Search Results (235)

One of most important parts of the female genital tract is the uterine cervix, both from the anatomical as well as physiological points of view. As there is currently a lack of detailed information on the presence, distribution pattern(s), and the chemical coding of phoenixin (PNX)-containing dorsal root ganglia (DRG) neurons supplying the porcine uterine cervix, this study, using combined retrograde tracing and double-immunofluorescence techniques, was aimed at analyzing (i) the distribution pattern of uterine cervix-supplying sensory neurons (UC-SNs) at the particular spinal cord levels, (ii) their intraganglionic distribution, and (iii) the patterns of PNX co-expression with other biologically active substances. UC-SNs were identified by the presence of deposits of Fast Blue (FB), in DRG of thoracic (Th10–Th15), lumbar (L1–L5) and sacral (S2–S4) spinal cord segments. FB⁺/PNX⁺ neurons constitute approximately 33% of all UC-SNs, 73% at the L, and 27% at the S neuromeres. These neurons were mainly small sized (52%), with a slightly smaller population of medium-sized cells (40%), while large-diameter cells made up the least numerous population (8%). The vast majority of FB⁺/PNX⁺ neurons simultaneously contained calcitonin gene-related peptide (CGRP; 80.9%) or substance P (SP; 77.9%); one-third of them showed immunoreactivity toward neuronal nitric oxide synthase (nNOS; 34%), while PNX⁺ UC-SNs containing pituitary adenylate cyclase-activating polypeptide (PACAP), galanin (GAL), calretinin (CRT), or somatostatin (SOM) formed significantly smaller populations (21.4%, 7.4%, 3.1%, and 0.7%, respectively). The results of the present study demonstrate the presence of PNX in DRG UC-SNs, and its co-occurrence with numerous neurotransmitters suggesting a putative role for this neuropeptide in the transmission of various types of sensory information and possible effects on the functioning of this organ in the body. Full article

Spinal cord injury (SCI) is a devastating, debilitating, and life-altering condition that lacks a cure or effective treatment as of today. An altered excitation/inhibition ratio after an injury, with an increase in inhibitory input, limits motor and sensory function. Together with the limited endogenous regeneration capacity of the affected neuronal circuits, this results in further loss of function. Hingorani and collaborators recently reported that transplantation of dissociated sensory neurons from neonatal dorsal root ganglia (DRGs) expressing the bacterial sodium channel NaChBac significantly improved locomotion in a severe SCI by increasing the excitatory neuronal input at the injury site. Here, we additionally target the potential axonal regeneration of endogenous and transplanted cells, using cytoskeleton-modulating drugs to enhance axonal length. We employ, alone or in combination, blebbistatin and epothilone B, tested in vitro. We found that individually, each compound significantly induced the sensory neurons’ axonal elongation; however, their combination completely abolished it. Interestingly, a combinatory treatment including the modification of DRGs to express the NaChBac sodium channel and the treatment with blebbistatin increased the axonal elongation in vitro. Nevertheless, when applied in vivo in a model of SCI, local and single para-amino-blebbistatin (a stable analogue of blebbistatin) administration and the transplanted NaChBac expressing sensory neurons limit the functional recovery enabled by neuronal transplantation alone. Thus, despite the beneficial outputs of isolated neuronal cultures that allow selection of in vivo combinatory strategies, the multifaced characteristics of CNS injuries limit the potential success of single and local treatment administration, demanding extended and sustained treatments. Full article

Background: The interaction between the endocannabinoid system (ECS), specifically the CB1 and CB2 cannabinoid receptors, and neuropathy has aroused great research interest due to the possible implications for treatment. Complications following type 1 diabetes, due to impaired glucose metabolism and chronic inflammation, may benefit from targeted therapeutic strategies involving the ECS. This study explores the effects of photobiomodulation therapy (PBMT) on streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN) in rats. The study assessed body mass, hyperglycemia, mechanical hyperalgesia, and the influence of PBMT on these conditions over four weeks. Results showed that while PBMT did not alter the metabolic aspects of type I diabetes, it significantly reduced mechanical hyperalgesia compared to untreated diabetic neuropathic rats. Notably, cannabinoid receptor antagonists for CB1 and CB2 elicited a transient reversal of this antihyperalgesic effect, indicating a potential role of these receptors in PBMT’s mechanism. However, CB2 modulation was not statistically significant, whereas changes in CB1 receptor expression were observed in the dorsal root ganglia, suggesting its involvement in PBMT’s effects. These findings highlight the importance of CB1 and CB2 receptors in DPN and suggest that PBMT may offer a therapeutic benefit by mitigating mechanical hyperalgesia. Further investigation into cannabinoid receptor dynamics in diabetes could help in new therapeutic strategies for managing diabetic complications. Full article

