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Ethnopharmacological Relevance: Jinmaitong (JMT) is a prescription of Traditional Chinese Medicine that is composed of 12 crude drugs. It has been used in the treatment of diabetic neuropathic pain (DNP) for more than 30 years., Aim of Study: Microglia are thought to play an important role in neuropathic pain. This study aimed to evaluate the protective effect of JMT against DNP and to investigate the underlying mechanisms in which the microglia and JAK2/STAT3 signaling pathway were mainly involved., Materials and Methods: The chemical composition of JMT was analyzed using liquid chromatography tandem mass spectrometry. The diabetes model was constructed using 11 to 12-week-old male Zucker diabetic fatty (ZDF) rat (fa/fa). The model rats were divided into 5 groups and were given JMT at three dosages (11.6, 23.2, and 46.4 g/kg, respectively, calculated as the crude drug materials), JAK inhibitor AG490 (positive drug, 10 μg/day), and placebo (deionized water), respectively, for eight weeks (n = 6). Meanwhile, Zucker lean controls (fa/+) were given a placebo (n = 6). Body weight was tested weekly and blood glucose was monitored every 2 weeks. The mechanical allodynia and heat hyperalgesia were assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. After treatment, the microglia activation marker Iba-1, CD11B, CD68, neuroinflammatory mediators, and mediators of the JAK2/STAT3 signaling pathway were compared between different groups. The mRNA and protein levels of target genes were assessed by quantitative real-time PCR and Western Blot, respectively., Results: We found that JMT significantly inhibited the overactivation of microglia in spinal cords, and suppressed neuroinflammation of DNP model rats, thereby ameliorating neurological dysfunction and injuries. Furthermore, these effects of JMT could be attributed to the inhibition of the JAK2/STAT3 signaling pathway., Conclusions: Our findings suggested that JMT effectively ameliorated DNP by modulating microglia activation via inhibition of the JAK2/STAT3 signaling pathway. The present study provided a basis for further research on the therapeutic strategies of DNP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peripheral nerve injury triggers rapid microglial activation, promoting M1 polarization within the spinal cord, which exacerbates the progression of neuropathic pain. C1q/TNF-related protein 9 (CTRP9), an adiponectin homolog, is known to suppress macrophage activation and exhibit anti-inflammatory properties through the activation of adiponectin receptor 1 (AdipoR1) in various disease contexts. Nevertheless, the involvement of CTRP9 in microglial polarization in the context of neuropathic pain is still unclear. Our study aimed to how CTRP9 influences spinal microglial polarization, neuroinflammation, and pain hypersensitivity, as well as the underlying mechanism, using a neuropathic pain model in male mice with spared nerve injury (SNI) of sciatic nerve. Our findings revealed SNI elevated the spinal CTRP9 and AdipoR1 levels in microglia. Furthermore, intrathecal administration of recombinant CTRP9 (rCTRP9) substantially weakened mechanical hypersensitivity and heat-related pain response triggered by SNI. On the other hand, rCTRP9 mediated a phenotypic switch in microglia, from the pro-inflammatory M1 state to the anti-inflammatory M2 state, by influencing the spinal AMPK/NF-κB mechanism in SNI mice. Additionally, treatment with AdipoR1 siRNA or an AMPK-specific antagonist both reversed the effects of CTRP9 on the phenotypic switching of spinal microglia and pain hypersensitivity. Collectively, these results indicate that CTRP9 ameliorates mechanical hypersensitivity and heat-related pain response, shifted the balance of microglia towards the anti-inflammatory M2 state, and suppresses neuroinflammatory responses by modulating the AMPK/NF-κB pathway, mediated by AdipoR1 activation, in mice with SNI., (© 2024. The Author(s).)

Background: Neuroinflammation and mitochondrial dysfunction have been implicated in the progression of neuropathic pain (NP) but can be mitigated by supplementation with gingerol-enriched ginger (GEG). However, the exact benefits of GEG for each sex in treating neuroinflammation and mitochondrial homeostasis in different brain regions and the colon remain to be determined., Objective: Evaluate the effects of GEG on emotional/affective pain and spontaneous pain behaviors, neuroinflammation, as well as mitochondria homeostasis in the amygdala, frontal cortex, hippocampus, and colon of male and female rats in the spinal nerve ligation (SNL) NP model., Methods: One hundred rats (fifty males and fifty females) were randomly assigned to five groups: sham + vehicle, SNL + vehicle, and SNL with three different GEG doses (200, 400, and 600 mg/kg BW) for 5 weeks. A rat grimace scale and vocalizations were used to assess spontaneous and emotional/affective pain behaviors, respectively. mRNA gene and protein expression levels for tight junction protein, neuroinflammation, mitochondria homeostasis, and oxidative stress were measured in the amygdala, frontal cortex, hippocampus, and colon using qRT-PCR and Western blot (colon)., Results: GEG supplementation mitigated spontaneous pain in both male and female rats with NP while decreasing emotional/affective responses only in male NP rats. GEG supplementation increased intestinal integrity (claudin 3) and suppressed neuroinflammation [glial activation (GFAP, CD11b, IBA1) and inflammation (TNFα, NFκB, IL1β)] in the selected brain regions and colon of male and female NP rats. GEG supplementation improved mitochondrial homeostasis [increased biogenesis (TFAM, PGC1α), increased fission (FIS, DRP1), decreased fusion (MFN2, MFN1) and mitophagy (PINK1), and increased Complex III] in the selected brain regions and colon in both sexes. Some GEG dose-response effects in gene expression were observed in NP rats of both sexes., Conclusions: GEG supplementation decreased emotional/affective pain behaviors of males and females via improving gut integrity, suppressing neuroinflammation, and improving mitochondrial homeostasis in the amygdala, frontal cortex, hippocampus, and colon in both male and female SNL rats in an NP model, implicating the gut-brain axis in NP. Sex differences observed in the vocalizations assay may suggest different mechanisms of evoked NP responses in females.

