Chronic pain is a debilitating medical condition that lacks effective treatments. Increasing evidence suggests that microglia and neuroinflammation underlie pain pathophysiology, which therefore supports a potential strategy for developing pain therapeutics. Here, our study is testing the hypothesis that the promise of pain amelioration can be achieved using the small-molecule pexidartinib (PLX-3397), a previously food and drug administration (FDA)-approved cancer medicine and a colony-stimulating factor-1 receptor (CSF-1R) inhibitor that display microglia-depleting properties.

We used the previously reported chronic constriction injury (CCI) mouse model, in which PLX-3397 or vehicle was orally administrated to mice daily for 21 days, then applied to the CCI model, followed by PLX-3397 or vehicle administration for an additional 28 days. Additionally, we examined microglia-related neuroinflammation markers using positron emission tomography (PET) neuroimaging and immunofluorescence (IF).

We showed that PLX-3397 significantly ameliorated pain-related behavioral changes throughout the entire experimental period after CCI (vehicle versus PLX-3397 at day 14, effect size: 2.57, P = .002). Microglia changes were first analyzed by live-animal PET neuroimaging, revealing PLX-3397-associated reduction of microglia by probing receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a protein primarily expressed in microglia, which were further corroborated by postmortem immunohistochemistry (IHC) analysis using antibodies for microglia, including ionized Ca 2+ binding adaptor molecule 1 (Iba-1) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 3.6, P = .011) and RIPK1 (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 2.9, P = .023. The expression of both markers decreased in the PLX-3397 group. Furthermore, we found that PLX-3397 led to significant reductions in various proteins, including inducible nitric oxide synthase (iNOS) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size: 2.3, P = .048), involved in neuroinflammation through IHC.

Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic.

The genesis of neuropathic pain after peripheral nerve injury is associated with changes in gene expression and cell metabolism in sensory neurons and the release of inflammatory cytokines. Here, we connected glycolytic metabolism induced by the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) to histone lactylation and changes in gene expression that promote chronic neuropathic pain. In both male and female mice subjected to peripheral nerve injury, the mRNA and protein abundance of AREG and its receptor EGFR was increased in dorsal root ganglia (DRGs). AREG-EGFR signaling induced glycolytic metabolism by activating the kinase PKM2. An increase in the glycolytic byproduct lactate facilitated lactylation of the histone lysines H3K18 and H4K12 by the lactyltransferase p300 in DRG neurons. These modifications promoted the expression of genes encoding various proinflammatory and pronociceptive proteins that contribute to the development and maintenance of pain. Deletion or knockdown of AREG or pharmacologically inhibiting EGFR, PKM2, or p300 alleviated neuropathic pain in mice and attenuated the injury-induced hyperexcitability of nociceptive neurons. Targeting this metabolically driven epigenetic mechanism may be a way to treat neuropathic pain in patients.

Histone deacetylase inhibitors (HDACi) that modulate epigenetic regulation and are approved for treating rare cancers have, in disease models, also been shown to mitigate neurological conditions, including chronic pain. They are of interest as non-opioid treatments, but achieving long-term efficacy with limited dosing has remained elusive. Here we employ a triple combination formulation (TCF) that includes the pan-HDAC vorinostat (Vo) administered at its FDA-approved daily dosage of 50 mg/Kg, along with the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD) and polyethylene glycol (PEG). This formulation enhances plasma and brain exposure of Vo in mice and rat models and shows specific activity in the spared nerve injury (SNI) model of chronic neuropathic pain. TCF (but not HPBCD and PEG) decreased mechanical allodynia for 4 weeks without antagonizing weight, anxiety, or mobility. This was achieved at less than 1% of the total dose of Vo approved for 4 weeks of tumor treatment, decreased RNA levels of two major inflammatory markers (CD11b and GFAP), and reduced proliferation of microglia in the ipsilateral (but not contralateral) spinal cord. A single TCF injection was sufficient for 3-4 weeks of efficacy. Pharmacodynamics suggested pain relief was sustained for weeks after Vo elimination. Doubling Vo in a single TCF injection tripled the response amplitude and remained effective for > 2 months in male rats. Together, these data suggest that the TCF enables single-dose effectiveness with extended action, reduces long-term HDACi dosage, and presents excellent potential to develop as a non-opioid treatment option for chronic pain. PERSPECTIVE: An epigenetic drug formulation (TCF) tested in rat and mouse chronic neuropathic pain models shows adequate and persistent pain relief, engaging spinal cord inflammatory mechanisms.

Neuropathic pain is a pervasive medical challenge currently lacking effective treatment options. Molecular changes at the site of peripheral nerve injury contribute to both peripheral and central sensitization, critical components of neuropathic pain. This study explores the role of the G-protein-coupled bile acid receptor (GPBAR1 or TGR5) in the peripheral mechanisms underlying neuropathic pain induced by partial sciatic nerve ligation in male mice. TGR5 was upregulated in the injured nerve site and predominantly colocalized with macrophages. Perisciatic nerve administration of the TGR5 agonist, INT-777 according to a prevention protocol (50 μg/μL daily from postoperative day [POD] 0 to POD6) provided sustained relief from mechanical allodynia and spontaneous pain, whereas the TGR5 antagonist, SBI-115 worsened neuropathic pain. Transcriptome sequencing linked the pain relief induced by TGR5 activation to reduced neuroinflammation, which was further evidenced by a decrease in myeloid cells and pro-inflammatory mediators (eg, CCL3, CXCL9, interleukin [IL]-6, and tumor necrosis factor [TNF] α) and an increase in CD86-CD206+ anti-inflammatory macrophages at POD7. Besides, myeloid-cell-specific TGR5 knockdown in the injured nerve site exacerbated both neuropathic pain and neuroinflammation, which was substantiated by bulk RNA-sequencing and upregulated expression levels of inflammatory mediators (including CCL3, CCL2, IL-6, TNF α, and IL-1β) and the increased number of monocytes/macrophages at POD7. Furthermore, the activation of microglia in the spinal cord on POD7 and POD14 was altered when TGR5 in the sciatic nerve was manipulated. Collectively, TGR5 activation in the injured nerve site mitigates neuropathic pain by reducing neuroinflammation, while TGR5 knockdown in myeloid cells worsens pain by enhancing neuroinflammation.

