The role of microglia in neuropathic pain: A systematic review of animal experiments

Background: Neuropathic pain develops from lesions or diseases that affect the peripheral or central somatosensory nervous system. External factors causing nervous system damage may induce neuropathic pain, which is often refractory and profoundly impairs patients’ quality of life and functional capacity. Objective: This study aims to evaluate animal studies on neuropathic pain in the past three years to elucidate the mechanism of microglia in neuropathic pain and to provide a theoretical basis for clinical treatment. Methods: Literature searches were conducted through seven databases, including Web of Science, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Data, China Science and Technology Journal Database (VIPC), and SinoMed. The neuropathic pain model animals' pain indicators (thermal pain threshold, mechanical pain threshold), microglia-related findings, and related mechanism discoveries were extracted from the included studies. Results: A total of 24 animal studies were included in this study. All studies showed that microglia exhibited an activated state in animal neuropathic pain models established by different methods. Twenty studies demonstrated that microglial activation exacerbates neuropathic pain by driving neuroinflammatory cascades. However, four studies confirmed that microglia could alleviate pain through the M2 phenotype and the release of endogenous opioid peptides. Conclusion: The mediating effect of microglia on neuropathic pain is bidirectional. Pain-activated microglia do not necessarily exacerbate pain. Polarization toward the M2 phenotype or stimulation of endogenous opioid peptide release from microglia may attenuate pain. Overall, there are still many uncertainties about the mechanism of microglia in neuropathic pain. It is suggested to further study the neurobiological mechanism of this process to provide ideas for the design of future clinical trials.