Development Of Neuropathic Pain Research Articles

SIX1 induced HULC modulates neuropathic pain and Schwann cell oxidative stress after sciatic nerve injury

Neuropathic pain is a severe and debilitating condition caused by damage to the peripheral nerve or central nervous system. Although several mechanisms have been identified, the underlying pathophysiology of neuropathic pain is still not fully understood. Unfortunately, few effective therapies are available for this condition. Therefore, there is an urgent need to investigate the underlying mechanisms of neuropathic pain to develop more effective treatments. Long non-coding RNAs (lncRNAs) have recently gained attention due to their potential to modulate protein expression through various mechanisms. LncRNAs have been implicated in many diseases, including neuropathic pain. This study aimed to identify a novel lncRNA involved in neuropathic pain progression. The lncRNA microarray analysis showed that lncRNA Upregulated in Liver Cancer (HULC) was significantly upregulated in spinal cord tissue of sciatic nerve injury (SNI) rats. Further experiments confirmed that HULC promoted neuropathic pain progression and aggravated H2O2-induced Schwann cell injury. Mechanistically, Sine Oculis Homeobox 1 (SIX1) regulated the transcriptional expression of HULC, and both SIX1 and HULC were involved in neuropathic pain and Schwann cell injury. The results of our research indicate the existence of a previously unknown SIX1/HULC axis that plays a significant role in the development and progression of neuropathic pain, shedding light on the complex mechanisms that underlie this debilitating condition. These findings offer novel insights into the molecular pathways involved in neuropathic pain. This study underscores the potential of targeting lncRNAs as a viable approach to alleviate the suffering of patients with neuropathic pain.

Biodegradable nanoparticles targeting circulating immune cells reduce central and peripheral sensitization to alleviate neuropathic pain following spinal cord injury.

Neuropathic pain is a critical source of comorbidity following spinal cord injury (SCI) that can be exacerbated by immune-mediated pathologies in the central and peripheral nervous systems. In this article, we investigate whether drug-free, biodegradable, poly(lactide- co -glycolide) (PLG) nanoparticle treatment mitigates the development of post-SCI neuropathic pain in female mice. Our results show that acute treatment with PLG nanoparticles following thoracic SCI significantly reduces tactile and cold hypersensitivity scores in a durable fashion. Nanoparticles primarily reduce peripheral immune-mediated mechanisms of neuropathic pain, including neuropathic pain-associated gene transcript frequency, transient receptor potential ankyrin 1 nociceptor expression, and MCP-1 (CCL2) chemokine production in the subacute period after injury. Altered central neuropathic pain mechanisms during this period are limited to reduced innate immune cell cytokine expression. However, in the chronic phase of SCI, nanoparticle treatment induces changes in both central and peripheral neuropathic pain signaling, driving reductions in cytokine production and other immune-relevant markers. This research suggests that drug-free PLG nanoparticles reprogram peripheral proalgesic pathways subacutely after SCI to reduce neuropathic pain outcomes and improve chronic central pain signaling.

Descending mechanism by which medial prefrontal cortex endocannabinoid signaling controls the development of neuropathic pain and neuronal activity of dorsal root ganglion.

Although regulation of nociceptive processes in the dorsal horn by deep brain structures has long been established, the role of cortical networks in pain regulation is minimally explored. The medial prefrontal cortex (mPFC) is a key brain area in pain processing that receives ascending nociceptive input and exerts top-down control of pain sensation. We have shown critical changes in mPFC synaptic function during neuropathic pain, controlled by endocannabinoid (eCB) signaling. This study tests whether mPFC eCB signaling modulates neuropathic pain through descending control. Intra-mPFC injection of cannabinoid receptor type 1 (CB1R) agonist WIN-55,212-2 (WIN) in the chronic phase transiently alleviates the pain-like behaviors in spared nerve injury (SNI) rats. By contrast, intra-mPFC injection of CB1R antagonist AM4113 in the early phase of neuropathic pain reduces the development of pain-like behaviors in the chronic phase. Spared nerve injury reduced the mechanical threshold to induce action potential firing of dorsal horn wide-dynamic-range neurons, but this was reversed in rats by WIN in the chronic phase of SNI and by mPFC injection of AM4113 in the early phase of SNI. Elevated dorsal root ganglion neuronal activity after injury was also diminished in rats by mPFC injection of AM4113, potentially by reducing antidromic activity and subsequent neuronal inflammation. These findings suggest that depending on the phase of the pain condition, both blocking and activating CB1 receptors in the mPFC can regulate descending control of pain and affect both dorsal horn neurons and peripheral sensory neurons, contributing to changes in pain sensitivity.

