Search Results (267)

Background: Lower phylogenetic species are known to rebuild cut-off caudal parts with regeneration of the central nervous system (CNS). In contrast, CNS regeneration in higher vertebrates is often attributed to immaturity, although this has never been conclusively demonstrated. The emergence of stem cells and their effective medical applications has intensified research into spinal cord regeneration. However, despite these advances, the impact of clinical trials involving spinal cord-injured (SCI) patients remains disappointingly low. Long-distance regeneration has yet to be proven. Methods: Our study involved a microsurgical dorsal myelotomy in fetal rats. The development of pioneering long primary afferent axons during early gestation was examined long after birth. Results: A single cut triggered the intrinsic ability of the dorsal root ganglion (DRG) neurons to reprogram. Susceptibility to hypoxia caused the axons to stop developing. However, the residual axonal outgrowth sheds light on the intriguing temporal and spatial events that reveal long-distance CNS regeneration. The altered phenotypes displayed axons of varying lengths and different features, which remained visible throughout life. The previously designed developmental blueprint was crucial for interpreting these enigmatic features. Conclusions: This research into immaturity enabled the exploration of the previously impenetrable domain of early life and the identification of a potential missing link in CNS regeneration research. Central axon regeneration appeared to occur much faster than is generally believed. The paradigm provides a challenging approach for exhaustive intrauterine reprogramming. When the results demonstrate pre-clinical effectiveness in CNS regeneration research, the transformational impact may ultimately lead to improved outcomes for patients with spinal cord injuries. Full article

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

This review explores current and emerging neuromodulation techniques targeting the cardiac autonomic nervous system for the treatment and prevention of atrial and ventricular arrhythmias. Arrhythmias remain a significant cause of morbidity and mortality, with the autonomic nervous system playing a crucial role in arrhythmogenesis. Interventions span surgical, pharmacological, and bioelectronic methods. We discuss the range of neuromodulation methods targeting the stellate ganglion, the spinal region, the parasympathetic system, and other promising methods. These include stellate ganglion block, stellate ganglion ablation, cardiac sympathetic denervation, subcutaneous electrical stimulation, thoracic epidural anesthesia, spinal cord stimulation, dorsal root ganglion stimulation, vagus nerve stimulation, baroreflex activation therapy, carotid body ablation, renal denervation, ganglionated plexi ablation, acupuncture, and transcutaneous magnetic stimulation. Both preclinical and clinical studies are presented as evidence for arrhythmia management. Full article

Neuropathic pain (NP) is a prevalent clinical condition resulting from diseases or injuries affecting the somatosensory system. Conventional analgesics often exhibit limited efficacy, leading to suboptimal therapeutic outcomes. The pathogenesis of NP is complex and involves multiple mechanisms. The existing evidence suggests that maladaptive neuronal plasticity plays a central role in NP development. Additionally, emerging research highlights the contribution of neuroinflammatory responses mediated by glial cells in the onset of NP and associated sensory hypersensitivity. Among non-invasive neuromodulation techniques, transcranial direct current stimulation (tDCS) has gained prominence as a potential treatment for NP. Numerous studies have demonstrated its analgesic effects; however, the precise regulatory mechanisms remain unclear. The current evidence indicates that tDCS may alleviate NP by enhancing glial–neuronal interactions, which suppress nociceptive signaling pathways and reduce pain sensitivity. The reciprocal modulation between tDCS-mediated anti-inflammatory actions, as evidenced by decreased levels of pro-inflammatory cytokines and increased levels of anti-inflammatory mediators, and its facilitation of adaptive neural plasticity represents a particularly compelling therapeutic axis. This review elucidates inflammatory regulation by tDCS as a fundamental mechanism for NP alleviation, while delineating important unresolved questions regarding these complex interactions. Full article

Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article

Schwann cells (SCs) play a crucial role in peripheral nerve repair by supporting axonal regeneration and remyelination. While extensive research has been conducted using rodent SCs, increasing attention is being directed toward human SCs due to species-specific differences in phenotypical and functional properties, and accessibility of human SCs derived from diverse sources. A major challenge in translating SC-based therapies for nerve repair lies in the inability to replicate human SC myelination in vitro, posing a significant obstacle to drug discovery and preclinical research. In this study, we compared the myelination capacity of human, rodent, and porcine SCs in various co-culture conditions, including species-matched and cross-species neuronal environments in a serum-free medium. Our results confirmed that rodent and porcine SCs readily myelinate neurites under standard culture conditions after treatment with ascorbic acid for two weeks, whereas human SCs, at least within the four-week observation period, failed to show myelin staining in all co-cultures. Furthermore, we investigated whether cell culture manipulation impairs human SC myelination by transplanting freshly harvested and predegenerated human nerve segments into NOD-SCID mice for four weeks. Despite supporting host axonal regeneration into the grafts, human SCs exhibited very limited myelination, suggesting an intrinsic species-specific restriction rather than a cell culture-induced defect. These observations suggest fundamental differences between human and rodent SCs and highlight the need for human-specific models and protocols to advance our understanding of SC myelination. Full article

Postamputation pain (PAP), including residual limb pain (RLP) and phantom limb pain (PLP), remains a significant and debilitating complication after limb loss. Despite advances in pharmacological management, many patients experience inadequate pain relief, underscoring the need for alternative therapeutic strategies. Objective: This narrative review critically synthesizes current interventional therapies for PAP, focusing on mechanisms, clinical efficacy and practical application. Methods: A literature search was conducted in PubMed, EMBASE, Scopus and Web of Science databases for studies published between 2015 and 2025. Relevant articles on peripheral nerve interventions as well as different neuromodulation techniques were included. Results: Peripheral interventions (such as alcohol neurolysis, radiofrequency ablation (RFA) and cryoneurolysis (CNL)) and neuromodulation techniques (including spinal cord stimulation (SCS), dorsal root ganglion (DRG) stimulation and cauda equina stimulation (CES)) demonstrate promising outcomes for PAP. Peripheral nerve stimulation (PNS) shows favorable safety and efficacy profiles and may help prevent the chronification of pain. Conclusions: Contemporary interventional therapies represent valuable options in the multidisciplinary management of PAP. Nevertheless, further research is required to standardize clinical algorithms, optimize therapeutic decision-making and improve long-term outcomes and quality of life for individuals with PAP. Full article

Nerve injury caused by chemotherapy drugs is a common side effect. How to reduce this kind of nerve injury and promote neuron recovery is of great significance. In this study, we found that tumor necrosis factor-α (TNF-α) promoted the recovery of dorsal root ganglion (DRG) neuron from cisplatin-induced injury. On DRG neurons cultured in vitro, we found that TNF-α promoted neurite regeneration after cisplatin injury. In addition, TNF-α accelerated the removal of DNA damage and promoted the regeneration of mitochondria on DRG neurons. Study of the mechanism showed that this effect of TNF-α was independent from the NGF signaling pathway and occurred mostly through the activation of TNFR2 receptors, together with nucleus translocation of p65 and upregulation of NF-κB expression. This study provides a new theoretical basis and therapeutic strategy for the treatment of nerve injury caused by chemotherapy drugs. Full article

Background/Objectives: Fabry disease (FD) is a lysosomal storage disorder often associated with early-onset neuropathic pain, attributed to small fibre neuropathy (SFN). The dorsal root ganglion (DRG) has emerged as a critical site of early pathophysiological involvement in FD, with structural and functional alterations implicated in the development of neuropathic symptoms. This exploratory study introduces DRG proton density (DRG-PD) as a novel MRI-derived biomarker and evaluates its association with SFN. Methods: Eighty genetically confirmed FD patients underwent high-resolution 3T MRI with DRG-PD quantification at the lumbosacral levels L5 and S1. DRG-PD was derived from B1-corrected multi-echo spin echo sequences and normalised to cerebrospinal fluid intensity. All patients underwent clinical, biochemical and histological evaluation to determine SFN status. Associations between DRG imaging parameters and clinical variables were analysed using correlation and regression models. Diagnostic performance was evaluated using receiver operating characteristic curve analysis. Results: DRG-PD values were significantly increased in patients with classical FD and SFN, demonstrating a large effect size (Cliff’s δ = 0.92) and excellent discriminatory performance (AUC = 0.96). In contrast, DRG volume and T2 relaxation time were not significantly associated with SFN status. DRG-PD remained an independent predictor of SFN in multivariable logistic regression (p = 0.019). Conclusions: DRG-PD is a non-invasive correlate of SFN in classical FD. It may provide superior diagnostic value compared to existing MRI metrics and reflects proximal ganglionic pathology not captured by distal histological assessments. Full article