Microalgae are emerging as innovative bioresources with diverse therapeutic applications, particularly in cardiovascular health, neuroprotection, anti-inflammatory, and antioxidant responses. These bioactive compounds effectively reduce inflammatory mediators, mitigate oxidative stress, and support mitochondrial health-critical factors in exercise performance, recovery, and chronic disease management. Notably, microalgae such as Spirulina and Chlorella exhibit promising biological activities in preclinical and limited clinical studies, including anti-inflammatory and neuroprotective effects. However, large-scale, randomized controlled trials (RCTs) remain scarce, limiting their clinical translation. Although preliminary evidence suggests potential benefits for sports performance, oxidative stress reduction, and cognitive function, most studies are small-scale, preclinical, or observational. Large, well-powered RCTs are needed to confirm their efficacy and safety. Within the framework of Predictive, Preventive, and Personalized Medicine (PPPM/3PM), this review explores microalgae's potential in predictive diagnostics, targeted prevention, and individualized supplementation strategies. Despite promising findings, clinical application requires a cautious approach due to insufficient high-quality trials supporting microalgae-based interventions in medical practice. Future research should prioritize RCTs, pharmacokinetic studies, and long-term safety assessments to establish evidence-based guidelines for their use in health and disease management.

The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO registration number: CRD42022364004). Literature search (PubMed, January 19, 2023) identified 49 articles, which were meta-analyzed using a random-effects model. The risk of bias was evaluated using SYRCLE's tool. The pooled effect considering all studies showed that neutrophil depletion induced a consistent pain reduction. Inflammatory, joint, neuropathic, and visceral pain showed significant pain alleviation by neutrophil depletion with medium-large effect sizes. However, muscle and postoperative pain were not significantly alleviated by neutrophil depletion. Further analysis showed a differential contribution of neutrophils to pain outcomes. Neutrophils had a higher impact on mechanical hyperalgesia, followed by nociceptive behaviors and mechanical allodynia, with a smaller contribution to thermal hyperalgesia. Interspecies (mice or rats) differences were not appreciated. Analyses regarding intervention unveiled a lower pain reduction for some commonly used methods for neutrophil depletion, such as injection of antineutrophil serum or an anti-Gr-1 antibody, than for other agents such as administration of an anti-Ly6G antibody, fucoidan, vinblastine, CXCR1/2 inhibitors, and etanercept. In conclusion, the contribution of neutrophils to pain depends on pain etiology (experimental model), pain outcome, and the neutrophil depletion strategy. Further research is needed to improve our understanding on the mechanisms of these differences.

The transition from acute to chronic pain is an important clinical phenomenon that significantly impacts the healthcare system. Despite decades of research, preventing this transition remains a complex challenge. Many studies have explored the various factors that contribute to the development of chronic pain, but the underlying mechanisms are still largely unclear. In this frame, vitamin D (VD) plays an important role in pain mechanism development, with emerging evidence suggesting it influences pain perception, inflammation, and nerve function.

A total of 14 eligible original research articles were identified.

Our qualitative analysis showed that VD did not directly influence the transition from acute to chronic pain, but it affected pain intensity, improving outcomes in patients at risk of developing chronic pain.

Additional randomized clinical trials, particularly double-blind, placebo-controlled studies, which are regarded as the gold standard in clinical research, are warranted to evaluate the role of vitamin D in the progression from acute to chronic pain.

Acute pain, a critical aspect of patient care, presents a challenge due to its subjective nature and complex biological underpinnings. Biomarkers for acute pain promise a paradigm shift in how pain is perceived, diagnosed, and managed. The study of genetic, inflammatory, and neurotransmission markers associated with pain experience may hold the key for the development of personalized and effective pain management strategies. This narrative review explores the neurobiological pathways of acute pain, encompassing inflammatory responses and neurotransmission mechanisms. It synthesizes current research on the identification and clinical application of biomarkers, emphasizing their potential to enhance diagnostic precision, treatment effectiveness, and risk prediction. We underscore the promising role of acute pain biomarkers in identifying patients at risk for developing acute and potentially chronic pain, predicting patients' response to pharmacological interventions, and aiding in the development of novel therapeutic and pain preventive strategies. The evolving landscape of biomarker research not only deepens our understanding of pain mechanisms but also lays the foundation for more tailored and patient-specific healthcare interventions.

Primary dorsal root ganglion (DRG) cell cultures provide a valuable model for studying in vitro sensory transduction, neuropathies, and chronic pain, as they replicate the in vivo heterogeneity of DRG neurons and non-neuronal cells. However, traditional patch-clamp techniques are invasive and cannot capture the collective cell dynamics. While planar multielectrode arrays (MEAs) offer a non-invasive alternative, they suffer from poor cell-electrode coupling and limited resolution for identifying specific DRG neuronal types like C-fiber nociceptors, key targets in chronic pain research. This work demonstrates that silicon nanowire (SiNW) mat-based MEAs, while maintaining their reduced invasiveness, enable continuous intracellular recordings from neurons in primary rat DRG cell cultures. Supported by a cortical astrocyte feeder layer, SiNW mats promote DRG neuron and glial cell growth preserving cells' in vivo morphological and functional characteristics. Integrated into a compartmentalized MEA, they enable reliable recordings of drug-modulated neuronal activity alongside a baseline related to the astrocyte layer. The recorded signals exhibit characteristics of intracellular action potentials, suggesting spontaneous intracellular access by SiNWs. Distinct electrophysiological signatures allow identifying C-fiber nociceptors, as confirmed by patch-clamp measurements. This platform represents a powerful tool for investigating in vitro pain mechanisms, with potential applications in preclinical pain research and pharmacological translational studies.

