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  • Review Article
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Pain-resolving immune mechanisms in neuropathic pain

Nature Reviews Neurology volume 19, pages 199–220 (2023)Cite this article

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Abstract

Interactions between the immune and nervous systems are of central importance in neuropathic pain, a common and debilitating form of chronic pain caused by a lesion or disease affecting the somatosensory system. Our understanding of neuroimmune interactions in pain research has advanced considerably. Initially considered as passive bystanders, then as culprits in the pathogenesis of neuropathic pain, immune responses in the nervous system are now established to underpin not only the initiation and progression of pain but also its resolution. Indeed, immune cells and their mediators are well-established promoters of neuroinflammation at each level of the neural pain pathway that contributes to pain hypersensitivity. However, emerging evidence indicates that specific subtypes of immune cells (including antinociceptive macrophages, pain-resolving microglia and T regulatory cells) as well as immunoresolvent molecules and modulators of the gut microbiota–immune system axis can reduce the pain experience and contribute to the resolution of neuropathic pain. This Review provides an overview of the immune mechanisms responsible for the resolution of neuropathic pain, including those involved in innate, adaptive and meningeal immunity as well as interactions with the gut microbiome. Specialized pro-resolving mediators and therapeutic approaches that target these neuroimmune mechanisms are also discussed.

Key points

  • Accumulating evidence indicates that subpopulations of immune cells and mediators help to suppress nociception and promote the resolution of neuropathic pain.

  • Pain-resolving immune cells infiltrate the peripheral nervous system following nerve damage, inhibit pronociceptive immune or glial cells, and dampen primary afferent excitability via the release of anti-inflammatory cytokines and opioids.

  • Pain-resolving meningeal immune cells and resident spinal cord microglia suppress central sensitization by inhibiting pronociceptive reactive glial cells and neuronal hyperexcitability.

  • Gut microbiota production of bile acids and butyrate, and restoration of a dysbiotic gut microbiome with probiotics, antibiotics or faecal microbiota transplantation, promote pain resolution by modulating neuroimmune signalling pathways.

  • Specialized pro-resolving mediators regulate glial reactivity and inflammatory signalling and modulate primary nociceptive neuronal activity by acting on transient receptor potential channels and G protein-coupled receptors.

  • Current treatments for neuropathic pain have limited efficacy; novel therapeutic approaches that target pain-resolving neuroimmune mechanisms provide exciting new avenues to treat neuropathic pain.

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Fig. 1: Interactions between nociceptive neurons and pain-resolving immune cells in peripheral nerves and DRG.
Fig. 2: Interactions between nociceptive neurons and pain-resolving immune cells in the spinal cord and meninges.
Fig. 3: Gut microbiota and pain resolution.
Fig. 4: Biosynthesis of SPMs and receptor signalling pathways.

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Acknowledgements

The authors gratefully acknowledge support from the National Health and Medical Research Council (NHMRC) of Australia (ID APP1162060 and ID APP1187416) awarded to G.M.-T. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Timothy Lee for providing professional medical illustration services used to generate the original figures.

Review criteria

The authors searched PubMed and Google Scholar for original research articles and reviews published in English, using the keywords or search terms “neuropathic pain” or “pain resolution” and “neutrophils”, “natural killer cells’, “fibroblasts”, “microglia”, “T cells’, “B cells”, “gut microbiota”, “microbiome”, “specialized pro-resolving mediators”, “animal models”, “inflammation”, “inflammatory response” and “immune response”. Relevant studies on other pain conditions were also included. CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov were searched for additional relevant clinical articles, using the following search terms and keywords: “inflammation” or “immune” and “pain” and “neuropathic” or “chronic”. Additional relevant articles were selected from the reference lists of publications identified in these searches. The final reference list was generated based on relevance to the topics covered, focusing on publications within the past 10 years.

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  1. Translational Neuroscience Facility, Department of Physiology, School of Biomedical Sciences, University of New South Wales (UNSW), Sydney, New South Wales, Australia

    Nathan T. Fiore, Sophie R. Debs, Jessica P. Hayes & Gila Moalem-Taylor

  2. The Wollongong Hospital, Illawarra Shoalhaven Local Health District, NSW Health, Wollongong, New South Wales, Australia

    Samuel S. Duffy

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Fiore, N.T., Debs, S.R., Hayes, J.P. et al. Pain-resolving immune mechanisms in neuropathic pain. Nat Rev Neurol 19, 199–220 (2023). https://doi.org/10.1038/s41582-023-00777-3

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