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Pain is a main symptom in inflammation, and inflammation induces pain via inflammatory mediators acting on nociceptive neurons. Macrophages and microglia are distinct cell types, representing immune cells and glial cells, respectively, but they share similar roles in pain regulation. Macrophages are key regulators of inflammation and pain. Macrophage polarization plays different roles in inducing and resolving pain. Notably, macrophage polarization and phagocytosis can be induced by specialized pro-resolution mediators (SPMs). SPMs also potently inhibit inflammatory and neuropathic pain via immunomodulation and neuromodulation. In this review, we discuss macrophage signaling involved in pain induction and resolution, as well as in maintaining physiological pain. Microglia are macrophage-like cells in the central nervous system (CNS) and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders. Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic transmission as neuromodulators. We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain. Thus, targeting macrophage and microglial signaling in distinct locations via pharmacological approaches, including immunotherapies, and non-pharmacological approaches will help to control chronic inflammation and chronic pain.

Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression‑enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.

Introduction Satellite glial cells (SGCs) reside in the peripheral nervous system (PNS), where they wrap around neuronal cell bodies and form a complete envelope, allowing for close neuron-SGC interactions in [...], G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNj10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNj10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.

Although chronic pain is one of the most important medical problems facing society, there has been very limited progress in the development of novel therapies for this condition. Here, we discuss high-impact research priorities to reduce the number of people transitioning from acute to chronic intractable pain.

Although chronic pain is one of the most important medical problems facing society, there has been very limited progress in the development of novel therapies for this condition. Here, we discuss high-impact research priorities to reduce the number of people transitioning from acute to chronic intractable pain.

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment. Editor's summary: Neuroinflammation contributes to the pathogenesis of neuropathic pain. The characterization of signaling pathways involved could help to identify new therapeutic targets. Here, Jiang et al. used a mouse model to show that the glycoprotein follistatin (FST) was up-regulated in sensory neurons in the dorsal root ganglia (DRG) after spinal nerve ligation. FST injections were sufficient to drive mechanical hypersensitivity and excitability of DRG neurons. FST interacted with insulin-like growth factor–1 receptor, and a peptide that blocked these interactions could alleviate neuropathic pain–related behaviors and FST-mediated voltage-gated sodium channel currents, highlighting a potential therapeutic strategy that warrants further examination. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Introduction Recent progress in preclinical research has advanced our understanding of molecular and cellular mechanisms of itch (1-3). These advances include the identification of molecular sensors and receptors of itch [...], Our understanding of neuropathic itch is limited due to a lack of relevant animal models. Patients with cutaneous T cell lymphoma (CTCL) experience severe itching. Here, we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produced time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early phase (20 days), CTCL caused hyperinnervations in the epidermis. However, chronic itch was associated with loss of epidermal nerve fibers in the late phases (40 and 60 days). CTCL was also characterized by marked nerve innervations in mouse lymphoma. Blockade of C-fibers reduced pruritus at early and late phases, whereas blockade of A- fibers only suppressed late-phase itch. Intrathecal (i.t.) gabapentin injection reduced late-phase, but not early-phase, pruritus. IL-31 was upregulated in mouse lymphoma, whereas its receptor Il31ra was persistently upregulated in Trpv1- expressing sensory neurons in mice with CTCL. Intratumoral anti-IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis (mechanical itch). Finally, i.t. administration of a TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.

Introduction Cancer pain is experienced by 70% of patients with advanced stage cancer; more than 80% of this pain is attributed to metastatic cancer-induced bone pain (1-3). Generally, bone metastasis [...], Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 ([Pd1.sup.-/-]) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, [Pd1.sup.-/-] mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in [Pd1.sup.-/-] mice. Consistently, these beneficial effects in [Pd1.sup.-/-] mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

While acute pain brings attention to injuries, chronic pain has no biological benefits. Chronic pain often arises from disease (e.g., arthritis, cancer) and trauma (e.g., nerve injury, spinal cord injury); [...], Regenerative pain medicine, which seeks to harness the body's own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.