Back Ground: 7-Methoxycoumarin (7-MC) is well recognized for its anti-inflammatory and anti-nociceptive actions. Its capacity to lessen neuropathic pain hasn't been documented yet. Hence the impact of 7-MC on vincristine-induced peripheral neuropathic pain in rodents was investigated. The investigation also looked at the impact of 7-MC in reducing neuropathic pain via voltage-gated calcium channels and phospholipase enzyme inhibition using pertinent in vitro and in silico methods., Methods and Results: Vincristine (0.1 mg/kg, i.p., daily) was administered continuously for 7 days to induce peripheral neuropathic pain in mice, with cold allodynia and thermal hyperalgesia and evaluated on the 8th day using the acetone bubble test and hot water tail immersion test. In order to derive the mechanistic approach for ameliorating neuropathic pain, the role of 7-MC in the inhibition of the phospholipase enzyme, gene expression studies on voltage-gated calcium channels using mouse BV2 microglial cells and in silico studies for its calcium channel binding affinity were also performed. The test compounds reduced vincristine-induced cold allodynia and thermal hyperalgesia in mice in a dose-dependent experiments. In vitro studies on phospholipase inhibition by 7-MC showed an IC 50 of 27.08 µg/ml and down-regulated the gene expression of calcium channels in the BV2 microglial cell line. In silico docking scores for 7-MCwere higher than the standard drug gabapentin., Conclusion: The compound 7-MC has shown promise in alleviating vincristine-induced peripheral neuropathicin mice. Studies conducted in parallel, both in silico and in vitro have demonstrated that 7-MC effectively reduces neuropathic pain. This pain reduction is achieved through two mechanisms: inhibiting the phospholipase enzyme and blocking voltage-gated calcium channels., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Addressing the intricate challenge of chronic neuropathic pain has significant implications for the physical and psychological well-being of patients, given its enduring nature. In contrast to opioids, electroacupuncture (EA) may potentially provide a safer and more efficacious therapeutic alternative. Our objective is to investigate the distinct analgesic effects and potential mechanisms of EA at frequencies of 2 Hz, 100 Hz, and 18 kHz in order to establish more precise frequency selection criteria for clinical interventions. Analgesic efficacy was evaluated through the measurement of mice's mechanical and thermal pain thresholds. Spinal cord inflammatory cytokines and neuropeptides were quantified via Quantitative Real-time PCR (qRT-PCR), Western blot, and immunofluorescence. Additionally, RNA sequencing (RNA-Seq) was conducted on the spinal cord from mice in the 18 kHz EA group for comprehensive transcriptomic analysis. The analgesic effect of EA on neuropathic pain in mice was frequency-dependent. Stimulation at 18 kHz provided superior and prolonged relief compared to 2 Hz and 100 Hz. Our research suggests that EA at frequencies of 2 Hz, 100 Hz, and 18 kHz significantly reduce the release of inflammatory cytokines. The analgesic effects of 2 Hz and 100 Hz stimulation are due to frequency-dependent regulation of opioid release in the spinal cord. Furthermore, 18 kHz stimulation has been shown to reduce spinal neuronal excitability by modulating the serotonergic pathway and downstream receptors in the spinal cord to alleviate neuropathic pain., (© 2024. The Author(s).)

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.

Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I 1 -receptor agonist LNP599 and whether the attenuation involves co-activation of α 2 -adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb. Additionally, GTPγS radioligand binding assay, β-arrestin recruitment and intracellular cAMP levels were used for receptor profiling in vitro. LNP599 (imidazoline I 1 receptor agonist) and clonidine (α 2 -adrenoceptor agonist) produced equal dose-related mechanical antihypersensitivity effects in both sexes. LNP599 attenuated heat nociception preferentially in males, while clonidine reduced heat nociception equally in males and females. Carbophenyline (another imidazoline I 1 receptor agonist) had no significant effect on mechanical hypersensitivity or heat nociception in males or females. Mechanical antihypersensitivity and heat antinociception induced by LNP599 in SNI males was prevented by pretreatments with yohimbine or atipamezole (two α 2 -adrenoceptor antagonists) but not by efaroxan (a mixed imidazoline I 1 receptor/α 2 -adrenoceptor antagonist). In vitro assays indicated that LNP599 does not activate α 2A - or other subtypes of α 2 -adrenoceptors. However, LNP599 was a weak partial agonist for 5-HT 2B receptors and bound to sigma-1 and sigma-2 receptors that all are involved in modulation of spinal nociception. The results indicate that the suppression of neuropathic pain hypersensitivity by LNP599 is not due to action on spinal imidazoline I 1 receptors, but rather due to indirect activation of spinal α 2 -adrenoceptors., Competing Interests: Declaration of Competing Interest Three of the authors (A.V., A.D., and A.K.) are employees of a pharmaceutical company (Orion Pharma). One of the authors (J.L.) has received funding from a pharmaceutical company (Orion Pharma). Other authors (H.W. and A.P.) declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain results from damage to nerves or the brain, and is characterized by symptoms such as allodynia, spontaneous pain, and hyperalgesia. The causes of this type of pain are intricate, which can make it difficult to treat. Sodium aescinate (SA), a natural extract from horse chestnut tree seeds, has been shown to act as a neuroprotector by inhibiting microglia activation. This study aims to explore the therapeutic potential of SA for neuropathic pain and the molecular mechanisms regulated by SA treatment. Through in vivo animal models and experiments, we found that SA treatment significantly reduced mechanical allodynia and heat hyperalgesia in neuropathic pain models. Additionally, SA inhibited O-GlcNAc-transferase (OGT)-induced O-GlcNAcylation (O-GlcNAc) modification in neuropathic pain mice. OGT overexpression could impede the therapeutic effects of SA on neuropathic pain. Further investigation revealed that Toll-like receptor 3 (TLR3), stabilized by OGT-induced O-GlcNAc modification, could activate the Mitogen activated protein kinase (MAPK) signaling pathway. Further in vivo experiments demonstrated that TLR3-mediated p38 mitogen-activated protein kinase (p38MAPK) activation is involved in SA-mediated relief of neuropathic pain. In conclusion, this study uncovers a novel molecular pathway deactivated by SA treatment in neuropathic pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain (NP) is associated with astrocytes activation induced by nerve injury. Reactive astrocytes, strongly induced by central nervous system damage, can be classified into A1 and A2 types. Vitexin, a renowned flavonoid compound, is known for its anti-inflammatory and analgesic properties. However, its role in NP remains unexplored. This study aims to investigate the effects of vitexin on astrocyte polarization and its underlying mechanisms. A mouse model of NP was established, and primary astrocytes were stimulated with sphingosine-1-phosphate (S1P) to construct a cellular model. The results demonstrated significant activation of spinal astrocytes on days 14 and 21. Concurrently, reactive astrocytes predominantly differentiated into the A1 type. Western blot analysis revealed an increase in A1 astrocyte-associated protein (C3) and a decrease in A2 astrocyte-associated protein (S100A10). Serum S1P levels increased on days 14 and 21, alongside a significant upregulation of Sphingosine-1-phosphate receptor 1 (S1PR1) mRNA expression and elevated expression of chemokines. In vitro, stimulation with S1P inhibited the Phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) signaling pathway and autophagy flux, promoting polarization of astrocytes towards the A1 phenotype while suppressing the polarization of A2 astrocytes. Our findings suggest that vitexin, acting on astrocytes but not microglia, attenuates S1P-induced downregulation of PI3K/Akt signaling, restores autophagy flux in astrocytes, regulates A1/A2 astrocyte ratio, and reduces chemokine and S1P secretion, thereby alleviating neuropathic pain caused by nerve injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Neuropathic pain, a common symptom of several disorders, exerts a substantial socioeconomic burden worldwide. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel predominantly ex-pressed in nociceptive neurons, plays a pivotal role in nociception, by detecting various endogenous and exogenous stimuli, including heat, pro-inflammatory mediators, and physical stressors. Dysregulation of TRPV1 signaling further contributes to the pathophysiology of neuropathic pain. Therefore, targeting TRPV1 is a promising strategy for developing novel analgesics with improved efficacy and safety profiles. Several pharmacological approaches to modulate TRPV1 activity, including agonists, antagonists, and biological TRPV1 RNA interference (RNAi, small interfering RNA [siRNA]) have been explored. Despite preclinical success, the clinical translation of TRPV1-targeted therapies has encountered challenges, including hyperthermia, hypothermia, pungency, and desensitization. Nevertheless, ongoing research efforts aim to refine TRPV1-targeted interventions through structural modifications, development of selective modulators, and discovery of natural, peptide-based drug candidates. Herein, we provide guidance for researchers and clinicians involved in the development of new interventions specifically targeting TRPV1 by reviewing the existing literature and highlighting current research activities. This study further discusses potential future research endeavors for enhancing the efficacy, safety, and tolerability of TRPV1 candidates, and thereby facilitates the translation of these discoveries into effective clinical interventions to alleviate neuropathic pain disorders., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain generally affects 7-10% population worldwide and an estimated ∼1 in every 20 individuals in western countries suffer and burden to society. The most limiting factor with existing therapies includes dose escalation issues, off-target side effects and poor translation of randomized trials into clinical practice. Neuropathic pain is a broad term that comprises direct injury/damage to the central and/or peripheral nervous system, leads to maladaptive changes in neuronal as well as in non-neuronal cells, which further contributes to the spontaneous pain, sensory and motor deficit along with altered sensitivity towards the noxious as well as non-noxious stimulus. Transient receptor potential (TRP) channels are polymodal, non-specific cation channels that operate as biosensors to various mechanical and chemical stimuli, including hyperosmolarity, shear stress, heat, mechanical stretch, extracellular ATP, and other products of inflammation. Modulation of these channels leads to various physiological and pathophysiological manifestations at molecular and cellular levels, leading to diseases including neuropathic pain. There are several molecules targeting TRP channels for neuropathic pain in pre-clinical studies, clinical trials and in the market. This review highlights the critical involvement of various pharmacological modulators for TRP channels targeting neuropathic pain and their possible outcomes to harness the therapeutic potential of TRP channels., Competing Interests: Declaration of competing interest The authors have no financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuropathic pain resulting from spinal cord injury (SCI) is a significant secondary health issue affecting around 60% of individuals with SCI. After SCI, activation of microglia, the immune cells within the central nervous system, leads to neuroinflammation by producing pro-inflammatory cytokines and affects neuropathic pain. This interplay between inflammation and pain contributes to the persistent and intense pain experienced by many individuals with SCI. MicroRNAs (miRs) have been critical regulators of neuroinflammation. Previous research in our laboratory has revealed upregulation levels of circulating miR-19a and miR-19b in individuals with SCI with neuropathic pain compared to those without pain. In this study, we treated primary microglial cultures from mice with miR-19a and miR-19b for 24 h and conducted RNA sequencing analysis. Our results showed that miR-19a and miR-19b up- and downregulate different genes according to the volcano plots and the heatmaps. miR-19a and miR-19b regulate inflammation through distinct signaling pathways. The results showed that miR-19a promotes inflammation via toll-like receptor signaling, TNF signaling, and cytokine-cytokine receptor interactions, while miR-19b increases inflammatory responses through the PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix receptor interactions. The protein-protein interaction (PPI) networks used the STRING database to identify transcription factors associated with genes up- or downregulated by miR-19a and miR-19b. Key transcription factors, such as STAT1, STAT2, and KLF4 for miR-19a, and Nr4a1, Nr4a2, and Nr4a3 for miR-19b, were identified and revealed their roles in regulating neuroinflammation. This study demonstrates that miR-19a and miR-19b modulate diverse patterns of gene expression, regulate inflammation, and induce inflammatory responses in microglia.

