Search Results (492)

The use of Botulinum Neurotoxin A (BoNT/A) to treat peripheral neuropathic pain from nerve injury has garnered interest for its long-lasting effects and safety. This study examined the effects of IncobotulinumtoxinA (Inco/A), a BoNT/A variant without accessory proteins, on nerve regeneration in rats using the chronic constriction injury (CCI) model. Inco/A was administered perineurally at two time points: on days 0 and 21 post CCI. Functional and histological assessments were conducted to evaluate the effect of Inco/A on nerve regeneration. Sciatic Functional Index (SFI) measurements and Compound Muscle Action Potential (CMAP) recordings were conducted at different time points following CCI. Inco/A-treated animals exhibited a 65% improved SFI and 22% reduction in CMAP onset latencies compared to the vehicle-treated group, suggesting accelerated functional nerve recovery. Tissue analysis revealed enhanced remyelination in Inco/A-treated animals and 60% reduction in CGRP and double S100β signal expression compared to controls. Strikingly, 30% reduced immune cell influx into the injury site was observed following Inco/A treatment, suggesting that its anti-inflammatory effect contributes to nerve regeneration. These findings show that two injections of Inco/A promote functional recovery by enhancing neuroregeneration and modulating inflammatory processes, supporting the hypothesis that Inco/A has a neuroprotective and restorative role in nerve injury conditions. Full article

Endometriosis is a disease characterized by the presence of endometrial glands and stroma outside of the uterine corpus, often clinically presenting with pain and/or infertility. Ectopic lesions exhibit features characteristic of epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells lose polarity and acquire mesenchymal traits, including migratory and invasive capabilities. During the process of EMT, epithelial traits are downregulated, while mesenchymal traits are acquired, with cells developing migratory ability, increasing proliferation, and resistance to apoptosis. EMT is promoted by exposure to hypoxia and stimulation by transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and estradiol. Signaling pathways that promote EMT are activated in most ectopic lesions and involve transcription factors such as Snail, Slug, ZEB-1/2, and TWIST-1/2. EMT-specific molecules present in the serum of women with endometriosis appear to have diagnostic potential. Strategies targeting EMT in animal models of endometriosis have demonstrated regression of ectopic lesions, opening the door for novel therapeutic approaches. This review summarizes the current understanding of the role of EMT in endometriosis and highlights potential targets for EMT-related diagnosis and therapeutic interventions. Full article

Inflammatory arthritis (IA) is a chronic condition marked by joint dysfunction and pain, posing significant challenges for effective drug delivery. This study separated Perilla frutescens leaf-derived exosome-like nanovesicles (PFE) to effectively penetrate the stratum corneum barrier. These nanovesicles and indomethacin (IND) were subsequently developed into a nanogel designed for topical drug delivery systems (PFE-IND-GEL). PFE exhibited a typical vesicular structure with a mean diameter of 98.4 ± 1.3 nm. The hydrodynamic size and zeta potential of PFE-IND-GEL were 129.6 ± 5.9 nm and −17.4 ± 1.9 mV, respectively. Mechanistic investigations in HaCaT keratinocytes showed that PFE significantly downregulated tight junction proteins (ZO-1 and Occludin, p < 0.01) via modulation of the IL-17 signaling pathway, as evidenced by transcriptomic analysis. In a sodium urea crystal-induced rat IA model, the topical application of PFE-IND-GEL significantly reduced joint swelling (p < 0.05) and serum levels of inflammatory cytokines (IL-6, IL-1α, TNF-α) compared to control groups. Histopathological analysis confirmed the marked attenuation of synovial inflammation and cartilage preservation in treated animals. These findings underscore the dual role of PFE as both a topical permeation enhancer and an anti-inflammatory agent, presenting a promising strategy for managing IA. Full article

Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and GABAergic systems has been investigated using a pharmacological approach in an animal model of inflammatory pain, i.e., the formalin test in mice. BoNTs were administered intracerebroventricularly, three days before testing, followed 15 min before testing by systemic administration of sub-analgesic doses of MK801, an NMDA receptor antagonist, or muscimol, a GABA_A receptor agonist. BoNT/A reduced the second phase of the formalin test without affecting both the first phase and the interphase, suggesting a selective action on excitatory glutamatergic circuits while sparing GABAergic inhibition. Co-administration of MK801 with BoNT/A did not enhance analgesia, and muscimol did not further reduce interphase, confirming preserved GABAergic transmission. In contrast, BoNT/B abolished the interphase, consistent with impaired GABA release. Co-administration of MK801 or muscimol with BoNT/B restored the interphase, indicating compensatory rebalancing of excitatory-inhibitory networks. These results demonstrate that BoNT/A and BoNT/B exert distinct effects on central neurotransmission and support the hypothesis that BoNT/A preferentially targets excitatory synapses, while BoNT/B targets inhibitory synapses. This work contributes to a deeper understanding of anti-inflammatory mechanisms of BoNTs and their selective interaction with central pain pathways. Full article

