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Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential

Key Points

  • Neuropathic pain that results from damage to the nervous system results from the pathological operation of the nervous system

  • Activated microglia in the dorsal horn of the spinal cord are necessary for synaptic alterations in this region and pain hypersensitivity after nerve injury

  • Microglia also become activated in the brain, contributing to sensory and/or non-sensory (emotion, reward and memory) aspects of neuropathic pain

  • Microglia are morphologically and molecularly activated by chronic opioids and contribute to opioid tolerance and dependence

  • New drugs targeting microglia and human microglia-like cells have been developed that may facilitate translation from bench to bedside

Abstract

Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms. It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside.

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Figure 1: Microgliosis mechanisms in the spinal dorsal horn after injury.
Figure 2: Microglia-mediated aberrant excitability of spinal dorsal horn neurons.
Figure 3: Multiple mechanisms for neuronal excitation by microglial inflammatory signals.

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Acknowledgements

This work was supported by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI) grant numbers 15H02522 (M.T.) and 25117013 (K.I.), the Core Research for Evolutional Science and Technology (CREST) programme (M.T.), the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) (M.T.), the Research Project on Elucidation of Chronic Pain, Platform for Drug Discovery, Informatics, and Structural Life Science (M.T.) from the Japan Agency for Medical Research and Development, and the Toray Science Foundation (M.T.). The authors also thank T. Masuda and Y. Ozono for personal communications regarding their experiments using conditional Vnut-knockout mice.

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K.I. and M.T. contributed to the discussion of content, wrote the article and reviewed and/or edited the article before submission.

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Correspondence to Kazuhide Inoue or Makoto Tsuda.

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Glossary

Hyperalgesia

Increased pain in response to a stimulus that normally provokes pain.

Allodynia

Pain in response to a stimulus that does not normally provoke pain.

Sexual dimorphism

The occurrence of different characteristics in individuals of each of the two sexes of the same species.

Diurnal cycle

A cyclic change in the biological processes in an organism with a period length of 24 hours.

Parabiosis mice

Model in which two mice are surgically joined and share circulating blood in order to generate a chimaera without irradiation and transplantation.

Inflammasomes

Intracellular multiprotein complexes that lead to the activation of caspase 1, which generates the active pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18.

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Inoue, K., Tsuda, M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19, 138–152 (2018). https://doi.org/10.1038/nrn.2018.2

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