Accumulating evidence suggests that glial mechanisms are pivotal in regulating chronic pain. Our previous findings revealed that the interactions between spinal microglia and astrocytes are crucial for burn-induced pain hypersensitivity. However, the mechanisms underlying burn-induced peripheral sensitisation remain incompletely understood.

Sensory neurone-satellite glial cell (SGC) interactions within peripheral dorsal root ganglia were investigated using in vitro and in vivo experiments. Behavioural tests were conducted to evaluate the therapeutic potential of targeting peripheral sensitisation mechanisms for burn pain management.

Burn injury upregulated calcitonin gene-related peptide (CGRP) expression in sensory neurones (1.5-fold; P=0.013) through transient receptor potential vanilloid 1 (TRPV1) channels. Pharmacological blockade of the TRPV1/CGRP signalling pathway effectively attenuated burn-induced mechanical allodynia and thermal hyperalgesia. Additionally, neurone-derived CGRP triggered SGC activation (from 6.8% pre-injury to 41.6% at day 5 post-injury), concomitant with enhanced gap junction-mediated SGC coupling (from 16.7% pre-injury to 40.5% at day 5 post-injury). Furthermore, chemokine expression (particularly CXCL1) in SGCs was elevated after burn injury, which potentiated sensory neurone excitability and exacerbated pain hypersensitivity. Blocking SGC coupling exerted potent analgesic effects in this burn pain model.

A novel neurone-SGC interaction mechanism drives burn-induced peripheral sensitisation, providing translational implications for burn pain therapeutics.

N6-methyladenosine (m6A), a prevalent post-transcriptional modification in eukaryotic RNA, plays a significant role in regulating sensory experiences, learning, and injury in the mammalian central nervous system. However, the pattern of lncRNA m6A methylation in the mouse cortex following repetitive mild traumatic brain injury (rmTBI) has not been explored. This study conducted a genome-wide analysis of lncRNA m6A methylation in the mouse cortex using methylated RNA immunoprecipitation sequencing (MeRIP-Seq). We identified 43,103 differentially methylated peaks. Notably, the expression of m6A peaks indicated altered methylation and expression levels of 423 lncRNAs after rmTBI. In addition, employing METTL3 inhibitor STM2457 demonstrated that functional METTL3 was essential for repairing neural damage caused by rmTBI and influenced spatial learning and memory in rmTBI-model mice. Thus, the m6A methylation pattern of lncRNA in the mouse cortex after rmTBI identifies METTL3 as a potential intervention target for epigenetic modification following such injuries. Clinical trial number Not applicable.

Folk medicine in Thailand has long made use of Pterocarpus indicus Willd. for treating inflammation-related disorders. However, scientific exploration of isolated compounds from P. indicus for improving inflammation-associated sickness conditions and their impact on central nervous system (CNS) safety remain unexplored. The present study initially screened the anti-neuroinflammatory effects of angolensin, a compound isolated from P. indicus heartwood in vitro. Following substantial findings, the efficacy of angolensin was further evaluated in a mouse model of lipopolysaccharide (LPS)-induced sickness behaviors, alongside an assessment of its CNS safety profiles. The anti-neuroinflammatory effects of angolensin were evaluated in LPS-induced BV-2 microglial cells. The effects of angolensin on sickness behaviors were examined in LPS-induced mice using the Laboratory Animal Behaviors Observation, Registration and Analysis System (LABORAS). Proinflammatory cytokine expression in plasma samples of mice was also determined. LABORAS and rotarod tests were conducted to investigate its impact on the CNS. In vitro assessment of the anti-inflammatory activity of angolensin on BV-2 microglial cells revealed a concentration-dependent reduction in the release of LPS-induced nitric oxide (NO) and proinflammatory cytokines (TNF-α and IL-6). At a concentration of 20 µM, angolensin showed comparable results to the positive control, 20 µM minocycline. In mice, angolensin significantly improved LPS-induced sickness behaviors, as indicated by improved home-cage behaviors. Consistent with the in vitro findings, angolensin attenuated the release of proinflammatory cytokines in the plasma of LPS-induced mice. Importantly, angolensin did not induce any adverse effects on locomotion, motor coordination, or general well-being, indicating a favorable CNS safety profile. Overall, these results highlight the anti-inflammatory potential of angolensin in mitigating sickness behaviors in mice, while demonstrating its CNS safety.

Neuro-immune interactions between macrophages and primary sensory neurons have been implicated in nerve injury and associated pain. This study aims to explore the function of the TAFA4 as a crucial neuroimmune regulator in modulating macrophage states within the context of neuropathic pain. To elucidate the role of TAFA4 in dorsal root ganglia (DRG) following a chronic constriction injury (CCI) model in male rats, immunofluorescent staining, western blot, flow cytometry analysis and enzyme-linked immunosorbent assay were performed. Microinjection of self-complementary adeno-associated virus expressing TAFA4 mRNA into the L4 and L5 DRGs was conducted to overexpress TAFA4 in the DRGs. Following peripheral nerve injury, we observed a downregulation of TAFA4 in ipsilateral DRG neurons. Restoring this downregulation effectively alleviated the mechanical and thermal nociceptive hypersensitivity by inhibiting pro-inflammatory mediators while promoting the secretion of anti-inflammatory cytokines on day 14 post-CCI. Notably, scAAV-TAFA4 microinjection also facilitated the polarization of macrophages in the DRGs towards the M2 phenotype. Mechanistically, TAFA4 modulates the functions of macrophages in a lipoprotein receptor-related protein 1-dependent manner. Our findings revealed the role of TAFA4 in shifting macrophages in favor of an anti-inflammatory phenotype and enhancing interleukin 10 concentrations in the DRG, suggesting it is a potential analgesic target for alleviating neuropathic pain.