Pain remains one of the most burdensome symptoms in rheumatoid arthritis (RA), often persisting despite inflammatory remission and profoundly impairing quality of life. This review aimed to evaluate the clinical efficacy and mechanistic pathways by which Janus kinase (JAK) inhibitors alleviate RA-related pain. Evidence from randomized clinical trials demonstrates that JAK inhibitors have demonstrated rapid and significant pain relief, often exceeding that of methotrexate or biologic DMARDs. Improvements in patient-reported pain scores seem to typically emerge within 1–2 weeks and are sustained over time. Beyond anti-inflammatory effects, JAK inhibitors modulate central sensitization and nociceptive signaling by attenuating IL-6 and GM-CSF activity, reducing astrocyte and microglial activation, and downregulating nociceptor excitability in dorsal root ganglia and spinal pathways. Preclinical models further suggest that JAK inhibition interrupts neuroimmune feedback loops critical to chronic pain maintenance. Comparative and network meta-analyses consistently position JAK inhibitors among the most effective agents for pain control in RA. However, individual variability in response, partly due to differential JAK-STAT activation and cytokine receptor uncoupling, underscores the need for biomarker-guided treatment approaches. JAK inhibitors represent a mechanistically distinct and clinically impactful class of therapies that target both inflammatory and non-inflammatory pain in RA. Their integration into personalized pain management strategies offers a promising path to address one of RA’s most persistent unmet needs. Full article

Neuropathic pain is a chronic condition driven by intertwined mechanisms of oxidative stress, inflammation, and cellular senescence. Nerve injury and metabolic stress elevate reactive oxygen and nitrogen species, disrupt mitochondrial function, and activate the DNA-damage response, which stabilizes p53 and induces p16/p21-mediated cell-cycle arrest. These events promote a senescence-associated secretory phenotype (SASP) rich in cytokines, chemokines, and prostanoids that amplify neuroimmune signaling. In the spinal dorsal horn and dorsal root ganglia, microglia and astroglia respond to redox imbalance and danger cues by engaging NF-κB and MAPK pathways, increasing COX-2–dependent prostaglandin synthesis, and releasing mediators such as IL-1β and BDNF that enhance synaptic transmission and reduce inhibitory tone through KCC2 dysfunction. At the periphery, persistent immune-glial cross-talk lowers activation thresholds of nociceptors and sustains ectopic firing, while impaired autophagy and mitophagy further exacerbate mitochondrial dysfunction and ROS production. Collectively, these processes establish a feed-forward loop in which redox imbalance triggers senescence programs and SASP, SASP perpetuates neuroinflammation, and neuroinflammation maintains central sensitization—thereby consolidating a self-sustaining redox–senescence–inflammatory circuit underlying neuropathic pain chronicity. Full article

Background/Objectives: Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Methods: Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model. Results: Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, n = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, n = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4. Conclusions: Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia. Full article