Objective: Neuropathic pain can be provoked by high mobility group box 1 (HMGB1) activation of toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling in the dorsal root ganglion (DRG). Electroacupuncture (EA) has been reported to effectively alleviate neuropathic pain with few side effects, but its precise mechanism of action remains unknown. The aim of this study was to explore whether 2 Hz EA stimulation suppresses TLR4/NF-κB signaling in the DRG following spared nerve injury (SNI) in a rat model., Methods: In this experiment, SNI rats were given 2 Hz EA once every other day for a total of 21 days. Paw withdrawal threshold (PWT) was measured to assess SNI-induced mechanical hypersensitivity, and western blotting and immunofluorescence staining were used to determine the levels of pain-related signaling molecules and pro-inflammatory mediators in the DRG., Results: SNI up-regulated HMGB1, TLR4, myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB p65 protein expression in the DRG. In addition, immunofluorescence staining demonstrated that SNI induced higher levels of TLR4 and MyD88 in the DRG. We also demonstrated co-localization of TLR4 and MyD88 with both calcitonin gene-related peptide (CGRP) and isolectin GS-IB4 in the DRG of SNI rats, respectively. Meanwhile, 2 Hz EA stimulation effectively reversed the elevations of HMGB1, TLR4, MyD88 and NF-κB p65 induced by SNI in the DRG, which was coupled with amelioration of SNI-induced mechanical hypersensitivity., Conclusions: The results of this study suggested that inhibition of the TLR4/NF-κB signaling pathway in the DRG by 2 Hz EA might be exploited as a therapeutic option for neuropathic pain., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression., Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior., Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice., Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Neuropathic pain is characterised by periodic or continuous hyperalgesia, numbness, or allodynia, and results from insults to the somatosensory nervous system. Peripheral nerve injury induces transcriptional reprogramming in peripheral sensory neurons, contributing to increased spinal nociceptive input and the development of neuropathic pain. Effective treatment for neuropathic pain remains an unmet medical need as current therapeutics offer limited effectiveness and have undesirable effects. Understanding transcriptional changes in peripheral nerve injury-induced neuropathy might offer a path for novel analgesics. Our literature search identified 65 papers exploring transcriptomic changes post-peripheral nerve injury, many of which were conducted in animal models. We scrutinize their transcriptional changes data and conduct gene ontology enrichment analysis to reveal their common functional profile. Focusing on genes involved in 'sensory perception of pain' (GO:0019233), we identified transcriptional changes for different ion channels, receptors, and neurotransmitters, shedding light on its role in nociception. Examining peripheral sensory neurons subtype-specific transcriptional reprograming and regeneration-associated genes, we delved into downstream regulation of hypersensitivity. Identifying the temporal program of transcription regulatory mechanisms might help develop better therapeutics to target them effectively and selectively, thus preventing the development of neuropathic pain without affecting other physiological functions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exercise has been proven to be an efficient intervention in attenuating neuropathic pain. However, the underlying mechanisms that drive exercise analgesia remain unknown. In this study, we aimed to examine the role of complement component 3 (C3) in neuropathic pain and whether antinociceptive effects are produced by exercise via regulating C3 in mice., Methods: In this study, using a spared nerve injury (SNI)-induced neuropathic pain mice model, C57BL/6J mice were divided into 3 groups: Sham mice, SNI mice, and SNI + Exercise (Ex) mice with 30-minute low-intensity aerobic treadmill running (10 m/min, no inclination). Paw withdrawal threshold; thermal withdrawal latency; and glial fibrillary acidic protein, C3, tumor necrosis factor-α, and interlukin-1β expression in the spinal cord were monitored. C3 knockout (KO) mice were further used to verify the role of C3 in neuropathic pain., Results: von Frey test, acetone test, and CatWalk gait analysis revealed that treadmill exercise for 4 weeks reversed pain behaviors. In addition, exercise reduced astrocyte reactivity (SNI mean = 14.5, 95% confidence interval [CI], 12.7-16.3; SNI + Ex mean = 10.3, 95% CI, 8.77-11.9, P = .0003 SNI + Ex versus SNI) and inflammatory responses in the spinal cord after SNI. Moreover, it suppressed the SNI-induced upregulation of C3 expression in the spinal cord (SNI mean = 5.46, 95% CI, 3.39-7.53; SNI + Ex mean = 2.41, 95% CI, 1.42-3.41, P = .0054 SNI + Ex versus SNI in Western blot). C3 deficiency reduced SNI-induced pain and spinal astrocyte reactivity (wild type mean = 7.96, 95% CI, 6.80-9.13; C3 KO mean = 5.98, 95% CI, 5.14-6.82, P = .0052 C3 KO versus wild type). Intrathecal injection of recombinant C3 (rC3) was sufficient to produce mechanical (rC3-Ex mean = 0.77, 95% CI, 0.15-1.39; rC3 mean = 0.18, 95% CI, -0.04 to 0.41, P = .0168 rC3-Ex versus rC3) and cold (rC3-Ex mean = 1.08, 95% CI, 0.40-1.77; rC3 mean = 3.46, 95% CI, 1.45-5.47, P = .0025 rC3-Ex versus rC3) allodynia in mice. Importantly, exercise training relieved C3-induced mechanical and cold allodynia, and the analgesic effect of exercise was attenuated by a subeffective dose of intrathecal injection of C3., Conclusions: Overall, these results suggest that exercise suppresses neuropathic pain by regulating astroglial C3 expression and function, thereby providing a rationale for the analgesic effect of exercise as an acceptable alternative approach for treating neuropathic pain., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