Integrated analysis reveals Atf3 promotes neuropathic pain via orchestrating JunB mediated release of inflammatory cytokines in DRG macrophage

The dorsal root ganglion (DRG) is actively involved in the development of neuropathic pain (NP), serving as an intermediate station for pain signals from the peripheral nervous system to the central nervous system. The mechanism by which DRG is involved in NP regulation is not fully understood. The immune system plays a pivotal role in the physiological and pathological states of the human body. In recent years, the immune system has been thought to play an increasingly important role in the pathogenesis of NP. The immune system plays a key role in pain through specific immune cells and their immune-related genes (IRGs). However, the mechanism by which IRGs of DRG regulate NP action has not been fully elucidated.Here, we performed Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of IRGs in DRG bulk-RNA sequencing data from spared nerve injury (SNI) model mice and found that their IRGs were enriched in many pathways, especially in the immune response pathway. Subsequently, we analyzed single-cell RNA sequencing (scRNA-seq) data from DRGs extracted from the SNI model and identified eight cell populations. Among them, the highest IRG activity was presented in macrophages. Next, we analyzed the scRNA and bulk-sequencing data and deduced five common transcription factors (TFs) from differentially expressed genes (DEGs). The protein-protein interaction (PPI) network suggested that Atf3 and JunB are closely related. In vitro experiments, we verified that the protein and mRNA expressions of Atf3 and JunB were up-regulated in macrophages after lipopolysaccharide (LPS) stimulation. Moreover, the down-regulation of Atf3 reduced the release of inflammatory cytokines and decreased the protein and mRNA expression levels of JunB. The down-regulation of JunB also reduced the release of inflammatory cytokines. Furthermore, overexpression of JunB attenuated the effect of Atf3 down-regulation in reducing the release of inflammatory cytokines. Therefore, we speculated that Atf3 might promote NP through JunB-mediated release of inflammatory factors in DRG macrophages.

Algorithm for multimodal medication therapy in patients with complex regional pain syndrome.

Complex regional pain syndrome (CRPS), previously known as reflex sympathetic dystrophy and causalgia, is a clinical entity characterized by classic neuropathic pain, autonomic involvement, motor symptoms, and trophic changes in the skin, nails, and hair. Although various therapeutic modalities are used to control CRPS-related pain, severe pain due to CRPS often persists and progresses to the chronic phase. In this study, we constructed an algorithm for multimodal medication therapy for CRPS based on the established pathology of CRPS. Oral steroid pulse therapy is recommended for initial pain management in patients with CRPS. Oral steroid therapy can reduce peripheral and central neuroinflammation, contributing to the development of neuropathic pain during the acute and chronic phases. If steroid pulse therapy offers poor relief or is ineffective, treatment to control central sensitization in the chronic phase should be initiated. If pain persists despite all drug adjustments, ketamine with midazolam 2 mg before and after ketamine injection can be administered intravenously to inhibit the N-methyl D-aspartate receptor. If this treatment fails to achieve sufficient efficacy, intravenous lidocaine can be administered for 2 weeks. We hope that our proposed drug treatment algorithm to control CRPS pain will help clinicians appropriately treat patients with CRPS. Further clinical studies assessing patients with CRPS are warranted to establish this treatment algorithm in clinical practice.

The dorsal root ganglion as a target for neurorestoration in neuropathic pain.

Neuropathic pain is a severe and chronic condition widely found in the general population. The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients. During the processing of pain, the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation. Furthermore, the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies. Here, we will review the complex interplay between cells (satellite glial cells and inflammatory cells) and factors (cytokines, neurotrophic factors and genetic factors) that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain. More importantly, we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.