Previous studies suggested the anti-inflammatory properties of modafinil. This study aimed to review the current literature to provide a comprehensive insight into the anti-inflammatory uses of modafinil in experimental studies. We conducted a systematic search using Medline (via PubMed), Web of Science, Scopus, and Embase databases from their commencement until 10 October 2022. All original articles focusing on modafinil anti-inflammatory effects were included. Our initial search yielded 1398 articles. Fourteen publications were included in our systematic review. Recent studies attempted to provide evidence for repurposing modafinil for several diseases, including autoimmune encephalomyelitis, nonalcoholic liver disease, gastric mucosal injury, neuropathic pain, atherosclerosis, intestinal ischemia, pulmonary hypertension, pancreatitis, ischemic stroke, testicular torsion, and lithium-pilocarpine-induced status epilepticus. Current evidence supports that modafinil can modulate inflammation, suppress the immune response, and improve disease severity partly by inhibiting NF-κB, NOS, Kca3.1, Kca2.3, and COX-2. By reviewing recent findings from experimental studies, we discussed the beneficial effects of modafinil on several inflammatory diseases, with a particular focus on the underlying mechanisms.

The immune and sensory nervous systems detect diverse threats, from tissue damage to infection, and coordinate protective responses to restore homeostasis. Like immune cells, sensory neurons exhibit remarkable heterogeneity, with advanced genetic models revealing that distinct subsets differentially regulate immune responses. Here, we review how various immune signals engage distinct subtypes of sensory neurons to mediate inflammatory pain, itch, relief, protective behavioral adaptations, and autonomic reflexes. We also highlight how specialized sensory neuron populations modulate immune function through the release of neuropeptides, neurokines, or glutamate. This functional specialization enables precise immunomodulation adapted to the kinetics and nature of immune responses, positioning sensory neurons as key regulators of host defense and tissue homeostasis.

Pain is entwined with inflammation, and biological sex often influences mechanisms of the immune system. Due to possible differences in inflammatory mechanisms, women are predisposed to autoimmune diseases and chronic pain. Despite sex as a critical variable in clinical cases of autoimmune conditions and its pain comorbidities, fundamental investigations have long underrepresented female subjects in their studies. Fundamental research in the 2010s, however, identified a binary sex specific mechanism for pain in rodents: male pain is microglia-driven while female pain is T cell-driven. Since then, studies have expanded in neuro-immunology to indicate that the sex differences and immune cells involved in these processes take on more elaborate roles when expanded to other causal modalities and anatomical levels of neuropathic and inflammatory pain. In this mini-review, we highlight updated roles for macrophages, T cells, and B cells in the peripheral nervous system during persistent pain conditions: neuropathic pain and inflammatory pain. We discuss sex similarities and sex differences in these cell types. By parsing out the sex specific roles of immune cells in persistent pain states, we may be better positioned to find immune-based therapies that can effectively target chronic pain in sex-biased autoimmune conditions.

Catheter-based total renal denervation (TRDN) has recently gained FDA approval to lower blood pressure in patients with treatment-resistant hypertension. Current TRDN technologies indiscriminately destroy efferent (sympathetic) and afferent (sensory) renal nerves. However, preclinical studies suggest that the beneficial effects of TRDN may be due to ablation of afferent, rather than efferent, renal nerves. We developed a novel method for chemical ablation of afferent renal nerves by periaxonal application of capsaicin which has been employed in mouse and rat models of hypertension. In certain rodent models afferent-specific renal denervation (ARDN) has been shown to lower arterial pressure to the same degree as TRDN. The objective of the present study was to develop a catheter-based method for ARDN in a large animal model with the long-term goal of translating this treatment to humans. We tested the feasibility of using the Peregrine™ catheter infusion system, currently used to perform TRDN in humans by injection of ethanol, to perform catheter-based afferent renal denervation in sheep by periaxonal application of capsaicin.

Castrated, adult, male, Friesen sheep underwent Sham RDN (saline, n = 2), TRDN (ethanol, n = 4), or ARDN (capsaicin, n = 4) with the Peregrine™ catheter before termination > 2 weeks after the procedure. Denervation of renal efferents was verified by measurement of renal cortical norepinephrine (NE) content and anti-tyrosine hydroxylase (TH) staining; denervation of renal afferents was verified with anti-calcitonin gene-related peptide (CGRP) staining.

There was a significant decrease in TH + and CGRP + fibers in TRDN kidneys and in CGRP + but not TH + fibers in ARDN kidneys. TRDN significantly reduced renal cortical norepinephrine (NE) content by 89% while ARDN had similar NE content to Sham RDN kidneys.

This study establishes the feasibility of performing catheter-based afferent renal denervation in a large animal model. Furthermore, this study provides a translational model to evaluate catheter-based ARDN as a potential treatment for hypertension.

Pain is an important symptom associated with the arboviral disease caused by the Chikungunya virus (CHIKV). For a significant number of patients, this symptom can persist for months or even years, negatively affecting their quality of life. Unfortunately, pharmacological options for this condition are limited and only partially effective, as the underlying mechanisms associated with CHIKV-induced pain are still poorly understood. The re-emergence of CHIKV has led to new outbreaks, and the expected high prevalence of pain in these global events requires new scientific advances to find more effective solutions. Here we review the main aspects of pain caused by CHIKV infection, such as the anatomy of the affected sites, the prevalence and management of this symptom, the diversity of possible cellular and molecular mechanisms, and finally highlight a promising meningeal pathway to elucidate the mechanisms involved in the unsolved problem of CHIKV-associated pain.

