathways during the process are highlighted. As such, future perspectives include targeting microglia and astrocytes for chronic visceral pain treatment⁸.

In chronic pain, microglia are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain⁹. Zhou et al.⁹ showed that microglial colony-stimulating factor 1 and brain-derived neurotrophic factor signaling are essential for spinal long-term potentiation and chronic pain and that the microglia-dependent transition from synaptic potentiation to structural changes in pain pathways may underlie pain chronicity⁹. Besides, much scientific data suggest that classical activation of microglia in the spinal cord mediates neuroinflammation that plays an essential role in developing central sensitization and nociplastic pain¹⁰.

In the early twentieth century, there was an increase in microglial studies in pain¹¹, with a particular focus on microgliosis in the spinal cord after nerve injury and in neuropathic pain¹². We now know that signaling molecules are altered in microglia and contribute to the pathogenesis of pain; microglial mediators such as pro- and anti-inflammatory cytokines are potent neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions; and microglia have an emerging role in pain resolution, in part via specialized pro-resolving mediators such as resolvins, protectins, and maresins¹¹.

Finally, pain, whether acute or chronic, involves inflammasome activation at the site of origin, the various relay stations, and the sensory and processing cortical areas¹³. Indeed, microglia are embedded in brain responses related to stress phenomena, the development of major depressive disorders (cognitive function), and pain-related neural processing¹³. However, there is a lack of robust or consistent clinical effects of microglial modulators due to the study designs and heterogeneity of the patient populations studied (or the underlying biology, of course)¹¹.

• Funding: TSM was funded by the São Paulo Research Foundation (FAPESP) (grant 2022/16649-5). LMS was funded by the FAPESP (grant 2023/03474-5), and APS was funded by FAPESP (grant 2022/08646-6). This study was partially supported by the Coordination for the Improvement of Higher Education Personnel (CAPES, code 001). The funding source had no role in the study design, collection, analysis, interpretation of data, writing of the report, or in the decision to submit the article for publication.

ACKNOWLEDGMENTS

We would like to thank the Coordination for the Improvement of Higher Education Personnel (CAPES), National Council for Scientific and Technological Development (CNPq), São Paulo Research Foundation (FAPESP), Federal University of Maranhão (UFMA), and Federal University of São Carlos (UFSCar).

REFERENCES

• ¹
  Sousa RAL, Cassilhas RC. Microglia role as the regulator of cognitive function. Rev Assoc Med Bras (1992). 2023;69(7):e20230412. https://doi.org/10.1590/1806-9282.20230412
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• ²
  Paudel A, Boltz M, Kuzmik A, Resnick B, Liu W, Holmes S. The association of cognitive impairment with depressive symptoms, function, and pain in hospitalized older patients with dementia. J Appl Gerontol. 2023;42(9):1974-81. https://doi.org/10.1177/07334648231168446
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• ³
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• ⁴
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• ⁵
  Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci. 2018;19(3):138-52. https://doi.org/10.1038/nrn.2018.2
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• ⁶
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• ⁸
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  Zhou LJ, Peng J, Xu YN, Zeng WJ, Zhang J, Wei X, et al. Microglia are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain. Cell Rep. 2019;27(13):3844-59.e6. https://doi.org/10.1016/j.celrep.2019.05.087
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• ¹⁰
  Atta AA, Ibrahim WW, Mohamed AF, Abdelkader NF. Microglia polarization in nociplastic pain: mechanisms and perspectives. Inflammopharmacology. 2023;31(3):1053-67. https://doi.org/10.1007/s10787-023-01216-x
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• ¹¹
  Chen G, Zhang YQ, Qadri YJ, Serhan CN, Ji RR. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron. 2018;100(6):1292-311. https://doi.org/10.1016/j.neuron.2018.11.009
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• ¹²
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• ¹³
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Publication Dates

• Publication in this collection
  22 Dec 2023
• Date of issue
  2024

History

• Received
  15 July 2023
• Accepted
  11 Aug 2023