Background: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect., Methods: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG)., Results: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1β and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG., Conclusions: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

This study investigated Cerium oxide nanoparticles (CeONPs) effect on central neuropathic pain (CNP). The compressive method of spinal cord injury (SCI) model was used for pain induction. Three groups were formed by a random allocation of 24 rats. In the treatment group, CeONPs were injected above and below the lesion site immediately after inducing SCI. pain symptoms were evaluated using acetone, Radian Heat, and Von Frey tests weekly for six weeks. Finally, we counted fibroblasts using H&E staining. We evaluated the expression of Cx43, GAD65 and HDAC2 proteins using the western blot method. The analysis of results was done by PRISM software. At the end of the study, we found that CeONPs reduced pain symptoms to levels similar to those observed in normal animals. CeONPs also increased the expression of GAD65 and Cx43 proteins but did not affect HDAC2 inhibition. CeONPs probably have a pain-relieving effect on chronic pain by potentially preserving GAD65 and Cx43 protein expression and hindering fibroblast infiltration., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathic pain (NPP) is a common type of chronic pain. Glial cells, including astrocytes (AS), are believed to play an important role in the progression of NPP. AS cells can be divided into various types based on their expression profiles, among which A1 and A2 types have clear functions. A1-type AS cells are neurotoxic, while A2-type AS cells exert neuroprotective functions. Some types of lysophosphatidic acid receptors (LPAR) have been shown to play a role in NPP. However, it remains unclear how AS cells and LPAR6 affect the occurrence and progression of NPP. In this study, we established a mouse model of chronic constriction injury (CCI) to simulate NPP. It was found that the expression of LPAR6 in AS cells of the spinal dorsal horn was increased in the CCI model, and the thresholds of mechanical and thermal pain were elevated after knocking out LPAR6, indicating that LPAR6 and AS cells participated in the occurrence of NPP. The experiment involved culturing primary AS cells and knocking down LPAR6 by Lentivirus. The results showed that the NF-κB signal pathway was activated and the number of A1-type AS cells increased in the CCI model. However, LPAR6 knockdown inhibited the NF-κB signal pathway and A1-type AS cells. The results of the mRNA sequencing and immunoprecipitation test indicate an interaction between LPAR6 and ROCK2. Inhibiting ROCK2 by Y-27632 increased mechanical and thermal pain thresholds and alleviated NPP at the molecular level. The study presents evidence that LPAR6 activates the NF-κB pathway through ROCK2 and contributes to the progression of NPP by increasing A1-type AS and decreasing A2-type AS. This suggests that LPAR6 could be a potential therapeutic target for alleviating NPP. Clinical applications that are successful can offer new therapeutic options, enhance the quality of life for patients, and potentially uncover new mechanisms for pain modulation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objective: Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of a sigma-1 receptor (σ1R) antagonist in managing neuropathic pain., Methods: A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084., Results: (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction (GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain., Conclusions: This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention., (© 2024. The Author(s).)