Background/Objectives: Fibromyalgia is a chronic pain syndrome with unclear etiology, meaning that it is difficult to treat effectively. The stimulation of cannabinoid receptor 1 (CB1) suppresses neuronal excitability and synaptic transmission in nociceptive pathways via reducing activity in the calcium channel and promoting the opening of the potassium channel. Methods: In this study, we examined whether CB1 activity contributes to the antinociceptive efficacy of electroacupuncture (EA) in a mouse fibromyalgia (FM) pain model established using intermittent cold stress (ICS). The model mice demonstrated both mechanical and thermal hyperalgesia measured using the von Frey and Hargreaves tests, respectively. Results: Electroacupuncture effectively reduced both forms of hyperalgesia and enhanced CB1 expression in the dorsal root ganglia, spinal cord, hypothalamus, and periaqueductal gray. In addition, EA attenuated the fibromyalgia-associated reactive transformation of microglia and astrocytes and the activation of the pain-related TLR4–MyD88–TRAF6 signaling pathway. The effects of ICS were also mitigated by the deletion of Trpv1, the gene encoding the transient receptor potential cation channel TRPV1 (capsaicin channel) implicated in nociceptive and inflammatory signaling. Further, the antinociceptive efficacy of EA was partially recapitulated by the acupoint injection of a CB1 agonist and abolished by the injection of a CB1 antagonist, suggesting that activating CB1 is essential for this therapeutic effect. Conclusions: Electroacupuncture can effectively alleviate mechanical and thermal hyperalgesia in a mouse model affected by fibromyalgia pain by activating the CB1 pathway, highlighting the therapeutic potential of CB1 agonism as a therapeutic strategy. Full article

Stereotactic body radiation therapy (SBRT) for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients’ quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using murine pre-osteoclast cell line Raw264.7, we induced differentiation with Receptor Activator of Nuclear Factor kappa-beta Ligand (RANKL), followed by 10 Gy gamma-irradiation. Conditioned media (C.M) from irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also exposed to 10 Gy radiation, with and without osteoclast co-culture. Osteoclast markers and pain-associated neuropeptides were analyzed using RT-qPCR and histochemical staining. Osteoclasts differentiation and activity were inhibited using osteoprotegerin (OPG) and risedronate. High-dose radiation significantly increased the size of tartrate-resistant-acid-phosphatase (TRAP)-positive osteoclasts (1.36-fold) and activity biomarkers (Ctsk, 1.35-fold, Mmp9, 1.76-fold). Neurons treated with C.M from irradiated osteoclasts showed ~1.5-fold increase in Calca (calcitonin gene-related peptide) and Tac1 (substance P) expression, which was mitigated by osteoclast inhibitors. These findings suggest that radiation enhances osteoclast activity and promotes pain signaling. Osteoclast inhibitors may represent a therapeutic strategy to reduce CWP and improve quality of life. Full article

Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) and dehydropeptidase-1 (DPEP1) in the DRG response to oxaliplatin (OxPt) and the modulatory effect of cilastatin. Behavioral assessment showed a robust nocifensive response to cold stimuli in OxPt-treated rats, attenuated by cilastatin co-treatment. Our confocal study revealed different cellular and subcellular expression patterns of IQGAP1 and DPEP1 in neurons, glia, and endothelial cells, where both signals overlap approximately one-third. OxPt enhanced cytosolic aggregation of IQGAP1 in neurons and upregulation of signal in glia, accompanied by co-expression of TNFα and IL-6, indicating involvement in the inflammatory process. DPEP1 showed altered subcellular distribution in OxPt-treated animals, suggesting a potential role in the inflammatory cascade. Notably, IQGAP1 expression was diminished in endothelial membranes under OxPt, while cilastatin preserved endothelial IQGAP1-CD31 colocalization, suggesting partial restoration of blood-nerve barrier integrity. These findings identify IQGAP1 and DPEP1 as key players in DRG inflammation and position cilastatin as a promising modulator of OIPN through neuro-glio-vascular stabilization. Full article

Cisplatin (CIS)-induced peripheral neuropathy and associated comorbidities have a detrimental effect on the lives of cancer patients. Currently, there are no effective therapies to alleviate these symptoms. Duloxetine (DULO) is a recommended treatment, but it is linked with important side effects, thus making it essential to explore novel approaches. We examined the impact of a prophylactic treatment with a low dose of DULO combined with hydrogen-rich water (HRW) on CIS-injected C57BL/6 male and female mice as a possible therapy for allodynia, muscle and body weight deficits, and emotive syndromes accompanying this type of chemotherapy. The prophylactic treatment with DULO and HRW prevented mechanical allodynia caused by CIS in both sexes and had greater effects than either treatment given individually. The combined treatment also prevented cold allodynia in male mice but only reduced it in females. Moreover, the coadministration of DULO with HRW avoided muscular deficits in both sexes. Furthermore, the body weight reduction induced by CIS in both sexes was not entirely mitigated by the combined therapy. However, all treatments avoided the anxiety- and depressive-like behaviors elicited by CIS. The antiallodynic actions and prevention of muscular deficits produced by the combined treatment might be explained by the inhibition of oxidative stress, inflammatory responses, and plasticity alterations provoked by CIS in the dorsal root ganglia of these subjects. This study proposes, for the first time, the cotreatment of DULO with HRW as an effective therapy for CIS-induced peripheral neuropathy and reveals the influence of sex on these actions. Full article