EXPLORING THE PREVALENCE OF NEUROPATHIC HAND PAIN AMONG YOUNG ADULTS AND ITS IMPACT ON HAND FUNCTION

Background and Aims: To explore the prevalence of neuropathic hand pain in young adults and how it affects hand functionality. Methodology: A convenience sampling was used to conduct a cross-sectional study on 192 medical students aged 18 to 28 years from October 2022 to March 2023. The purpose of the study was to evaluate the prevalence of neuropathic hand pain in young adults and how it affects hand functionality. Both the Duruoz Hand Index and the Douleur Neuropathique Four Questionnaire were used. Results: This study included 192 participants, the majority of whom were females (84%) and aged 20-24 years. 16.1% of participants reported having had surgery or an injury to their upper limb in the past. Participants described neuropathic pain symptoms such as electric shocks (21.4%), burning pain (18.2%), and painful cold (15.6%). Limitations and Future Implications: A small sample size and a focus on a particular group of medical students may restrict the generalizability of the findings. To improve the generalizability of the findings, future research should replicate these findings using larger sample sizes and diverse populations. Insights into the development and chronicity of neuropathic hand pain in young adults may also come from longitudinal studies. Conclusion: Our study demonstrates the prevalence of neuropathic hand pain in young adults and how it affects hand functionality. Female participants were more likely to experience pain and functional hand impairments.

Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion.

Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key regulator of the chemotherapy response, as chemotherapy drugs induce PRMT5 expression. However, little is known about the PRMT5-mediated epigenetic mechanisms involved in PTX-induced neuropathic allodynia. Sprague-Dawley rats were intraperitoneally given PTX to induce neuropathic pain. Biochemical analyses were conducted to measure the protein expression levels in the dorsal root ganglion (DRG) of the animals. The von Frey test and hot plate test were used to evaluate nociceptive behaviors. PTX increased the PRMT5 (mean difference [MD]: 0.68, 95% confidence interval [CI], 0.88-0.48; P < .001 for vehicle)-mediated deposition of histone H3R2 dimethyl symmetric (H3R2me2s) at the transient receptor potential vanilloid 1 ( Trpv1 ) promoter in the DRG. PRMT5-induced H3R2me2s recruited WD repeat domain 5 (WDR5) to increase trimethylation of lysine 4 on histone H3 (H3K4me3) at Trpv1 promoters, thus resulting in TRPV1 transcriptional activation (MD: 0.65, 95% CI, 0.82-0.49; P < .001 for vehicle) in DRG in PTX-induced neuropathic pain. Moreover, PTX increased the activity of NADPH oxidase 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 for vehicle), PRMT5-induced H3R2me2s, and WDR5-mediated H3K4me3 in the DRG in PTX-induced neuropathic pain. Pharmacological antagonism and the selective knockdown of PRMT5 in DRG neurons completely blocked PRMT5-mediated H3R2me2s, WDR5-mediated H3K4me3, or TRPV1 expression and neuropathic pain development after PTX injection. Remarkably, NOX4 inhibition not only attenuated allodynia behavior and reversed the above-mentioned signaling but also reversed NOX4 upregulation via PTX. Thus, the NOX4/PRMT5-associated epigenetic mechanism in DRG has a dominant function in the transcriptional activation of TRPV1 in PTX-induced neuropathic pain.

Effect of Aerobic Training and Melatonin Consumption on TNF-α Expression in the Spinal Cord Tissue of Male Rats with Type 1 Diabetes

