Search Results (120)

Background: Peripheral nerve injury drives persistent remodeling of the dorsal root ganglion (DRG) microenvironment, but the cellular states and intercellular signaling mechanisms that sustain neuropathic pain remain poorly understood. Methods: Here, we integrated single-cell transcriptomics with histological, behavioral, and electrophysiological approaches to identify an interferon-responsive state in satellite glial cells (SGCs) of the DRG following spared nerve injury (SNI). Results: This state was distinguished by STAT1-associated interferon-responsive genes’ activation and enhanced chemokine signaling, particularly involving CXCL10 and its receptor CXCR3. These molecular alterations were accompanied by remodeling of intercellular communication among SGCs, sensory neurons, and immune cells. Pharmacological inhibition of STAT1 or blockade of CXCR3 not only reduced sensory-neuron hyperexcitability but also attenuated pain hypersensitivity and improved deficits in hindlimb weight bearing and gait after SNI. Conclusions: Collectively, our findings indicate that interferon-responsive SGCs (IFN SGCs) contribute to the maintenance of neuropathic pain by regulating STAT1-dependent chemokine signaling in the DRG. Targeting this signaling pathway may provide a therapeutic strategy for persistent neuropathic pain. Full article

Endometriosis and irritable bowel syndrome (IBS) are chronic pain disorders that frequently coexist and share key pathophysiological features, including neuroinflammation, visceral hypersensitivity, peripheral sensitization, and central sensitization. Emerging evidence suggests that extracellular adenosine triphosphate (ATP)-mediated activation of the P2X3 receptor is a common mechanism driving persistent nociceptive signaling in both conditions. This narrative review examines the role of ATP–P2X3 signaling in the pathogenesis of endometriosis and IBS, highlighting its involvement in neuroimmune crosstalk, dorsal root ganglion plasticity, and cross-organ sensitization. We summarize experimental and clinical evidence supporting P2X3 as a therapeutic target and discuss the development of selective P2X3 antagonists, including gefapixant, eliapixant, sivopixant, and camlipixant. Although these agents have shown clinical benefit in refractory chronic cough, their application to endometriosis and IBS remains largely unexplored. Current evidence is predominantly preclinical, underscoring the need for biomarker-driven translational studies and clinical trials. Overall, ATP–P2X3 signaling represents a promising shared mechanistic pathway linking endometriosis and IBS and a potential target for the development of precision, nonopioid therapies for chronic pelvic and visceral pain. Full article

Background: Hantavirus pulmonary syndrome (HPS), also designated hantavirus cardiopulmonary syndrome, is caused by New World hantaviruses, principally Sin Nombre virus in North America and Andes virus in South America. The syndrome is characterized by rapidly progressive noncardiogenic pulmonary edema and myocardial depression, with case fatality rates of 25% to 40%. A 2026 outbreak aboard an expedition cruise ship in the South Atlantic, comprising 13 cases and three deaths, confirmed that Andes virus can be transmitted between humans in a confined setting remote from the rodent reservoir. Methods: Virological, pathophysiological, clinical, and therapeutic aspects of HPS were reviewed, with particular emphasis on cardiopulmonary mechanisms. Sources were identified through PubMed, Scopus, and Google Scholar, with priority given to original research articles, clinical series, and controlled trials published through 2025. Literature published in English and Spanish was included. Results: Pathogenic hantaviruses enter endothelial cells and platelets via αvβ3 integrins, disrupting the VEGF-VEGFR2 signaling axis and rendering endothelial cells hypersensitive to physiological VEGF concentrations. Expansion of CD8+ T cells and activated macrophages releases TNF-alpha, IFN-gamma, and nitric oxide, amplifying microvascular permeability and contributing to myocardial depression. Autopsy studies demonstrate direct hantaviral myocarditis with viral antigen in cardiac endothelium and interstitial macrophages. Transpulmonary thermodilution confirms simultaneous hypovolemia, reduced global ejection fraction, and elevated extravascular lung water. Because the incubation period is long and the cardiopulmonary phase is substantially immune-mediated, seroconversion precedes rather than follows clinical deterioration, which preserves the diagnostic utility of IgM serology in a disease that can kill within 48 h. VA-ECMO initiated at the first signs of cardiopulmonary decompensation has reported survival rates approaching 80% in selected experienced centers. No antiviral has demonstrated efficacy in controlled trials during the cardiopulmonary phase, and no licensed vaccine exists. Conclusions: HPS produces a mixed shock state through increased microvascular permeability, T cell-mediated immunopathology, and direct myocarditis. Management follows a stepwise algorithm: suspected HPS triggers immediate complete blood count with peripheral blood smear and concurrent hantavirus IgM serology and RT-PCR, followed by ICU admission, conservative fluid resuscitation guided by transpulmonary thermodilution, and early contact with an ECMO-capable center at the first sign of rising lactate, falling cardiac index, refractory shock, arrhythmia, or rapid oxygenation failure. Full article