Isoeugenol is a phenylpropanoid that is commonly found in essential oils and has been commonly used as a flavoring agent in the culinary field and an anesthetic in fish. Yet despite its similarity to well-known eugenol, there is a lack of data regarding how isoeugenol would directly modulate neuronal excitability to interfere with pain signaling. Here, we studied the effects of isoeugenol on voltage-activated Na⁺ currents (I_Na) as a means of starting to close the gap regarding the inhibitory properties of isoeugenol on neuronal excitability. We used rat dorsal root ganglia neurons under whole cell voltage clamp for the isolation of I_Na.. We show that isoeugenol effectively inhibits I_Na fully, reversibly, and in a dose-dependent manner. Our detailed analysis also indicates the direct interaction of isoeugenol with voltage-gated Na⁺ channels (VGSC) is likely state-dependent, as the inhibitory activity is enhanced by membrane depolarization. This effect is beneficial for pain management, as the drug would act more effectively as neuronal activity is promoted by membrane depolarization. Our data indicates a direct inhibition of VGSC by isoeugenol might constitute the main mechanism whereby this phenylpropanoid produces analgesia. This study serves as a basis for future approaches to deeply investigate the therapeutic potential of this drug or its derivatives. Full article

Background/Objectives: Chemotherapy-induced neuropathic pain (CINP) represents a critical challenge in oncology, emerging as a common and debilitating side effect of widely used chemotherapeutic agents, such as paclitaxel (PTX). Current therapeutic interventions and preventive strategies for CINP are largely insufficient, as they fail to address the underlying peripheral nerve damage, highlighting an urgent need for the development of new drugs. This study aimed to investigate the dual-function effects on normal cell protection and tumor suppression of BMX-001, a redox-active manganese metalloporphyrin that has demonstrated antioxidant and anti-inflammatory properties, which offers potential in protecting central nervous system tissues and treating CINP. Methods: This study assessed BMX-001’s different roles in protecting normal cells while acting as a pro-oxidant and pro-inflammatory molecule in cancer cells in vitro. We also evaluated its neuroprotective effect in preclinical PTX-induced CINP models in vivo. Results: Our results showed significant reductions in mechanical and cold allodynia, decreased pro-inflammatory cytokine levels, and restored antioxidant capacity in peripheral nerves and dorsal root ganglia (DRGs) following BMX-001 treatment. Conclusions: Overall, our study highlights the therapeutic potential of BMX-001 to mitigate CINP and enhance anticancer efficiency. Its dual-selective mechanism supports the future clinical investigation of BMX-001 as a novel adjunct to chemotherapeutic regimens. 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

For centuries, researchers have been fascinated by the composition of scorpion venom and its local and systemic effects on humans. During a sting, scorpions inject peptides and proteins that can affect immune cells and neurons. While the immune and nervous systems have been studied independently in the context of scorpion stings, here we reveal part of the mechanism by which Tityus serrulatus venom induces hyperalgesia in mice. Through behavioral, immune, imaging assays, and mice genetics, we demonstrate evidence of neuroimmune crosstalk during scorpion stings. Tityus serrulatus venom induced mechanical and thermal hyperalgesia in a dose-dependent manner, as well as overt pain-like behavior. The venom directly activated dorsal root ganglia neurons and increased the recruitment of macrophages and neutrophils, releasing pro-inflammatory cytokines TNF-α and IL-1β. Blocking TRPV1⁺ neurons, TNF-α, IL-1β, and NFκB reduced the mechanical and thermal hyperalgesia, overt pain-like behavior, and the migration of macrophages and neutrophils induced by Tityus serrulatus venom. Collectively, Tityus serrulatus venom targets primary afferent nociceptive TRPV1⁺ neurons to induce hyperalgesia through the recruitment of macrophages and neutrophils and the release of pro-inflammatory cytokines. 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