Background: Neuroinflammation plays a central role in the onset and development of diabetic neuropathic pain. Objectives: This study aims to thoroughly investigate the effects of aerobic training and melatonin on TNF-α expression in rats suffering from diabetic neuropathic pain. Methods: Twenty-five male Wistar rats, aged 8 weeks and weighing 204 ± 11.3 g, were randomly assigned to one of five groups: Diabetic, melatonin-treated diabetic, exercise-trained diabetic, melatonin and exercise-trained diabetic, and control. Diabetes was induced by injecting streptozotocin (STZ) at a dose of 50 mg/kg. After verifying the development of diabetes through a pain perception test, the training group underwent six weeks of continuous aerobic training on a treadmill with an average intensity of 15 meters per minute for 30 minutes. The melatonin groups received a daily dose of 10 mg per kilogram of body weight for 6 weeks. TNF-α expression levels were measured using real-time PCR. Results: The combination of aerobic training and melatonin supplementation significantly decreased TNF-α expression levels (P &lt; 0.05). Additionally, the levels of TNF-α expression were found to be lower in the diabetic group compared to the control group (P &lt; 0.05). Conclusions: It appears that combining aerobic training with melatonin supplementation can regulate TNF-α expression levels and enhance the sensitivity of nociceptors to nociceptive factors resulting from the gradual deterioration of sensory neurons caused by diabetes.

Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206+ myeloid cells

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund’s Adjuvant inflammatory pain model, we show that Pi16-/- mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16-/- mice display reduced macrophage density in the CFA-injected hindpaw. Furthermore, there was a significant bias toward CD206hi (anti-inflammatory) macrophages in the hindpaw and associated dorsal root ganglia. Following CFA, intrathecal depletion of CD206+ macrophages using mannosylated clodronate liposomes promoted sustained pain in Pi16-/- mice. Similarly, an IL-10 neutralizing antibody also promoted sustained CFA pain in the Pi16-/ when administered intrathecally. Collectively, our results point to fibroblast-derived PI16 mediating substantial differences in macrophage phenotype in the pain neuroaxis under conditions of inflammation. The co-expression of PI16 alongside fibroblast markers in human DRG raise the likelihood that a similar mechanism operates in human inflammatory pain states. Collectively, our findings may have implications for targeting fibroblast-immune cell crosstalk for the treatment of chronic pain.

Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway.

MOTS-c, a recently discovered mitochondrial-derived peptide, plays an important role in many physiological and pathological functions via adenosine monophosphate-activated protein kinase (AMPK) activation. Numerous studies have demonstrated that AMPK is an emerging target for the modulation of neuropathic pain. Meanwhile, microglia-activation-evoked neuroinflammation is known to contribute to the development and progression of neuropathic pain. MOTS-c is also known to inhibit microglia activation, chemokine and cytokine expression, and innate immune responses. Accordingly, in this study, we evaluated the effects of MOTS-c on neuropathic pain and investigated the putative underlying mechanisms. We found that MOTS-c levels in plasma and spinal dorsal horn were significantly lower in mice with spared nerve injury (SNI)-induced neuropathic pain than in control animals. Accordingly, MOTS-c treatment produced pronounced dose-dependent antinociceptive effects in SNI mice; however, these effects were blocked by dorsomorphin, an AMPK inhibitor, but not naloxone, a nonselective opioid receptor antagonist. Moreover, intrathecal (i.t.) injection of MOTS-c significantly enhanced AMPKα1/2 phosphorylation in the lumbar spinal cord of SNI mice. MOTS-c also significantly inhibited proinflammatory cytokine production and microglia activation in the spinal cord. The antinociceptive effects of MOTS-c were retained even when microglia activation in the spinal cord was inhibited by minocycline pretreatment, indicating that spinal cord microglia are dispensable for the antiallodynic effects of MOTS-c. In the spinal dorsal horn, MOTS-c treatment inhibited c-Fos expression and oxidative damage mainly in neurons rather than microglia. Finally, in contrast to morphine, i.t. administration of MOTS-c resulted in limited side effects relating to antinociceptive tolerance, gastrointestinal transit inhibition, locomotor function, and motor coordination. Collectively, the present study is the first to provide evidence that MOTS-c may be a promising therapeutic target for neuropathic pain.

Neuron-associated macrophage proliferation in the sensory ganglia is associated with peripheral nerve injury-induced neuropathic pain involving CX3CR1 signaling.

Resident macrophages are distributed across all tissues and are highly heterogeneous due to adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophages in the sensory ganglia, which have been implicated in different conditions, including neuropathic pain development. However, it is still under debate whether macrophage accumulation in the sensory ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or a result of blood monocyte infiltration. Here, we confirmed that the number of macrophages increased in the sensory ganglia after the spared nerve injury (SNI) model in mice. Using different approaches, we found that the increase in the number of macrophages in the sensory ganglia after SNI is a consequence of the proliferation of resident CX3CR1+ macrophages, which participate in the development of neuropathic pain, but not due to infiltration of peripheral blood monocytes. These proliferating macrophages are the source of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation and neuropathic pain development after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner accounting for neuropathic pain development. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain.