Background: Thymus numidicus Poiret. (Lamiaceae) is an endemic plant with well-known antibacterial properties. It has been largely used in traditional Algerian medicine. This study aimed to compare the chemical composition of essential oils (EOs) extracted from leaves and flowers using the gas chromatography–mass spectrometry method, as well as to investigate its analgesic and anti-inflammatory activities. Results: The EOs were rich in monoterpenes and classified as a thymol chemotype. In vivo experiments revealed that acute treatment with T. numidicus EO (20 and 80 mg/kg) significantly increased the thermal threshold on the hot-plate at all tested hours compared to the control animals (p < 0.001, respectively), while only the higher dose had a similar effect to the metamizole group at 2 and 3 h. In the mechanical stimulus test, both doses of the EO led to a late analgesic effect presented with increased paw withdrawal threshold only during the third hour compared to the control group (p < 0.05, respectively). In the plethysmometer test both doses of the EO dose-dependently reduced paw volume with nearly 10% and 15% compared to the control animals at all tested hours (p < 0.001, respectively), with a more pronounced volume reduction in the higher dose. In a neuropathic pain model, the EO (20 mg/kg and 80 mg/kg) dose-dependently increased the withdrawal latency time towards thermal stimuli and enhanced the paw withdrawal threshold in response to mechanical pressure at all tested hours compared to the CCI-group (p < 0.001, respectively). These findings demonstrate the potent analgesic and anti-inflammatory effects of T. numidicus EO in models of acute and neuropathic pain. Full article

Aim: This systematic review aims to evaluate the effectiveness of microbiota-modulating interventions (such as probiotics, prebiotics, and fecal microbiota transplantation) in reducing cognitive symptoms, pain, and neuroinflammation in human studies relevant to fibromyalgia (FM). The review will investigate the role of gut–brain axis modulation through these interventions and explore the potential therapeutic benefits for FM management. Materials and Methods: A comprehensive search was conducted in electronic databases including PubMed, Scopus, and the Cochrane Library for studies published from 1 January 2015 to 30 April 2025. Studies were eligible if they were randomized controlled trials (RCTs), pilot studies, or observational studies assessing the impact of microbiota-targeted interventions (probiotics, prebiotics, fecal microbiota transplantation) on cognitive function, pain, or neuroinflammation in patients with FM. Studies were excluded if they involved animal models, lacked relevant outcome measures, or were not peer-reviewed. Although only a subset of the included studies directly involved FM patients, all were selected for their relevance to symptom domains (e.g., pain, cognition, mood) and mechanisms (e.g., neuroinflammation, gut–brain axis dysfunction) that are central to FM. A total of 11 human studies were included in the final qualitative synthesis. Results: Preliminary findings from the included studies suggest that microbiota-targeted interventions, particularly probiotics and prebiotics, show promise in reducing cognitive symptoms, pain, and neuroinflammation in FM patients. Improvements in mood and quality of life were also reported, indicating potential benefits for overall well-being. However, heterogeneity in study designs, sample sizes, and outcome measures limit the ability to draw definitive conclusions. Conclusions: This systematic review highlights the potential of microbiota modulation as a therapeutic strategy for managing FM symptoms, particularly cognitive dysfunction and neuroinflammation. Full article

Cartilage injuries, due to their limited regenerative capacity, often result in chronic pain and functional impairment. These injuries are difficult to manage with conventional surgical repair techniques; therefore, alternative treatments are necessary. Gelatin methacrylate (GelMA) has emerged as a promising biomaterial for cartilage tissue engineering due to its biocompatibility, tunable mechanical properties, and ability to be used in advanced applications like 3D bioprinting. This review examines the synthesis, properties, and limitations of GelMA in cartilage repair, focusing on its applications in 3D bioprinting for the creation of patient-specific cartilage constructs. It also highlights preclinical studies exploring the potential of GelMA-based scaffolds in various animal models. Despite its advantages, challenges remain, such as the mechanical limitations of GelMA and its degradation rate in dynamic environments. Hybrid scaffolds, in situ bioprinting, and personalized bioinks offer solutions to these issues. Ultimately, long-term clinical trials are needed to assess the durability and efficacy of GelMA-based scaffolds in human applications. Future research is aimed at overcoming these challenges, improving the mechanical strength of GelMA scaffolds, and enhancing their clinical translation for cartilage repair. Full article