Kappa opioid receptors (KOR) expressed by peripheral pain-sensing neurons (nociceptors) are a promising target for development of effective and safer analgesics for inflammatory pain that are devoid of central nervous system adverse effects. Here we sought to delineate the signaling pathways that underlie peripheral KOR-mediated antinociception in adult male and female Sprague-Dawley rats. In an inflammatory model of pain, local intraplantar (i.pl.) injection of pertussis toxin prevented antinociception induced by the KOR agonist, U50488, indicating that members of the Gi/o family mediate the antinociceptive response. Furthermore, i.pl. injection of the G protein-coupled inward-rectifying potassium (GIRK) channel blocker, TPNQ, as well as GIRK2 subunit-targeted siRNA abolished U50488-mediated antinociceptive behavioral responses in both male and female rats. Consistent with these data, i.pl. injection of ML297, a direct activator of GIRK1 subunit-containing channels, elicited peripheral antinociceptive behavior. It is well known that intraepidermal nerve fibers (IENF) that innervate the hindpaw propagate nociceptive signals to the spinal cord. However, recent studies suggest that keratinocytes, the major cell type in the epidermis, also play an active role in pain and sensory processing. Results from RT-qPCR, RNAscope and immunohistochemistry experiments confirmed that both KOR and GIRK are expressed in keratinocytes in the epidermal layer of the rat hindpaw. Knockdown of either KOR or GIRK2 subunits selectively in keratinocytes by i.pl. injection of shRNA plasmids, prevented the antinociceptive response to U50488. Taken together, these data suggest that KOR-mediated activation of GIRK channels in keratinocytes is required for peripherally-mediated antinociception.

Histone deacetylase (HDAC)6 is a broadly expressed class IIb HDAC that regulates cytoskeletal dynamics and some nuclear processes. Previously research has shown that HDAC6 enzymatic inhibition has analgesic properties in models of chemotherapy-induced peripheral neuropathy. Here, we evaluated the effects of genetic and pharmacologic inhibition of HDAC6 on the development of sensory hypersensitivity in mouse models of peripheral nerve injury and peripheral inflammation. Daily administration of the peripherally restricted HDAC6 inhibitor, ACY1215 (Regenacy Pharmaceuticals, Inc), attenuated mechanical allodynia in the von Frey assay within 2 days of treatment initiation, with no signs of analgesic tolerance after 21 days of administration. We observed a similar antiallodynic effect across the implemented injury models after conditionally knocking down Hdac6 in the adult dorsal root ganglia (DRGs). Bioinformatic analysis of whole-transcriptome RNA-sequencing data predicted that ACY1215 treatment predominantly attenuated proinflammatory mechanisms, such as the suppression of immune cell infiltration into the DRG after injury. Accordingly, we demonstrated a reduction in the expression of various immune cell markers in the DRG after pharmacologic and genetic HDAC6 inhibition in both neuropathic and inflammatory pain models. We identified a direct relationship between Ccl5/Ccr5 and Hdac6 downregulation, as well as reduced hypersensitivity after hind paw CCL5 administration upon Hdac6 knockdown in the DRG. Our findings highlight that peripheral inhibition of HDAC6 ameliorates sensory hypersensitivity in models of postoperative inflammatory and neuropathic pain through mechanisms beyond reduction of tubulin deacetylation. SIGNIFICANCE STATEMENT: Recent studies highlight the role of histone deacetylase (HDAC)6 in chemotherapy-induced peripheral neuropathy, through mechanisms of action including tubulin acetylation and mitochondrial trafficking. In this study, various murine models of acute and chronic pain are applied to show that inhibition of HDAC6 activity in the periphery, using the clinically tested ACY1215 compound, and genetic inactivation of the Hdac6 gene in the dorsal root ganglia, alleviated mechanical hypersensitivity in male and in female mice through mechanisms that include targeting injury-induced inflammation.

Although oxidative stress is the main pathophysiology of the development of diabetic neuropathy, oral administration of antioxidants has given disappointing results. Here, we hypothesized that local delivery of antioxidants would provide protective effects on Schwann cells due to the high concentration of local lesions. We prepared alpha-tocopherol (ATF)-loaded liposomes and tested their skin penetration after sonication. An in vitro study using IMS-32 cells was conducted to determine the level of reactive oxygen species (ROS) scavenging effects of ATF-liposomes. ATF reduced ROS in high-glucose-exposed IMS-32 cells in a dosedependent manner. ATF-liposomes also reduced the ROS level in vitro and ultrasound irradiation enhanced delivery to the dermis in porcine ear skin. This study showed that it is feasible to deliver ATF through the skin and can effectively reduce ROS. This model is worthy of development for clinical use.

This study aimed to determine the clinical relevance of the influence of coadministration of immune checkpoint inhibitors (ICIs) on the analgesic effects of opioids, focusing on the amount of change in opioid dosage.

This study used data from patients who used opioids during anticancer therapy at the Oita University Hospital between September 2014 and October 2023. The primary outcome measure was the amount of change in morphine mg equivalent opioid dose during the period of anticancer therapy. Propensity score matching was performed to reduce confounding effects.

The study enrolled 235 patients; 101 received ICI and 134 received no ICI. Before propensity score matching, there were significant differences between the ICI and non-ICI groups in lines of anticancer therapy, type of primary cancer, body mass index, maximum opioid dose and the amount of change in opioid dose. Following propensity score matching, 73 patients each were included in the ICI and non-ICI groups. Analysis of the propensity score-matched cohort showed a significant increase in the median amount of change in opioid dose in ICI group vs non-ICI group (22.5 vs. 15.0 morphine mg equivalents, interquartile range; 0.0, 40.0 vs. 0.0, 30.0, P = .044). Multiple regression analysis identified ICI administration and body mass index as significant independent factors associated with the amount of change in opioid dose (P = .014 and .027, respectively).

ICI administration significantly increased opioid dosage regardless of patient background. Our findings would provide valuable insight into future pain management strategies.