Reduction of SIRT1-Mediated Epigenetic Upregulation of Nav1.7 Contributes to Oxaliplatin-Induced Neuropathic Pain

BACKGROUND: Clinically, neuropathic pain is a severe side effect of oxaliplatin chemotherapy, which usually leads to dose reduction or cessation of treatment. Due to the unawareness of detailed mechanisms of oxaliplatin-induced neuropathic pain, it is difficult to develop an effective therapy and limits its clinical use. OBJECTIVES: The aim of the present study was to identify the role of sirtuin 1 (SIRT1) reduction in epigenetic regulation of the expression of voltage-gated sodium channels 1.7 (Nav1.7) in the dorsal root ganglion (DRG) during oxaliplatin-induced neuropathic pain. STUDY DESIGN: Controlled animal study. SETTING: University laboratory. METHODS: The von Frey test was performed to evaluate pain behavior in rats. Real-time quantitative polymerase chain reaction, western blotting, electrophysiological recording, chromatin immunoprecipitation, and small interfering RNA (siRNA) were used to illustrate the mechanisms. RESULTS: In the present study, we found that both the activity and expression of SIRT1 were significantly decreased in rat DRG following oxaliplatin treatment. The activator of SIRT1, resveratrol, not only increased the activity and expression of SIRT1, but also attenuated the mechanical allodynia following oxaliplatin treatment. In addition, local knockdown of SIRT1 by intrathecal injection of SIRT1 siRNA caused mechanical allodynia in naive rats. Besides, oxaliplatin treatment enhanced the action potential firing frequency of DRG neurons and the expression of Nav1.7 in DRG and activation of SIRT1 by resveratrol reversed this effect. Furthermore, blocking Nav1.7 by ProTx II (a selective Nav1.7 channel blocker) reversed oxaliplatin-induced mechanical allodynia. In addition, histone H3 hyperacetylation at the Nav1.7 promoter in DRG of rats following oxaliplatin treatment was significantly suppressed by activation of SIRT1 with resveratrol. Moreover, both the expression of Nav1.7 and histone H3 acetylation at the Nav1.7 promoter were upregulated in the DRG by local knockdown of SIRT1 with SIRT1 siRNA in naive rats. LIMITATIONS: More underlying mechanism(s) of SIRT1 reduction after oxaliplatin treatment needs to be explored in future research. CONCLUSIONS: These findings suggest that reduction of SIRT1-mediated epigenetic upregulation of Nav1.7 in the DRG contributes to the development of oxaliplatin-induced neuropathic pain in rats. The intrathecal drug delivery treatment of activating SIRT1 might be a novel therapeutic option for oxaliplatin-induced neuropathic pain. KEY WORDS: SIRT1, neuropathic pain, dorsal root ganglion, NAV1.7 voltage-gated sodium channel, oxaliplatin

Incidence of Chronic Pain following Oral Soft Tissue Biopsies: A Retrospective Study

Soft tissue oral biopsies (STOB) are commonly performed in the medical field to obtain tissue samples for diagnostic purposes. However, like all invasive procedures, these biopsies may carry risks, such as the development of chronic long-lasting neuropathic pain. This study aims to examine the occurrence of chronic pain following STOBs. A retrospective study was conducted on the medical records of 695 patients who underwent STOBs at the Maxillofacial Surgery Department of Hadassah Medical Center between the years 2013 and 2022. Demographic information, details of the procedure, histopathological diagnosis, and data related to post-procedure pain in the biopsy area were collected and analyzed. Out of the 695 patients, only 4 reports of chronic pain with mild intensity lasting more than three months following oral biopsy were documented, with incidence rate of 0.57%; all were females with a median age of 59 ± 2.0 years. The biopsies were taken from various sites and the common diagnoses were lichen planus, venous malformation, and fibromas. In conclusion, chronic pain after oral soft-tissue biopsies is rare, generally mild, and typically does not require extra therapy. These insights can aid clinicians and patients in making informed decisions about these procedures.