Chronic pain affects a significant portion of the population, with fewer than 30% achieving adequate relief from existing treatments. This study describes the humanization methodology and characterization of an effective non-opioid single-chain fragment variable (scFv) biologic that reverses pain-related behaviors, in this case by targeting P2X4. After nerve injury, ATP release activates/upregulates P2X4 receptors (P2X4R) sequestered in late endosomes, triggering a cascade of chronic pain-related events. Nine humanized scFv (hscFv) variants targeting a specific extracellular 13-amino-acid peptide fragment of human P2X4R were generated via CDR grafting. ELISA analysis revealed nanomolar binding affinities, with most humanized molecules exhibiting comparable or superior affinity compared to the original murine antibody. Octet measurements confirmed that the lead, HC3-LC3, exhibited nanomolar binding kinetics (KD = 2.5 × 10⁻⁹ M). In vivo functional validation with P2X4R hscFv reversed nerve injury-induced chronic pain-related behaviors with a single dose (0.4 mg/kg, intraperitoneal) within two weeks. The return to naïve baseline remained durably reduced > 100 days. In independent confirmation, the spared nerve injury (SNI) model was similarly reduced. This constitutes an original method whereby durable reversals of chronic nerve injury pain, anxiety and depression measures are accomplished. Full article

Background: Cannabidiol (CBD), a non-intoxicating phytocannabinoid, has garnered interest as a potential therapeutic agent for managing pain and inflammation associated with upper-quarter disorders, including temporomandibular disorders (TMDs), orofacial pain, myofascial dysfunction, and postoperative dental pain. Methods: This systematic review critically evaluated clinical, preclinical, and mechanistic studies on the efficacy and safety of CBD in the management of such conditions. A total of 10 studies, comprising randomized clinical trials and animal models, met the inclusion criteria and were assessed for methodological quality and risk of bias. Results: The findings suggest that CBD demonstrates analgesic, anti-inflammatory, and muscle-relaxant effects in chronic myofascial TMDs and bruxism, particularly when applied topically or intraorally. In contrast, studies on acute nociceptive pain (e.g., pulpitis, third molar surgery) yielded inconsistent results. Notably, CBD enhanced the effects of conventional analgesics such as opioids and NSAIDs in several preclinical models, indicating synergistic potential. However, substantial heterogeneity in CBD dosage, formulation, administration routes, and outcome measures limited comparability across studies. Adverse effects were minimal in clinical trials, yet underreported. Conclusions: While early evidence supports CBD’s potential as an adjunctive treatment for certain upper-quarter conditions, especially those involving chronic myofascial pain, further high-quality, condition-specific trials are required to establish standardized dosing, delivery methods, and long-term safety. Full article

Pain is a complex, multifaceted sensory–emotional state. It still poses a significant challenge in clinical treatment, especially in cases of chronic pain. Concerns associated with the use of opioids as analgesics have led to the search for new and safer pain relievers. This review examines the potential of lysine in pain control by exploring its molecular mechanisms and the preclinical evidence and clinical implications. Lysine has demonstrated analgesic effects by inhibiting NMDA receptors, modulating dopamine and serotonin pathways, and interfering with neuroimmune signaling cascades. Studies in animal models have shown that the administration of lysine reduces pain responses without altering motor function. Despite the favorable profile of lysine in terms of minor side effects and its promising effectiveness as a nutritional supplement, more research is needed to optimize its efficacy, adjust its dosage, and ensure its safety for long-term use. Full article

TNF-α is a pro-inflammatory cytokine that plays a pivotal role in the regulation of immune responses. It is predominantly produced by activated macrophages, although other cell types, such as T lymphocytes and NK cells, also contribute to its secretion. TNF-α participates in various physiological processes, including cell proliferation and differentiation. Moreover, TNF-α has been implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Recent studies have highlighted the important role of TNF-α in neuropathic pain, a complex and frequently disabling condition caused by nerve injury or dysfunction. Increased TNF-α levels in the nervous system have been associated with the onset of neuropathic pain, contributing to neuronal sensitization and alterations in pain signaling pathways. This study supports the idea that TNF-α connects the immune system with the nervous system, thereby supporting our understanding of the neuroimmune interface of pain and bringing a potential treatment against neuropathic pain: targeting TNF-α. Anti-TNF-α antibody administration reduces pain behaviors and neuroinflammation in preclinical animal models. Simultaneously, clinical trials are evaluating the safety and efficacy of anti-TNF-α treatments, with preliminary results indicating promising outcomes in patients experiencing neuropathic pain. Here, targeting TNF-α goes beyond its conventional spectrum of inflammatory pathologies and initiates a new mechanism-based approach to defining neuropathic pain, thereby improving the quality of life of the individuals affected and bringing together an area of colossal unmet clinical need. Full article