The voltage-gated sodium channel β2 subunit protein (SCN2B) plays a crucial role in neuropathic pain. However, the role and mechanisms of SCN2B in orofacial neuropathic pain are still unclear. This study aimed to investigate the upstream regulatory mechanisms of SCN2B in the trigeminal ganglion (TG) underlying orofacial neuropathic pain. Chronic constriction injury of the infraorbital nerve (CCI-ION) of mice was performed to establish the model of orofacial neuropathic pain. Von Frey filament test was performed to detect the head withdrawal threshold (HWT) of mice. Quantitative reverse transcription-polymerase chain, western blotting (WB), fluorescence in situ hybridization, and immunofluorescence (IF) staining were used to detect the expression and distribution of SCN2B and miR-6954-3p in the TG of mice. A luciferase activity assay was carried out to prove the binding between SCN2B messenger ribonucleic acid (mRNA) and miR-6954-3p. After the CCI-ION surgery, the levels of Scn2b mRNA and protein significantly increased and miR-6954-3p decreased in the TG of mice with decreasing HWT. IF staining revealed that SCN2B was expressed specifically in the TG neurons. Silencing SCN2B in the TG of CCI-ION mice significantly increased the HWT. Importantly, the 3'-untranslated region of Scn2b mRNA was proved to bind with miR-6954-3p. Fluorescence in situ hybridization and IF staining demonstrated that miR-6954-3p was expressed in TG neurons and co-expressed with SCN2B. Furthermore, intraganglionic injection of miR-6954-3p agomir into the TG of CCI-ION mice resulted in the downregulation of SCN2B and increased the HWT. These findings suggest that the downregulation of miR-6954-3p in the TG promotes orofacial neuropathic pain by promoting SCN2B expression following trigeminal nerve injury. PERSPECTIVE: This study points to the important role of SCN2B in orofacial neuropathic pain. Furthermore, miR-6954-3p is proven to regulate the expression of SCN2B by binding to the 3'-untranslated region of Scn2b mRNA. These findings indicate that SCN2B and miR-6954-3p are potential therapeutic targets for the treatment of orofacial neuropathic pain., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain (NP) remains one of the world's most difficult problems, and people suffering from NP have their quality of life affected to a great extent and constantly suffer from pain. Sensitization of injurious receptors, ectopic firing of afferent nerves after nerve injury, and coupling between sympathetic and sensory neurons are involved in the onset or development of NP, but the pathogenesis of NP is still not well understood. We found that the ubiquitin system is involved in the pathogenesis of NP and has a crucial role in it. The ubiquitin system can be involved in the onset or reversal of NP by affecting ion channels, cellular signal transduction, glial cells, and the regulation of non-coding RNAs. This provides new ideas for the treatment of NP. The ubiquitin system may be a new effective target for the treatment of NP. A continued, in-depth understanding of the mechanisms of the ubiquitin system involved in NP could further refine the study of analgesic targets and improve pharmacological studies., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationship., (Copyright © 2024. Published by Elsevier Masson SAS.)

Although previous studies suggest that Piezo2 regulates chronic pain in the orofacial area, few studies have reported the direct evidence of Piezo2's involvement in inflammatory and neuropathic pain in the orofacial region. In this study, we used male Sprague Dawley rats to investigate the role of the Piezo2 pathway in the development of inflammatory and neuropathic pain. The present study used interleukin (IL)-1 β -induced pronociception as an inflammatory pain model. Subcutaneous injection of IL-1 β produced significant mechanical allodynia and thermal hyperalgesia. Subcutaneous injection of a Piezo2 inhibitor significantly blocked mechanical allodynia and thermal hyperalgesia induced by subcutaneously injected IL-1 β . Furthermore, the present study also used a neuropathic pain model caused by the misplacement of a dental implant, leading to notable mechanical allodynia as a consequence of inferior alveolar nerve injury. Western blot analysis revealed increased levels of Piezo2 in the trigeminal ganglion and the trigeminal subnucleus caudalis after inferior alveolar nerve injury. Furthermore, subcutaneous and intracisternal injections of a Piezo2 inhibitor blocked neuropathic mechanical allodynia. These results suggest that the Piezo2 pathway plays a critical role in the development of inflammatory and neuropathic pain in the orofacial area. Therefore, blocking the Piezo2 pathway could be the foundation for developing new therapeutic strategies to treat orofacial pain conditions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Min-Jeong Jo et al.)

Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 50%) of chemotherapy induced peripheral neuropathy in patients. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hanna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell-IgG-FcγR axis is required for the development of neuropathic pain in mice.

Nerve injury can induce aberrant changes in the spine; these changes are due to, or at least partly governed by, transcription factors that contribute to the genesis of neuropathic allodynia. Here, we showed that spinal nerve ligation (SNL, a clinical neuropathic allodynia model) increased the expression of the transcription factor Tbx5 in the injured dorsal horn in male Sprague Dawley rats. In contrast, blocking this upregulation alleviated SNL-induced mechanical allodynia, and there was no apparent effect on locomotor function. Moreover, SNL-induced Tbx5 upregulation promoted the recruitment and interaction of GATA4 and Brd4 by enhancing its binding activity to H3K9Ac, which was enriched at the Trpv1 promotor, leading to an increase in TRPV1 transcription and the development of neuropathic allodynia. In addition, nerve injury-induced expression of Fbxo3, which abates Fbxl2-dependent Tbx5 ubiquitination, promoted the subsequent Tbx5-dependent epigenetic modification of TRPV1 expression during SNL-induced neuropathic allodynia. Collectively, our findings indicated that spinal Tbx5-dependent TRPV1 transcription signaling contributes to the development of neuropathic allodynia via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic allodynia by targeting Tbx5., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Inflammatory arthritis leads to peripheral nerve sensitization, but the therapeutic effect is often unsatisfactory. Our preliminary studies have found that in mice with inflammatory arthritis, the use of ionotropic glutamate receptor antagonists can produce a good analgesic effect without altering foot swelling, suggesting that pain relief may be related to the improvement of neuropathic pain. However, the underlying mechanisms remain unclear. To further investigate the effects of neuropathic pain medications on inflammatory arthritis and the impact of the ionotropic glutamate receptor NR2B subunit (NR2B) on inflammatory arthritis, this study employed gabapentin (GBP) treatment on the inflammatory arthritis mouse model (the adjuvant induced arthritis, AIA), and we found a significant reduction in pain. Further studies revealed that in AIA, the expression levels of NR2B, TRPV1, pain-related molecules (substance P, PGE 2 ), inflammatory cytokines (IL-1, IL-6, TNF-α, and GM-CSF) and Ca 2+ were elevated in the foot and dorsal root ganglia (DRG). GBP treatment was able to influence the downregulation of the expression levels of NR2B, TRPV1, pain-related molecules, inflammatory cytokines and Ca 2+ . Mechanistic studies have shown that GBP treatment affects the downregulation of NR2B, and the downregulation of NR2B expression leads to the downregulation of TRPV1, pain-related molecules and inflammatory cytokines, thereby alleviating pain. These results suggest that in peripheral sensitization caused by AIA, GBP can play a role in improving pain, and NR2B may be a key target of peripheral nerve sensitization induced by inflammatory arthritis. GBP provides a theoretical basis for the clinical treatment of inflammatory arthritis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuropathic pain (NPP) is a devastating and unbearable painful condition. As prevailing treatment strategies have failed to mitigate its complications, there remains a demand for effective therapies. Electroacupuncture (EA) has proved a potent remedial strategy in NPP management in humans and mammals. However, past studies have investigated the underlying mechanism of the analgesic effects of EA on NPP, focusing primarily on adenosine receptors in peripheral tissues. Herein, we elucidate the role of the adenosine (Adora-3) signaling pathway in mediating pain relief through EA in the central nervous system, which is obscure in the literature and needs exploration. Specific pathogen-free (SPF) male adult mice (C57BL/6 J) were utilized to investigate the effect of EA on adenosine metabolism (CD73, ADA) and its receptor activation (Adora-3), as potential mechanisms to mitigate NPP in the central nervous system. NPP was induced via spared nerve injury (SNI). EA treatment was administered seven times post-SNI surgery, and lumber (L4-L6) spinal cord was collected to determine the molecular expression of mRNA and protein levels. In the spinal cord of mice, following EA application, the expression results revealed that EA upregulated ( p < 0.05) Adora-3 and CD73 by inhibiting ADA expression. In addition, EA triggered the release of adenosine (ADO), which modulated the nociceptive responses and enhanced neuronal activation. Meanwhile, the interplay between ADO levels and EA-induced antinociception, using an Adora-3 agonist and antagonist, showed that the Adora-3 agonist IB-MECA significantly increased ( p < 0.05) nociceptive thresholds and expression levels. In contrast, the antagonist MRS1523 exacerbated neuropathic pain. Furthermore, an upregulated effect of EA on Adora-3 expression was inferred when the Adora-3 antagonist was administered, and the EA treatment increased the fluorescent intensity of Adora-3 in the spinal cord. Taken together, EA effectively modulates NPP by regulating the Adora-3 signaling pathway under induced pain conditions. These findings enhance our understanding of NPP management and offer potential avenues for innovative therapeutic interventions.

Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin β3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin β3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin β3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study utilized network pharmacology and docking analyses to explore a groundbreaking therapeutic approach for managing the neuropathic pain and depressive disorder (NP/DD) comorbidity. Schisandra chinensis (SC), a common Chinese medicine, has demonstrated numerous beneficial effects in treating neuropsychological disorders. The main objective of this study was to identify potential bioactive components of SC and investigate their interactions with relevant target genes associated with NP/DD. To gain insights into the underlying molecular mechanisms, GO and KEGG analyses were conducted. Furthermore, molecular docking analysis was employed to validate the therapeutic relevance of SC's active ingredients. Seven bioactive components of SC, namely Longikaurin A, Deoxyharringtonine, Angeloylgomisin O, Schisandrin B, Gomisin A, Gomisin G, and Gomisin R, exhibited effectiveness in the treatment of NP/DD. From this list, the first five components were selected for further analysis. The analyses revealed a complex network of interactions between the targets of SC and NP/DD, providing valuable information about the molecular mechanisms involved in the treatment of NP/DD with SC. SC components demonstrated the ability to regulate pathways involving tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), and other growth hormones (GH). Overall, this study contributes to our understanding of the molecular mechanisms underlying the effects of SC in treating NP/DD. Further investigation is necessary to explore the therapeutic potential of SC as a viable strategy for NP/DD comorbidity. These findings lay a solid foundation for future research endeavors in this field, holding potential implications for the development of novel therapeutic interventions targeting NP/DD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca 2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery., Competing Interests: Competing interests statement:The authors declare no competing interest.

Neuropathic pain (NPP) remains a clinically challenging condition, driven by the activation of spinal astrocytes and the complex release of inflammatory mediators. This study aimed to examine the roles of Rab8a and SNARE complex proteins in activated astrocytes to uncover the underlying mechanisms of NPP. The research was conducted using a rat model with chronic constriction injury (CCI) of the sciatic nerve and primary astrocytes treated with lipopolysaccharide. Enhanced expression of Rab8a was noted specifically in spinal dorsal horn astrocytes through immunofluorescence. Electron microscopy observations showed increased vesicular transport and exocytic activity in activated astrocytes, which was corroborated by elevated levels of inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α detected through quantitative PCR. Western blot analyses confirmed significant upregulation of Rab8a, VAMP2, and Syntaxin16 in these cells. Furthermore, the application of botulinum neurotoxin type A (BONT/A) reduced the levels of vesicle transport-associated proteins, inhibiting vesicular transport in activated astrocytes. These findings suggest that the Rab8a/SNARE pathway in astrocytes enhances vesicle transport and anchoring, increasing the secretion of bioactive molecules that may play a crucial role in the pathophysiology of NPP. Inhibiting this pathway with BONT/A offers a novel therapeutic target for managing NPP, highlighting its potential utility in clinical interventions.

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Purpurin, a natural anthraquinone compound from Rubia tinctorum L., has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of purpurin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess the pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with purpurin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although purpurin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons and restored nerve conduction velocity in sciatic nerves. Notably, the analgesic actions of purpurin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of purpurin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes., Competing Interests: Declaration of Competing interest The authors declare no conflicts of interest in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Neuropathic pain remains a significant unmet medical challenge due to its elusive mechanisms. Recent clinical observations suggest that vitamin D (VitD) holds promise in pain relief, yet its precise mechanism of action is still unclear. This study explores the therapeutical role and potential mechanism of VitD 3 in spared nerve injury (SNI)-induced neuropathic pain rat model., Methods: The analgesic effects and underlying mechanisms of VitD 3 were evaluated in SNI and naïve rat models. Mechanical allodynia was assessed using the Von Frey test. Western blotting, immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the molecular and cellular effects of VitD 3 ., Results: Ferroptosis was observed in the spinal cord following SNI. Intrathecal administration of VitD 3 , the active form of VitD, activated the vitamin D receptor (VDR), suppressed ferroptosis, and alleviated mechanical nociceptive behaviors. VitD 3 treatment preserved spinal GABAergic interneurons, and its neuroprotective effects were eliminated by the ferroptosis inducer RSL3. Additionally, VitD 3 mitigated aberrant mitochondrial morphology and oxidative metabolism in the spinal cord. Mechanistically, VitD 3 inhibited SNI-induced activation of spinal PKCα/NOX4 signaling. Inhibition of PKCα/NOX4 signaling alleviated mechanical pain hypersensitivity, accompanied by reduced ferroptosis and mitochondrial dysfunction in SNI rats. Conversely, activation of PKCα/NOX4 signaling in naïve rats induced hyperalgesia, ferroptosis, loss of GABAergic interneurons, and mitochondrial dysfunction in the spinal cord, all of which were reversed by VitD 3 treatment., Conclusions: Our findings provide evidence that VitD 3 attenuates neuropathic pain by preserving spinal GABAergic interneurons through the suppression of mitochondria-associated ferroptosis mediated by PKCα/NOX4 signaling, probably via VDR activation. VitD, alone or in combination with existing analgesics, presents an innovative therapeutic avenue for neuropathic pain., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aim: We aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism., Methods: Rats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post-injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post-injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord., Results: CLP290 and bumetanide alleviated SCI-associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate-Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K + -Cl - cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na + -K + -Cl - cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non-significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group., Conclusion: Combined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhances GABA A receptor-mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short-term effect., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated., Methods and Results: We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD + ) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD + level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity., Conclusion: The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1β in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1β. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1β, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1β. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain., Competing Interests: Declaration of competing interest The authors have approved the manuscript entitled “Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1β” and agreed with the submission to Neurochemistry International. All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Increasing evidence demonstrated the involvement of microRNAs (miRNAs) in the onset and development of neuropathic pain (NP). Exploring the molecular mechanism underlying NP and identifying key molecules could provide potential targets for the therapy of NP. The function and mechanism of miR-125b-5p in regulating NP have been studied, aiming to find a potential therapeutic target for NP., Methods: NP rat models were established by the chronic constriction injury (CCI) method. The paw withdrawal threshold and paw withdrawal latency were assessed to evaluate the establishment and recovery of rats. Highly aggressive proliferating immortalized (HAPI) micoglia cell, a rat microglia cell line, was treated with lipopolysaccharide (LPS). The M1/M2 polarization and inflammation were evaluated by enzyme-linked immunosorbent assay and western blotting., Results: Decreasing miR-125b-5p and increasing SOX11 were observed in CCI rats and LPS-induced HAPI cells. Overexpressing miR-125b-5p alleviated mechanical allodynia and thermal hyperalgesia and suppressed inflammation in CCI rats. LPS induced M1 polarization and inflammation of HAPI cells, which was attenuated by miR-125b-5p overexpression. miR-125-5p negatively regulated the expression of SOX11 in CCI rats and LPS-induced HAPI cells. Overexpressing SOX11 reversed the protective effects of miR-125b-5p on mechanical pain in CCI rats and the polarization and inflammation in HAPI cells, which was considered the mechanism underlying miR-125b-5p., Conclusion: miR-125b-5p showed a protective effect on NP by regulating inflammation and polarization of microglia via negatively modulating SOX11., (© 2024 Wiley Periodicals LLC.)