Pain hypersensitivity is a hallmark of rheumatoid arthritis (RA); however, the underlying mechanisms and effective therapies remain largely undefined. Emerging studies suggest that neutrophils play a significant role in the pathology of RA, yet their involvement in RA-associated pain is still unclear. The present study investigates whether neutrophil activity contributes to pain pathogenesis in RA. Our flow cytometry analysis reveals that the accumulation and N1 polarization (indicated by the ratio of CD45+CD66b+CD95+ subset) of neutrophils occur in synovial fluid samples from RA patients, positively correlating with pain scores. In the collagen-induced rheumatoid arthritis (CIA) model, mice demonstrate neutrophil accumulation, N1 polarization (indicated by the ratio of CD45+Ly-6G+CD95+ subset), and reactive oxygen species (ROS) production in affected paw tissues. Geranyl hydroquinone (GHQ), a natural meroterpenoid with antioxidative properties, reverses N1 polarization and ROS production in synovial neutrophils from RA patients in vitro. Moreover, a 10-day oral administration of GHQ alleviates pain hypersensitivity and reduces neutrophil accumulation, N1 polarization, and ROS production in CIA mice. Notably, GHQ treatment reverses TNF-α-evoked ROS production in neutrophils in vitro through downregulating gene expression associated with the ROS pathway. Further, liquid chromatography-tandem mass spectrometry and biochemical analyses indicate that GHQ binds to microsomal glutathione S-transferase 3 (MGST3) in neutrophils. In vitro and in vivo evidence demonstrates that the RA-specific analgesic and antioxidative effects of GHQ require MGST3. Lastly, GHQ administration exhibits superior therapeutic effects compared to methotrexate, a first-line disease-modifying antirheumatic drug, in CIA mice. Collectively, our findings indicate that neutrophil accumulation, N1 polarization and ROS production contribute to RA-associated pain, suggesting that targeting these pathways, such as with GHQ, could be a viable strategy for RA treatment.

Neuroimmunology is a multidisciplinary field that investigates the interactions between the nervous and immune systems. Neuroimmune interactions persist throughout the entire lifespan, and their dysregulation can lead to the onset and development of multiple diseases. Despite significant progress over the past decades in elucidating the interaction between neuroscience and immunology, the exact mechanism underlying neuroimmune crosstalk has not yet been fully elucidated. In recent years, natural products have emerged as a promising avenue for the therapeutic implications of neuroimmune diseases. Naturally derived anti-neuroimmune disease agents, such as polyphenols, flavonoids, alkaloids, and saponins, have been extensively studied for their potential neuroimmune modulatory effects. This comprehensive review delves into the specific molecular mechanisms of bidirectional neuro-immune interactions, with particular emphasis on the role of neuro-immune units. The review synthesizes a substantial body of evidence from in vitro and in vivo experiments as well as clinical studies, highlighting the therapeutic potential of various natural products in intervening in neuroimmune disorders.

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

Neuropathic pain is characterized by a high prevalence and associated with a variety of disorders of the peripheral and central nervous systems. It remains a major challenge for clinical management due to lack effective treatments. Our previous studies have demonstrated that nerve injury-induced neuroinflammation plays a critical role in regulating the development and maintenance of neuropathic pain. In the present study, we found that chronic constriction injury (CCI) led to a significant increase in the number of macrophages at the site of injured nerves. To elucidate the role of macrophage activation in CCI-induced neuropathic pain, we employed chemical agents, including clodronate liposomes, which is known for their ability to deplete macrophages, and minocycline, an inhibitor of macrophage function. Both intravenous injection of liposome-encapsulated clodronate and intrasciatic delivery of minocycline effectively attenuated CCI-induced mechanical and heat hyperalgesia. Furthermore, transfer of polarized M2 macrophages significantly alleviated CCI-induced neuropathic pain, but not under the condition of M1 macrophage transfer. Mechanistically, our findings indicated that pretreatment with minocycline increased the expression level of CD206 but decreased that of IL-1β, while post-polarization treatment markedly decreased the expression level of both. Additionally, an in vitro migration assay revealed that minocycline exerts an inhibitory effect on macrophage migration. In brief, our study elucidates the effect of CCI-induced macrophage activation on neuropathic pain and provides new insights into the potential clinical application of minocycline for managing neuropathic pain.

Chemotherapy-induced peripheral neuropathy (CIPN) significantly impacts patient's quality of life and complicates cancer treatment. Neuroprotectin D1 (NPD1)/protectin D1 (PD1), derived from docosahexaenoic acid (DHA), exhibits analgesic actions in animal models of inflammatory pain and neuropathic pain. GPR37, a receptor for NPD1/PD1, is known to regulate macrophage phagocytosis and inflammatory cytokine expression, but its role in primary sensory neurons and CIPN remains poorly understood. We found Gpr37 mRNA expression in both neurons and macrophages in mouse dorsal root ganglia (DRG), furthermore, GPR37 is downregulated by the chemotherapy agent paclitaxel. Gpr37 mRNA was notably high in neonatal mouse DRG neurons. In contrast, Gpr37l1 is primarily expressed by satellite glial cells in DRG. Chemotherapy-induced neuropathic pain symptom (mechanical allodynia) resolved within seven weeks in wild-type mice, but it persisted in Gpr37 knockout mice, highlighting GPR37's role in acute-to-chronic pain transition. Consistently, intra-DRG knockdown of Gpr37 in naive animals was sufficient to induce mechanical allodynia. In primary DRG cultures, NPD1 facilitated neurite outgrowth of sensory neurons in the presence of paclitaxel, in a GPR37-dependent manner. NPD1 treatment also mitigated mechanical allodynia and prevented the loss of intraepidermal nerve fibers in hind paw skins in wild-type mice undergoing chemotherapy, but these protective effects are absent in Gpr37 knockout mice. Finally, spatial transcriptomics analysis revealed macrophage and neuronal expression of GPR37 in human DRG. Our findings indicate that GPR37 deficiency drives pain chronicity in CIPN. This study also underscores the potential of NPD1 in safeguarding against sensory neuron degeneration and neuropathic pain in CIPN through GPR37.

The repair of peripheral nerve injury (PNI) presents a multifaceted and protracted challenge, with current therapeutic approaches failing to achieve optimal repair outcomes, thereby not satisfying the considerable clinical demand. The advent of tissue engineering has led to a growing body of experimental evidence indicating that the synergistic application of nerve conduits, which provide structural guidance, alongside the biological signals derived from exosomes and stem cells, yields superior therapeutic results for PNI compared to isolated interventions. This combined approach holds great promise for clinical application. In this review, we present the latest advancements in the treatment of PNI through the integration of stem cells or exosomes with nerve conduits. We have addressed the inadequate efficiency of exosomes or stem cells in conjunction with nerve conduits from 3 perspectives: enhancing stem cells or exosomes, improving nerve conduits, and incorporating physical stimulation.