Osteoarthritis (OA) is a chronically progressive degenerative arthropathy characterized by the loss of cartilage, changes in subchondral architecture, and ongoing inflammation resulting in reduced mobility and pain. This study assessed the treatment potential of a combination of chondroitin and glucosamine enriched with Curcumin C3 Complex (C3GC) in modulating the pathophysiological features in mouse models with surgically induced OA and in dogs with naturally occurring OA. A cohort of 24 male C57BL/6 mice aged 3 months old were surgically destabilized with medial meniscus (DMM) to cause osteoarthritis. These animals underwent a nutritional intervention with C3GC or with GC over a course of 8 weeks. In order to evaluate cartilage health and subchondral bone structure, we carried out a combination of behavioral tests, micro-computed tomography (micro-CT), and histopathological examinations. In addition, a cohort of 12 OA-diagnosed retired police dogs were administered C3GC supplements or conventional care over a course of 30 days, with pain measurement and serum concentrations of MMP-3 and TNF-α determined before and after treatment. According to our findings, the administration of C3GC was determined to preserve subchondral microarchitectural structure integrity (p < 0.05) and resulted in better motor function in comparison with GC. In animals taking nutritional supplements, the OARSI scores of joint tissue sections were reduced, with the medial tibial plateau OARSI score being particularly low in the C3GC group (p < 0.0001). In dogs, treatment with C3GC resulted in a 24.5% reduction in serum MMP-3 levels (p < 0.01), and there was also a 20.8% decrease in serum TNF-α levels (p < 0.05), along with a decrease in subjective pain assessment. The results are in support of the chondroprotective, anti-inflammatory, and analgesic properties of C3GC and justify future research on the potential utility of C3GC in treating osteoarthritis. Full article

The presence and function of the opioidergic system in sensory dorsal root ganglia (DRG) was demonstrated in various animal models of pain. To endorse recent functional and transcriptional evidence of opioid receptors in human DRG, this study compared morphological and transcriptional evidence in human and rat DRG using immunofluorescence confocal microscopy and mRNA transcript analysis. Specifically, it examined the neuronal expression of mu (MOR), delta (DOR), and kappa (KOR) opioid receptors, opioid peptide precursors (POMC, PENK, and PDYN), and key pain-signaling molecules. The results demonstrate abundant immunoreactivity in human DRG for key pain transduction receptors, including the thermosensitive ion channels TRPV1, TRPV4 and TRPA1, mechanosensitive PIEZO1 and PIEZO2, and the nociceptive-specific Nav1.8. They colocalized with calcitonin gene-related peptide (CGRP), a marker for peptidergic sensory neurons. Within this same subpopulation, we identified MOR, DOR, and KOR, while their ligand precursors were less abundant. Notably, the mRNA transcripts of MOR and PENK in human DRG were highest among the opioid-related genes; however, they were considerably lower than those of key pain-signaling molecules. These findings were corroborated by functional evidence in demonstrating the fentanyl-induced inhibition of voltage-gated calcium currents in rat DRG, which was antagonized by naloxone. The immunohistochemical and transcriptional demonstration of opioid receptors and their endogenous ligands in both human and rat DRG support recent electrophysiologic and in situ hybridization evidence in human DRG and confirms their potential as analgesic targets. This peripherally targeted approach has the advantage of mitigating central opioid-related side effects, endorsing the potential of future translational pain research from rodent models to humans. 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

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models fail to fully replicate chronic RDEB wounds. In this study, we used Collagen VII-hypomorphic mice (Col7a1^flNeo/flNeo) and created full-thickness wounds on their paw skin, an area prone to fibrosis due to mechanical stress. We analyzed the healing process using histology, immunofluorescence, and electron microscopy. The RDEB mice showed delayed wound closure, increased inflammation, and poor granulation tissue formation. At 30 days post-injury, we observed persistent fibrosis, with elevated levels of Collagen I, α-SMA+ myofibroblasts, and tenascin-C. These mice also had fewer intraepidermal nerve fibers, which may help explain the neuropathic pain associated with RDEB. Our model reproduces the main features of chronic RDEB wounds. It offers a useful tool for evaluating therapies aimed at reducing inflammation, fibrosis, and tumor risk in these patients. Full article