Oligodendrocytes form myelin in the central nervous system, and their dysfunction can cause severe neurological symptoms, as large-scale analyses have highlighted numerous gene expression alterations in pathological conditions. Although in vivo functional gene analyses are preferable, they have several limitations, especially in large-scale studies. Therefore, standardized in vitro systems are needed to facilitate efficient and reliable functional analyses of genes identified in such studies. Here, we describe a practical and efficient method for oligodendrocyte precursor cell (OPC) isolation from mouse brains on postnatal day 6–8 and a gene delivery method for the isolated OPCs. By modifying the magnetic-activated cell sorting (MACS) procedure with reduced processing volumes, we simplified OPC isolation, allowing simultaneous handling of multiple samples and improving workflow efficiency. We also optimized electroporation parameters to achieve robust transfection efficiency with minimal cell death. Transfected OPCs are suitable for both monoculture-based differentiation assays and co-culture with dorsal root ganglion (DRG) explants, in which they reliably differentiate into mature oligodendrocytes and myelinate along the axons. This system enables stable and reproducible in vitro analysis of oligodendrocyte function, supports investigations into both intrinsic differentiation and neuron–glia interactions, and provides a powerful platform for oligodendrocyte research with efficient and timely gene manipulation. Full article

Aging is associated with altered itch perception, potentially due to changes in neuronal function and pruriceptive signaling. The underlying mechanisms, however, remain unclear. We investigated age-related differences in itch sensitivity at behavioral, cellular, and molecular levels. Young and old mice were intradermally injected with various pruritogens, including small molecules (histamine, chloroquine, and serotonin) and peptides (BAM8–22, AY-NH₂, and SLIGRL-NH₂). Scratching behavior and mechanical itch sensitivity were assessed, and calcium imaging was used to evaluate sensory neuron responses in the dorsal root ganglia. Additionally, immunofluorescence staining was performed to analyze the expression of TRPV1 and Cav3.2. Old mice exhibited reduced scratching behavior following injections, and their neuronal responses to histamine and chloroquine were diminished. Although all treated groups showed increased mechanical alloknesis, the effect was less pronounced in old animals. The expression of TRPV1 and Cav3.2 was also reduced in dorsal root ganglia neurons of old mice. These findings suggest that aging impairs both functional responsiveness and molecular signaling in sensory neurons, contributing to reduced chemical itch sensitivity in aged individuals. Full article

The presence of dichotomizing neurons in the dorsal root ganglia (DRG) of cattle, innervating both the reticulum and the withers, may indicate a pre-spinal convergence of visceral and cutaneous sensory information, i.e., that the DRG primary sensory neurons may elaborate the sensory information coming from two different anatomical areas before reaching the secondary sensory neurons within the spinal cord. This anatomical feature could be the underlying basis for the cutaneous allodynia observed in traumatic reticuloperitonitis, also known as the “Kalchschmidt pain test”. The aim of the study was to identify the DRG primary sensory neurons innervating the reticulum and the withers by using two different retrograde fluorescent tracers, Fast Blue (FB, affinity for cytoplasm) and Diamidino Yellow (DY, affinity for nucleus). In two anesthetized calves, FB and DY were injected into the reticulum and skin of the withers, respectively. At the end of the experimental period, the calves were deeply anesthetized and then euthanatized. The thoracic (T1–T8) DRG were collected and processed to obtain cryosections which were examined on a fluorescent microscope. A large number of neurons localized, especially in the T7 DRG, presented nuclei labeled with DY. On the contrary, only a few neurons localized exclusively in T6 and T7 DRG presented the cytoplasm labeled with FB. No neurons displayed FB and DY simultaneously within the cytoplasm and nucleus, respectively. The absence of double-labeled DRG neurons suggests that the convergence of visceral and somatic sensory inputs underlying the Kalchschmidt pain response likely does not occur at the level of individual DRG neurons. Rather, it may involve higher-order integrative centers, possibly including vagal pathways and brainstem nuclei which integrate the afferent information to coordinate respiratory movements of the diaphragm, intercostal muscles, and larynx. Although limited by the sample size, this case study provides a neuroanatomical basis for further investigation into central mechanisms of referred visceral pain in cattle. Full article