Neonatal hindpaw incision can evoke long-lasting changes in nociceptive processing following repeat injury in adulthood. Studies have focused on the effects and mechanisms in the spinal cord and brain, however changes in inflammation and macrophages in the periphery, especially at the site of early life injury, remain poorly defined. In this paper, we investigated the role of macrophages in the injured tissue in pain hypersensitivity caused by repeat hindpaw incisions and primed by neonatal injury.

Hindpaw incision was performed in anesthetized adult rats. Among them, some had neonatal hindpaw incisions on postnatal day 3. To assess the role of inflammatory response in the priming of adult incision pain, the rats were treated with clodronate liposome, a macrophage depletion agent, and ketorolac tromethamine, the commonly used anti-inflammatory drug following surgery. Their mechanical pain sensitivity was measured via von Frey filaments. Inflammation induced by hindpaw incision was evaluated via Enzyme-linked Immunosorbent Assay, H&E, and immunofluorescence staining. The phenotypes of macrophages were examined by analyzing their surface markers by flow cytometry.

Mechanical pain hypersensitivity caused by the hindpaw incision in the adult rats was enhanced by previous neonatal injury, which also significantly increased microglial activation in the spinal dorsal horn, aggravation of inflammation, and infiltration of both M1 and M2 macrophages in damaged hindpaw tissue after the repeat incision in the adult rats on POD 5. Intraperitoneal injection of clodronate liposome alleviates nociceptive and inflammatory responses in neonatal injured rats. Intramuscular injection of ketorolac tromethamine decreased mechanical hyperalgesia and inflammatory responses primed by prior neonatal injury.

Neonatal tissue injury exacerbated mechanical hypersensitivity, infiltration, and activation of macrophages evoked by repeat hindpaw incision in adulthood.

N-type calcium channel (CaV2.2) protein contributes to neuronal excitability and overactivation in sympathetic ganglion (SG) following myocardial infarction (MI), thereby easily triggering cardiac remodeling and ventricular arrhythmias (VAs). Despite much advances in the understanding of CaV2.2, a neuron-targeted modifying treatment is, yet, infrequently realized. Moreover, establishing a specific delivery strategy and stable probe architecture with an extensive molecular structure in pursuit of the complex CaV2.2 regulation still remains a challenge. Herein, we develop a smart DNA nanoflower (sDNF) composite by utilizing the customizable design and scalable production from a multifunctionality-encoded template that self-assembles into a biomimetic nanoarchitecture. The nanoarchitecture contains a neuron-targeting aptamer and a decorated CaV2.2 mediator peptide-DNA bioconjugate. The combined targeted delivery and the release of the CaV2.2 mediator peptide synergistically led to an ∼31% reduction of the peak calcium current in neuron cells. Moreover, sDNF alleviated MI-induced SG hyperactivity and improved in vivo outcomes, such as decreasing susceptibility to VAs and relieving neuropathic pain for 10 h. The infarct size treated with sDNF is reduced to approximately 11.1%. It is envisioned that the DNF-based nanostructure for cardiac remodeling suppression and VAs inhibition along with pain relief provides a potential approach for the clinical treatment of sympathetic-associated cardiovascular diseases.

Chronic pain conditions frequently coexist and share common genetic vulnerabilities. Despite evidence showing associations between pain and depression, the additive effect of co-occurring pain conditions on depression risk and the underlying mechanisms remain unclear. Leveraging data from 431,038 UK Biobank participants with 14-year follow-up, we found a significantly increased risk of depression incidence in individuals reporting pain, irrespective of body site or duration (acute or chronic), compared with pain-free individuals. The depression risk increased with the number of co-occurring pain sites. Mendelian randomization supported potential causal inference. We constructed a composite pain score by combining individual effects of acute or chronic pain conditions across eight body sites in a weighted manner. We found that depression risks increased monotonically in parallel with composite pain scores. Moreover, some inflammatory markers, including C-reactive protein, partially mediated the association between composite pain scores and depression risk. Considering the high prevalence of comorbid depression and pain, pain screening may help identify high-risk individuals for depression.

Typically, neuropathic pain (NP) is difficult to manage as it is refractory to conventional medications. Electroacupuncture (EA) at 5/100 Hz has emerged as an effective and promising treatment for NP; however, its mechanism of action is still uncertain. Accordingly, this study investigated the alleviatory mechanism of EA in chronic compression injury (CCI)-induced chronic pain via the C-C chemokine ligand 3 / C-C chemokine receptor type 5 (CCL3/CCR5) axis.

The CCI model was established in rats to induce NP. Mechanical and thermal hyperalgesia were assessed with von Frey and Hargreaves tests, respectively. From day 8 after CCI, EA (5/100 Hz) was performed for 1 week (30 min/day). CCL3 and CCR5 expression was detected with Western blotting and immunofluorescence. Glial cell activation was determined through co-labeling of neurons and glial cells with antibodies against CCL3 and CCR5. The release of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α was tested with enzyme-linked immunosorbent assay (ELISA).

EA markedly ameliorated CCI-induced chronic NP in rats and reduced CCL3 and CCR5 expression in the rat spinal cord. CCL3 and CCR5 were co-expressed by neurons and microglia in the central nervous system. In addition, EA also repressed the activation of glial cells and levels of IL-1β, IL-6 and TNF-α.

EA may mitigate chronic NP in rats by blocking the CCL3/CCR5 axis in the spinal cord. In addition, EA appeared to exert anti-inflammatory and analgesic effects by suppressing glial cell activation. These findings add to our understanding of the mechanism of EA-induced analgesia.