High-throughput transcriptome sequencing reveals the critical role of long non-coding RNA Gm14376 in the occurrence of neuropathic pain

Long noncoding RNAs (lncRNAs) have been suggested as important regulators in neuropathic pain. Our study aims to explore the possible molecular mechanism underlying the role of long non-coding RNA (lncRNA) Gm14376 in neuropathic pain in mice by high-throughput transcriptome sequencing. A mouse model of spared nerve injury (SNI) was constructed for mechanical, thermal and spontaneous pain testing. Transcriptomic changes in lncRNAs and mRNAs in the dorsal root ganglion (DRG) of SNI mice were analyzed using RNA-sequencing techniques in conjunction with public data analysis. AAV5 viral vector was constructed to assess the effect of Gm14376 on SNI-induced pain hypersensitivity and inflammatory response. Cis-target genes of Gm14376 were obtained and the functions of Gm14376 were analyzed by GO and KEGG pathway enrichment analyses. Results from bioinformatic analysis identified a conserved Gm14376, which was up-regulated in the DRG of SNI mice, specifically in response to nerve injury. Overexpression of Gm14376 in DRG induced neuropathic pain-like symptoms in mice. Furthermore, the functions of Gm14376 were related to the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and fibroblast growth factor 3 (Fgf3) was identified as the cis-target gene of Gm14376. Gm14376 could directly up-regulate Fgf3 expression to activate the PI3K/Akt pathway, which alleviated pain hypersensitivity to mechanical and thermal stimuli and reduced the release of inflammatory factors in SNI mice. From our data, we conclude that SNI-induced up-regulation of Gm14376 expression in DRG activates the PI3K/Akt pathway through up-regulation of Fgf3 expression, thereby promoting the development of neuropathic pain in mice.

Insulin-like Growth Factor-1 (IGF-1) Related Drugs in Pain Management.

Objective. The aim of this review is to explore the role of IGF-1 and IGF-1R inhibitors in pain-related conditions and assess the effectiveness of IGF-1-related drugs in pain management. Specifically, this paper investigates the potential involvement of IGF-1 in nociception, nerve regeneration, and the development of neuropathic pain. Methods. We conducted a search of the PUBMED/MEDLINE database, Scopus, and the Cochrane Library for all reports published in English on IGF-1 in pain management from origination through November 2022. The resulting 545 articles were screened, and 18 articles were found to be relevant after reading abstracts. After further examination of the full text of these articles, ten were included in the analysis and discussion. The levels of clinical evidence and implications for recommendations of all the included human studies were graded. Results. The search yielded 545 articles, of which 316 articles were deemed irrelevant by reading the titles. There were 18 articles deemed relevant after reading abstracts, of which 8 of the reports were excluded due to lack of IGF-1-related drug treatment after reviewing the full text of the articles. All ten articles were retrieved for analysis and discussion. We found that IGF-1 may have several positive effects on pain management, including promoting the resolution of hyperalgesia, preventing chemotherapy-induced neuropathy, reversing neuronal hyperactivity, and elevating the nociceptive threshold. On the other hand, IGF-1R inhibitors may alleviate pain in mice with injury of the sciatic nerve, bone cancer pain, and endometriosis-induced hyperalgesia. While one study showed marked improvement in thyroid-associated ophthalmopathy in humans treated with IGF-1R inhibitor, two other studies did not find any benefits from IGF-1 treatment. Conclusions. This review highlights the potential of IGF-1 and IGF-1R inhibitors in pain management, but further research is needed to fully understand their efficacy and potential side effects.