Studies indicate that the lysine-specific demethylase 4A (KDM4A), acts as a key player in neuropathic pain, driving the process through its involvement in promoting neuroinflammation. Emerging evidence reveals that C-C Motif Chemokine Ligand 2 (CCL2) participates in neuroinflammation, which plays an important role in the development and maintenance of neuropathic pain. However, it remains unclear if KDM4A plays a role in regulating CCL2 in neuropathic pain. This study found that following spinal nerve transection (SNT) of the lumbar 5 nerve root in rats, the expression of KDM4A and CCL2 increased in the ipsilateral L4/5 dorsal root ganglia (DRG). Injecting KDM4A siRNA into the DRGs of rats post-SNT resulted in a higher paw withdrawal threshold (PWT) and paw-withdrawal latency (PWL) compared to the KDM4A scRNA group. In addition, prior microinjection of AAV-EGFP-KDM4A shRNA also alleviates the decrease in PWT and PWL caused by SNT. Correspondingly, microinjection of AAV-EGFP-KDM4A shRNA subsequent to SNT reduced the established mechanical and thermal hyperalgesia. Furthermore, AAV-EGFP-KDM4A shRNA injection decreased the expression of CCL2 in DRGs. ChIP-PCR analysis revealed that increased binding of p-STAT1 with the CCL2 promoter induced by SNT was inhibited by AAV-EGFP-KDM4A shRNA treatment. These findings suggest that KDM4A potentially influences neuropathic pain by regulating CCL2 expression in DRGs., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Accumulating evidence has demonstrated that M1 microglial polarization and neuroinflammation worsen the development of neuropathic pain. However, the mechanisms underlying microglial activation during neuropathic pain remain incompletely understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), which is a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, plays a crucial role in the regulation of microglial polarization. However, the effect of Mer on microglial polarization during neuropathic pain has not been determined. In this study, western blotting, immunofluorescence analysis, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA) were used to examine the role of Mer in pain hypersensitivity and microglial polarization in rats with chronic constriction injury (CCI) of the sciatic nerve. The results indicated that Mer expression in microglia was prominently increased in the spinal cords of rats subjected to CCI. Furthermore, treatment with recombinant protein S (PS, an activator of Mer) alleviated mechanical allodynia and thermal hyperalgesia, promoted the switch in microglia from the M1 phenotype to the M2 phenotype, and ameliorated neuroinflammation in rats subjected to CCI. However, the use of suppressor of cytokine signalling 3 (SOCS3) siRNA abolished these changes. These results indicated that Mer regulated M1/M2 microglial polarization and neuroinflammation and may be a potential target for treating neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple studies have shown that astrocytes in the medullary dorsal horn (MDH) play an important role in the development of pathologic pain. However, little is known about the structural reorganization of the peripheral astrocytic processes (PAP), the main functional part of the astrocyte, in MDH in neuropathic state. For this, we investigated the structural relationship between PAP and their adjacent presynaptic axon terminals and postsynaptic dendrites in the superficial laminae of the MDH using electron microscopical immunohistochemistry for ezrin, a marker for PAP, and quantitative analysis in a rat model of neuropathic pain following chronic constriction injury of the infraorbital nerve (CCI-ION). We found that, compared to controls, in rats with CCI-ION, (1) the number, % area, surface density, and volume fraction of ezrin-positive (+) PAP, as well as the fraction of synaptic edge apposed by ezrin + PAP and the degree of its coverage of presynaptic axon terminals and postsynaptic dendrites increased significantly, (2) these effects were abolished by administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). These findings indicate that PAP undergoes structural reorganization around the central synapses of sensory afferents following nerve injury, suggest that it may be mediated by mGluR5, and may represent the structural basis for enhancing astrocyte-neuron interaction in neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We investigated the function and molecular mechanism of long non-coding RNA (lncRNA) small nucleolar RNA host gene 16 (Snhg16) in modifying ozone treatment for neuropathic pain (NP) in a mouse model of chronic constriction injury (CCI). Pain-related behavioral responses were evaluated using paw withdrawal threshold (PWT), paw lifting number (PLN), and paw withdrawal latency (PWL) tests. Interleukin (IL)-1β, IL-10, IL-6, and tumor necrosis factor-alpha (TNF-α) were measured by ELISA and qRT-PCR to evaluate neuroinflammation. qRT-PCR was performed to detect expressions of Snhg16, microRNA (miR)-719, sodium voltage-gated channel alpha subunit 1 (SCN1A), and inflammatory factors. Bioinformatics, dual-luciferase reporter assay, and RNA pull-down verified the underlying molecular mechanisms. Snhg16 expression increased in CCI mice. Snhg16 overexpression retarded the curative effect of ozone and induced NP. miR-719 was sponged by Snhg16. SCN1A was a target of miR-719. Inhibition of miR-719 markedly reversed the effects of Snhg16 on pain-related behavioral responses and neuroinflammation. Upregulation of SCN1A partly abrogated the effects of elevated miR-719 levels on the occurrence of NP. The findings demonstrate that lncRNA Snhg16 promotes NP progression in CCI mice by binding to miR-719 to increase SCN1A expression. The Snhg16/miR-719/SCN1A axis may influence the curative effects of ozone therapy in treating NP., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A-Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yong-Jing Gao reports article publishing charges and equipment, drugs, or supplies were provided by STI2030-Major Projects. Yong-Jing Gao reports equipment, drugs, or supplies was provided by the National Natural Science Foundation of China. Ling-Jie Ma reports equipment, drugs, or supplies was provided by the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuropathic pain, a debilitating condition, remains a significant challenge due to the lack of effective therapeutic solutions. This study aimed to evaluate the potential of mesenchymal stromal cell (MSC)-derived conditioned medium in alleviating neuropathic pain induced by sciatic nerve compression injury in adult male rats. Forty Wistar rats were randomly assigned to four groups: control, nerve injury, nerve injury with intra-neural injection of conditioned medium, and nerve injury with intra-neural injection of culture medium. Following sciatic nerve compression, the respective groups received either 10 µl of conditioned medium from amniotic fluid-derived stem cells or an equal volume of control culture medium. Behavioral tests for cold allodynia, mechanical allodynia, and thermal hyperalgesia were conducted, and the spinal cord was analyzed using Western Blot and oxidative stress assays. The behavioral experiments showed a decrease in mechanical hyperalgesia and cold allodynia in the group receiving conditioned medium compared to the injury group and the control medium group. Western blot data revealed a decrease in the expression of the CCL2 protein and an increase in GAD65. Oxidative stress tests also showed increased levels of SOD and glutathione in conditioned media-treated animals compared to animals with nerve injury. The findings suggest that conditioned medium derived from amniotic fluid-derived stem cells can effectively reduce neuropathic pain, potentially through the provision of supportive factors that mitigate oxidative stress and inflammation in the spinal cord., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Disorders of the trigeminal nerve, a sensory nerve of the orofacial region, often lead to complications in dental practice, including neuropathic pain, allodynia, and ectopic pain. Management of these complications requires an understanding of the cytoarchitecture of the trigeminal ganglion, where the cell bodies of the trigeminal nerve are located, and the mechanisms of cell-cell interactions., Highlights: In the trigeminal ganglion, ganglion, satellite, Schwann, and immune cells coexist and interact. Cell-cell interactions are complex and occur through direct contact via gap junctions or through mediators such as adenosine triphosphate, nitric oxide, peptides, and cytokines. Interactions between the nervous and immune systems within the trigeminal ganglion may have neuroprotective effects during nerve injury or may exacerbate inflammation and produce chronic pain. Under pathological conditions of the trigeminal nerve, cell-cell interactions can cause allodynia and ectopic pain. Although cell-cell interactions that occur via mediators can act at some distance, they are more effective when the cells are close together. Therefore, information on the three-dimensional topography of trigeminal ganglion cells is essential for understanding the pathophysiology of ectopic pain., Conclusions: A three-dimensional map of the somatotopic localization of trigeminal ganglion neurons revealed that ganglion cells innervating distant orofacial regions are often apposed to each other, interacting with and potentially contributing to ectopic pain. Elucidation of the complex network of mediators and their receptors responsible for intercellular communication within the trigeminal ganglion is essential for understanding ectopic pain., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Diabetic peripheral neuropathy (DPN) is caused by several factors, including reactive free oxygen radicals (ROS)-induced excessive Ca 2+ influx. Transient receptor potential (TRP) vanilloid 4 (TRPV4) is a member of the Ca 2+ -permeable TRP superfamily. Resveratrol (RESV) has been extensively utilized in TRP channel regulation due to its pharmacological properties, which include antioxidant and TRP inhibitory effects. The protective function of RESV and the contribution of TRPV4 to streptozotocin (STZ)-induced neuropathic pain in mice are still unclear. Here, we evaluated the effects of RESV through the modulation of TRPV4 on Ca 2+ influx, ROS-mediated pain, apoptosis, and oxidative damage in the mouse dorsal root ganglion (DRGs). From the 32 mice, four groups were induced: control, RESV, STZ, and STZ + RESV. We found that the injection of RESV reduced the changes caused by the STZ-induced stimulation of TRPV4, which in turn increased mechanical/thermal neuropathic pain, cytosolic Ca 2+ influx, TRPV4 current density, oxidants (lipid peroxidation, mitochondrial ROS, and cytosolic ROS), and apoptotic markers (caspase-3, -8, and -9). The RESV injection also increased the STZ-mediated reduction of viability of DRG and the amounts of glutathione, glutathione peroxidase, vitamin A, β-carotene, and vitamin E in the brain, erythrocytes, plasma, liver, and kidney. All of these findings suggest that TRPV4 stimulation generates oxidative neurotoxicity, neuropathic pain, and apoptosis in the STZ-induced diabetic mice. On the other hand, neurotoxicity and apoptosis were reduced due to the downregulation of TRPV4 carried out through the RESV injection., (© 2024. The Author(s).)

