Pain-resolving immune mechanisms in neuropathic pain.

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.

Sex-specific transcriptome of spinal microglia in neuropathic pain due to peripheral nerve injury.

Neuropathic pain is a prevalent and debilitating chronic disease that is characterized by activation in glial cells in various pain-related regions within the central nervous system. Recent studies have suggested a sexually dimorphic role of microglia in the maintenance of neuropathic pain in rodents. Here, we utilized RNA sequencing analysis and in vitro primary cultures of microglia to identify whether there is a common neuropathic microglial signature and characterize the sex differences in microglia in pain-related regions in nerve injury and chemotherapy-induced peripheral neuropathy mouse models. While mechanical allodynia and behavioral changes were observed in all models, transcriptomic analysis of microglia revealed no common transcriptional changes in spinal and supraspinal regions and in the different neuropathic models. However, there was a substantial change in microglial gene expression within the ipsilateral lumbar spinal cord 7 days after chronic constriction injury (CCI) of the sciatic nerve. Both sexes upregulated genes associated with inflammation, phagosome, and lysosome activation, though males revealed a prominent global transcriptional shift not observed in female mice. Transcriptomic comparison between male spinal microglia after CCI and data from other nerve injury models and neurodegenerative microglia demonstrated a unique CCI-induced signature reflecting acute activation of microglia. Further, in vitro studies revealed that only male microglia from nerve-injured mice developed a reactive phenotype with increased phagocytotic activity. This study demonstrates a lack of a common neuropathic microglial signature and indicates distinct sex differences in spinal microglia, suggesting they contribute to the sex-specific pain processing following nerve injury.

The cannabinoid system and microglia in health and disease.

Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.