MG53 ameliorates nerve injury induced neuropathic pain through the regulation of Nrf2/HO-1 signaling in rats

Neuropathic pain is one of the most common types of chronic pain, and it arises as a direct consequence of a lesion or disease that affects the somatosensory system. Mitsugumin53 (MG53), which is a member of the TRIM family of proteins and is known as TRIM72, exerts protective effects on muscle, lung, kidney, brain, and other cells or tissues. Recently, increasing evidence has indicated that MG53 plays a vital role in regulating neuroinflammation and oxidative stress. However, the relationship between MG53 and neuropathic pain is unclear. In this study, we aimed to explore the role of MG3 in neuropathic pain after chronic constriction injury (CCI) to the sciatic nerve in rats. To explore the mechanism of MG53 regulating the development of neuropathic pain, the rats was injected (intrathecal injection) of recombinant human MG53 (rhMG53) protein and/or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA after CCI. Mechanical allodynia or thermal hyperalgesia was assessed by the 50% paw withdrawal threshold (PWT) or the paw withdrawal latency (PWL). The target molecules was detected using western blotting (WB), immunofluorescence (IF), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), biochemical evaluations, and Dihydroethidium (DHE) staining. The results indicated that the expression level of MG53 in the spinal cord was increased after CCI in rats. Moreover, intrathecal injection with rhMG53 protein notably alleviated CCI-induced mechanical allodynia, thermal hyperalgesia, neuroinflammation，oxidative stress and the increased level of reactive oxygen species (ROS) via activation of the Nrf2/heme oxygenase-1 (HO-1) signaling pathway. However, administration of Nrf2 siRNA abrogated the analgesic, anti-inflammatory and antioxidant effects of rhMG53 in CCI model rats. Our study demonstrated that MG53 improved neuropathic pain, neuroinflammation, and oxidative stress via activation of the Nrf2/HO-1 signaling pathway in the spinal cord of CCI model rats, which suggested that MG53 may serve as a new target for the treatment of neuropathic pain.

Downregulation of ciRNA-Kat6b in dorsal spinal horn is required for neuropathic pain by regulating Kcnk1 in miRNA-26a-dependent manner.

Nerve injury-induced maladaptive changes in gene expression in the spinal neurons are essential for neuropathic pain genesis. Circular RNAs (ciRNA) are emerging as key regulators of gene expression. Here, we identified a nervous-system-tissues-specific ciRNA-Kat6 with conservation in humans and mice. We aimed to investigate whether and how spinal dorsal horn ciRNA-Kat6b participates in neuropathic pain. Unilateral sciatic nerve chronic constrictive injury (CCI) surgery was used to prepare the neuropathic pain model. The differentially expressed ciRNAs were obtained by RNA-Sequencing. The identification of nervous-system-tissues specificity of ciRNA-Kat6b and the measurement of ciRNA-Kat6b and microRNA-26a (miRNA-26a) expression level were carried out by quantitative RT-PCR. The ciRNA-Kat6b that targets miRNA-26a and miRNA-26a that targets Kcnk1 were predicted by bioinformatics analysis and verified by in vitro luciferase reports test and in vivo experiments including Western-blot, immunofluorescence, and RNA-RNA immunoprecipitation. The correlation between neuropathic pain and ciRNA-Kat6b, miRNA-26a, or Kcnk1 was examined by the hypersensitivity response to heat and mechanical stimulus. Peripheral nerve injury downregulated ciRNA-Kat6b in the dorsal spinal horn of male mice. Rescuing this downregulation blocked nerve injury-induced increase of miRNA-26a, reversed the miRNA-26a-triggered decrease of potassium channel Kcnk1, a key neuropathic pain player, in the dorsal horn, and alleviates CCI-induced pain hypersensitivities. On the contrary, mimicking this downregulation increased the miRNA-26a level and decreased Kcnk1 in the spinal cord, resulting in neuropathic pain-like syndrome in naïve mice. Mechanistically, the downregulation of ciRNA-Kat6b reduced the accounts of miRNA-26a binding to ciRNA-Kat6b, and elevated the binding accounts of miRNA-26a to the 3' untranslated region of Kcnk1 mRNA and degeneration of Kcnk1 mRNA, triggering in the reduction of KCNK1 protein in the dorsal horn of neuropathic pain mice. The ciRNA-Kat6b/miRNA-26a/Kcnk1 pathway in dorsal horn neurons regulates the development and maintenance of neuropathic pain, ciRNA-Kat6b may be a potential new target for analgesic and treatment strategies.