Brain-derived neurotrophic factor (BDNF) is vital for synaptic plasticity, cell persistence, and neuronal development in peripheral and central nervous systems (CNS). Numerous intracellular signalling pathways involving BDNF are well recognized to affect neurogenesis, synaptic function, cell viability, and cognitive function, which in turn affects pathological and physiological aspects of neurons. Stroke has a significant psycho-socioeconomic impact globally. Central post-stroke pain (CPSP), also known as a type of chronic neuropathic pain, is caused by injury to the CNS following a stroke, specifically damage to the somatosensory system. BDNF regulates a broad range of functions directly or via its biologically active isoforms, regulating multiple signalling pathways through interactions with different types of receptors. BDNF has been shown to play a major role in facilitating neuroplasticity during post-stroke recovery and a pro-nociceptive role in pain development in the nervous system. BDNF-tyrosine kinase receptors B (TrkB) pathway promotes neurite outgrowth, neurogenesis, and the prevention of apoptosis, which helps in stroke recovery. Meanwhile, BDNF overexpression plays a role in CPSP via the activation of purinergic receptors P2X4R and P2X7R. The neuronal hyperexcitability that causes CPSP is linked with BDNF-TrkB interactions, changes in ion channels and inflammatory reactions. This review provides an overview of BDNF synthesis, interactions with certain receptors, and potential functions in regulating signalling pathways associated with stroke and CPSP. The pathophysiological mechanisms underlying CPSP, the role of BDNF in CPSP, and the challenges and current treatment strategies targeting BDNF are also discussed., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats., Methods: Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested., Results: In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region., Conclusion: These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc-EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids., (Copyright © 2024 International Anesthesia Research Society.)