Neuropathic pain (NP) is a debilitating disease and is associated with energy metabolism alterations. This study aimed to identify energy metabolism-related differentially expressed genes (EMRDEGs) in NP, construct a diagnostic model, and analyze immune cell infiltration and single-cell gene expression characteristics of NP. GSE89224, GSE123919, and GSE134003 were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) analysis and an intersection with highly energy metabolism-related modules in weighted gene co-expression network analysis (WGCNA) was performed in GSE89224. Least absolute shrinkage and selection operator (LASSO), random forest, and logistic regression were used for model genes selection. NP samples were divided into high- and low-risk groups and different disease subtypes based on risk score of LASSO algorithm and consensus clustering analysis, respectively. Immune cell composition was estimated in different risk groups and NP subtypes. Datasets 134,003 were performed for identification of single-cell DEGs and functional enrichment. Cell-cell communications and pseudo-time analysis to reveal the expression profile of NP. A total of 38 EMRDEGs were obtained and are majorly enriched in metabolism about glioma and inflammation. LASSO, random forest, and logistic regression identified 6 model genes, which were Itpr1, Gng8, Socs3, Fscn1, Cckbr, and Camk1. The nomogram, based on six model genes, had a good predictive ability, concordance, and diagnostic value. The comparisons between different risk groups and NP subtypes identified important pathways and different immune cells component. The immune infiltration results majorly associated with inflammation and energy metabolism. Single-cell analysis revealed cell-cell communications and cells differentiation characteristics of NP. In conclusion, our results not only elucidate the involvement of energy metabolism in NP but also provides a robust diagnostic tool with six model genes. These findings might give insight into the pathogenesis of NP and provide effective therapeutic regimens for the treatment of NP.

The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.

Neuropathic pain is a prevalent and debilitating condition experienced by the majority of individuals with spinal cord injury (SCI). The complex pathophysiology of neuropathic pain, involving continuous activation of microglia and astrocytes, reactive gliosis, and altered neuronal plasticity, poses significant challenges for effective treatment. This review focuses on the pivotal roles of microglia and astrocytes, the two major glial cell types in the central nervous system, in the development and maintenance of neuropathic pain after SCI. We highlight the extensive bidirectional interactions between these cells, mediated by the release of inflammatory mediators, neurotransmitters, and neurotrophic factors, which contribute to the amplification of pain signaling. Understanding the microglia-astrocyte crosstalk and its impact on neuronal function is crucial for developing novel therapeutic strategies targeting neuropathic pain. In addition, this review discusses the fundamental biology, post-injury pain roles, and therapeutic prospects of microglia and astrocytes in neuropathic pain after SCI and elucidates the specific signaling pathways involved. We also speculated that the extracellular matrix (ECM) can affect the glial cells as well. Furthermore, we also mentioned potential targeted therapies, challenges, and progress in clinical trials, as well as new biomarkers and therapeutic targets. Finally, other relevant cell interactions in neuropathic pain and the role of glial cells in other neuropathic pain conditions have been discussed. This review serves as a comprehensive resource for further investigations into the microglia-astrocyte interaction and the detailed mechanisms of neuropathic pain after SCI, with the aim of improving therapeutic efficacy.

Neuroinflammation is a key driver of neurological disorders. Evodiamine (EVO), an alkaloid from the traditional Chinese herb Evodia rutaecarpa, possesses potent biological activities, notably anticancer and anti-inflammatory effects. This study investigates EVO's potential to attenuate LPS-induced neuroinflammation, focusing on identifying its therapeutic targets and mechanisms of action. EVO treatment significantly improved mitochondrial function and reduced oxidative stress in LPS-stimulated BV2 cells, while also lowering levels of pro-inflammatory factors (IL-6, NO, IL-1β) in brain organoids. In mice, EVO treatment alleviated behavioral abnormalities, especially in cognition and memory, and lowered hippocampal inflammation marker levels. To elucidate the critical mechanisms by which EVO exerts its anti-inflammatory effects, we analyzed LPS-induced inflammatory injury in BV2 cells and used transcriptomics to investigate whether EVO modulates the C/EBP-β signaling pathway. Further validation using si-C/EBP-β confirmed EVO's regulatory effect on the C/EBP-β-COX2 axis, showing that knockdown significantly reduced pro-inflammatory factor expression, thereby providing neuroprotection. Moreover, molecular docking and dynamics simulations confirmed a stable interaction between EVO and C/EBP-β, supporting its role in attenuating LPS-induced neuroinflammation. In summary, these findings suggest that EVO regulates inflammation-related pathways by targeting the C/EBP-β-COX2 axis, offering neuroprotective benefits and mitigating neuroinflammatory responses.

The aim is to explore the mechanisms underlying pain development in chronic prostatitis and identify therapeutic targets for pain management in patients with chronic prostatitis. RNA sequence of the spinal cord dorsal horns and proteomic analysis of spinal macrophages of experimental autoimmune prostatitis (EAP) mice were conducted to identify pain-related genes, proteins and signalling pathways. The clodronate liposome, CXCR3 and P-STAT3 inhibitors, NGF antibody and cromolyn sodium were used to investigate the roles of the CXCL10/CXCR3, JAK/STAT3 and NGF/TrKA pathways in spinal macrophage recruitment and pain response. Finally, prostate tissues from benign prostate hyperplasia (BPH) patients were collected to validate the aforementioned results. Neuron and astrocyte-derived CXCL10 was associated with spinal macrophage recruitment, and CXCL10/CXCR3 axis could regulate the chemotaxis of macrophage to the spinal cord in EAP mice. Results of proteomic analysis found that CXCL10 could regulate the JAK/STAT3 pathway to mediate neuroinflammation in EAP, which was validated in vivo and in vitro experiments. The number of mast cells and expressions of NGF, TrKA and PGP9.5 increased in the prostates of EAP mice and BPH patients, and targeting NGF could reduce spinal macrophage recruitment and pain response. NGF was the triggering factor to induce chemotaxis of spinal macrophages and neuroinflammation, and the CXCL10/CXCR3 axis and JAK/STAT3 pathway was involved in spinal macrophage recruitment and infiltration, which provided therapeutic targets for pain management.