Fibromyalgia, one of the most challenging pains to treat, lacks impartial considerations for diagnosis and useful assessment. The core symptoms are persistent extensive pain accompanied by fatigue, psychological disorders, sleep disturbance, and obesity. This study aims to explore the role of cannabinoid receptor 1 (CB1) on transient receptor potential V1 (TRPV1) signaling pathways in a mouse model of fibromyalgia. This model was subjected to intermittent cold stress (ICS) to induce fibromyalgia, as measured by the nociceptive behavior determined by von Frey and Hargreaves’ tests. Our results showed a lower mechanical threshold (2.32 ± 0.12 g) and thermal latency (4.14 ± 0.26 s) in ICS-induced fibromyalgia mice. The hyperalgesia could be alleviated by 2 Hz electroacupuncture (EA) or by TRPV1 knockout. We found decreased CB1 receptors, upregulated TRPV1, and related kinases in the dorsal root ganglion, spinal cord, hypothalamus, and periaqueductal gray in fibromyalgia mice. EA reversed these effects associated with fibromyalgia, aligning with observations in Trpv1^−/− mice. Peripheral acupoint or the intracerebral ventricle injection of a CB1 agonist significantly attenuated mechanical and thermal hyperalgesia. The EA analgesic effect was reversed by a CB1 antagonist injection, suggesting the involvement of the CB1 signaling pathway. The accurate chemogenetic activation of paraventricular nucleus (PVN), which is a structure of the hypothalamus, initiated fibromyalgia pain. The chemogenetic inhibition of PVN attenuated fibromyalgia pain via the downregulation of TRPV1 pathway. Our discoveries shed light on the involvement of CB1 in the TRPV1 signaling pathway in the effects of EA in fibromyalgia, suggesting its potential as a treatment target. Full article

Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus for which effective treatments remain undeveloped. Metabolic changes and inflammation are proposed as primary mechanisms underlying DPN pathogenesis. Our previous studies demonstrate that exogenous pyruvate plays a crucial role in maintaining glycolysis-tricarboxylic acid cycle flux under high-glucose conditions and also exhibits anti-inflammatory properties. To evaluate its therapeutic potential, we assessed whether pyruvate administration could restore DPN in vivo and in vitro. We assessed casual blood glucose levels, body weight, motor and sensory nerve conduction velocities, mechanical sensitivity, and intraepidermal nerve fiber density in streptozotocin-induced diabetic C57/BL/6J mice that received drinking water with or without sodium pyruvate (10 mg/mL) from 2 to 13 weeks after diabetes induction. In addition, we evaluated neurite length in ND7/23 cells, a dorsal root ganglion neuron cell line, under high-glucose conditions. Pyruvate administration in diabetic mice alleviated mechanical sensitivity deficits and improved intraepidermal nerve fiber density. Additionally, neurite length in ND7/23 cells was inhibited under high-glucose conditions but was fully restored by supplementation with high concentrations (10 mM) of pyruvate. These findings suggest that exogenous pyruvate may be a promising therapeutic candidate for DPN. Full article

As a subtype of voltage-gated sodium channel and predominantly expressed in the sensory neurons located in the dorsal root ganglion (DRG), the Nav1.8 channel encoded by the SCN10A gene is found to have different variants in patients suffering chronic pain or insensitivity to pain due to the gain-of-function or loss-of-function of Nav1.8 channels. In animal models of chronic pain, Nav1.8 is also verified to be involved, suggesting that Nav1.8 may be a potential target for treatment of chronic pain. Another voltage-gated sodium channel, Nav1.7, is also proposed to be a target for chronic pain, supported by clinical findings in patients and laboratory animal models; however, there is no Nav1.7-specific drug that has passed clinical trials, although they demonstrated satisfactory effects in laboratory animals. This discrepancy between clinical and preclinical studies may be related to the differences between humans and laboratory animals or due to the degeneracy in different sodium channels governing the DRG neuronal excitability, which is thought of as the underlying machinery of chronic pain and mostly studied. This review summarizes recent findings of Nav1.8 in chronic pain from clinics and laboratories and discusses the difference, which may be helpful for future investigation of Nav1.8 in chronic pain, considering the dilemma of the Nav1.7 channel in chronic pain. Full article