REPRINTED WITH PERMISSION OF EFIC EJP: 27 (2023): 4453: A systematic review and meta-analysis of neuropathicpain associated with coronavirus disease 2019

&lt;br&gt;&lt;b&gt;Background and objective:&lt;/b&gt; Neuropathic pain is an occasionally reported complication of coronavirus disease 2019(COVID-19) that has received increased attention in scientific literature. In this systematic review and meta-analysis, weaimed to provide information on the frequency of neuropathic pain associated with COVID-19.&lt;/br&gt;&lt;br&gt;&lt;b&gt;Databases and data treatment:&lt;/b&gt; We systematically reviewed and analysed literature regarding neuropathic pain associatedwith COVID-19. Literature searches were conducted in PubMed, EMBASE and Cochrane Library databases. We consideredprospective and retrospective studies published up until September 2022 (limitations included English language, full-textpublications and studies including at least 10 patients). A random effects meta-analysis was performed and heterogeneityand publication bias were assessed.&lt;/br&gt;&lt;br&gt;&lt;b&gt;Results:&lt;/b&gt; We identified 149 studies. We included 17 studies in the systematic review, and six studies reporting the frequencyof neuropathic pain in the acute/ subacute phase of COVID-19 in the meta-analysis. The estimated frequency of neuropathicpain ranged between 0.4 and 25%. Forest plot analysis showed that the random effect overall frequency was 10% (95%confidence interval: 515%), with a high level of heterogeneity (Chi&lt;sup&gt;2&lt;/sup&gt; = 104; Tau&lt;sup&gt;2&lt;/sup&gt; = 0.004; df = 5; I&lt;sup&gt;2&lt;/sup&gt; = 95%; test for overalleffect: Z = 3.584; p &lt; 0.0005). The overall risk of bias was moderate in all studies selected, particularly due to the poordescription of neuropathic pain diagnostic criteria.&lt;/br&gt;&lt;br&gt;&lt;b&gt;Conclusions:&lt;/b&gt; The pooled estimated frequency of neuropathic pain associated with COVID-19 should be considered withcaution due to the high heterogeneity across studies and the poor description of the neuropathic pain diagnostic criteriaapplied.&lt;/br&gt;&lt;br&gt;&lt;b&gt;Significance:&lt;/b&gt; Emerging evidence supports the development of neuropathic pain as a complication of COVID-19. However,longitudinal studies enrolling consecutive patients with COVID-19 that detail the diagnostic criteria for neuropathic pain areneeded to better assess the frequency of this condition.&lt;/br&gt;

The potential effects of untreated sleep-related breathing disorders on neuropathic pain, spasticity, and cardiovascular dysfunction following spinal cord injury: A cross-sectional prospective study protocol.

Sleep-related breathing disorders (SRBDs), neuropathic pain, spasticity and cardiovascular autonomic dysfunction are common after spinal cord injury (SCI). Prior studies suggest that systemic inflammation following SCI may be implicated in the development of neuropathic pain, spasticity and cardiovascular dysfunction. Given that SRBDs also cause a systemic inflammatory response, we hypothesized that individuals with SCI who develop more severe SRBDs would experience more intense neuropathic pain, more severe spasticity and more significant cardiovascular autonomic dysfunction. This cross-sectional prospective study will explore the previously understudied hypothesis that SRBDs are associated with increased neuropathic pain, spasticity, and cardiovascular autonomic dysfunction in adult individuals with low-cervical/high-thoracic (injury level at C5 to T6), complete/incomplete (ASIA Impairment Scale A, B, C or D) SCI. To our knowledge, no prior study has addressed this clinically relevant question on whether the degree of SRBDs affects the intensity of neuropathic pain, spasticity, and cardiovascular autonomic dysfunction in individuals with SCI. We anticipate that the results of this original study will provide key information for a future clinical trial on the use of continuous positive airway pressure (CPAP) therapy for moderate-to-severe SRBDs, which may better control neuropathic pain, spasticity, and cardiovascular autonomic dysfunction among individuals with SCI. The research protocol for this study was registered in the ClinicalTrials.gov website (NCT05687097). https://clinicaltrials.gov/ct2/show/NCT05687097.