Background/Objectives: The NLRP3 inflammasome–Caspase-1–IL-1β pyroptotic axis participates in peripheral inflammatory responses, yet its function in peripheral–central neuroimmune crosstalk underlying endometriosis (EM)-associated pain remains unclear. This study aimed to clarify whether NLRP3-mediated pyroptosis establishes a brain–lesion neuroimmune axis connecting ectopic lesion inflammation with central neuroimmune remodeling and to explore the therapeutic mechanism of transcranial direct current stimulation (tDCS). Methods: An EM rat model was established to detect NLRP3 pathway expression in ectopic lesions and anterior cingulate cortex (ACC), together with central nervous system pathological alterations. Animals received tDCS intervention to evaluate inflammatory, neuropathological and pain behavioral changes. The closed-loop brain–lesion regulatory circuit was further interpreted. In a clinical cohort including 40 EM patients, pain and quality-of-life scores were compared between active and sham tDCS groups. Results: NLRP3, Caspase-1 and IL-1β were upregulated in ectopic lesions and ACC of EM rats, accompanied by ACC mitochondrial injury, microglial activation and thalamic demyelination. tDCS inhibited pyroptosis-related molecules, decreased systemic proinflammatory cytokines, improved central pathological lesions and relieved pain hypersensitivity. Mechanically, top-down descending pain inhibitory pathways, vagal cholinergic anti-inflammatory pathway and the HPA axis jointly mediate therapeutic effects, whereas circulating cytokines and visceral afferents transmit peripheral inflammatory signals to the brain. Clinical data demonstrated that active tDCS effectively alleviated EM-related pain and improved patients’ quality of life. Conclusions: NLRP3-mediated pyroptosis acts as a key mediator linking peripheral and central neuroimmune communication. Targeting this pathway via tDCS interrupts the inflammation–pain vicious cycle through multiple neuroregulatory pathways and remodels the central neuroimmune microenvironment in endometriosis. Full article

Background/Objectives: Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus characterized by progressive nerve degeneration and chronic neuropathic pain. Current therapies, including pregabalin, primarily provide symptomatic pain relief and have limited effects on preventing structural nerve damage. Therefore, the development of disease-modifying therapies remains an important unmet clinical need. This study investigated the neuroprotective effects of choline alfoscerate (CA) and its ability to attenuate mechanical hypersensitivity in a streptozotocin (STZ)-induced rat model of DPN. Methods: Diabetes was induced in rats using STZ, and administration protocols were optimized to establish sustained hyperglycemia while minimizing mortality. CA treatment was initiated immediately after STZ administration and continued throughout the study period. Mechanical sensitivity was assessed using the von Frey test. Histopathological examination of sciatic nerves was performed to evaluate structural alterations, and serum biochemical and lipid parameters were analyzed to assess systemic metabolic changes. Results: STZ-treated diabetic rats developed persistent hyperglycemia, mechanical allodynia, elevated serum triglyceride levels, and marked structural deterioration of sciatic nerve fascicles. CA treatment significantly increased paw withdrawal thresholds despite sustained hyperglycemia, indicating attenuation of mechanical hypersensitivity independent of glycemic control. Histopathological evaluation demonstrated reduced nerve fiber degeneration, attenuation of edema-like changes, and preservation of sciatic nerve architecture in CA-treated animals. In addition, CA significantly reduced serum triglyceride levels compared with diabetic controls. Conclusions: CA attenuated mechanical hypersensitivity and exerted neuroprotective effects in STZ-induced diabetic rats. These benefits occurred independently of glucose lowering and were accompanied by improvements in nerve morphology and lipid metabolism. The findings suggest that CA may represent a promising therapeutic candidate for preserving peripheral nerve integrity and attenuating neuropathic progression in diabetic peripheral neuropathy. Full article

The basophil activation test (BAT) is a modern in vitro functional assay used for the diagnosis of immunoglobulin E-mediated allergic reactions. The method is based on flow cytometric assessment of activation marker expression on peripheral blood basophils after stimulation with specific allergens. BAT has gained increasing clinical relevance in allergology, particularly in patients with anaphylaxis risk, polysensitization, drug hypersensitivity, and inconclusive skin or serological test results. This narrative review summarizes current evidence on the diagnostic performance and clinical applications of BAT in food allergy, drug hypersensitivity, Hymenoptera venom allergy, latex sensitization, and allergen immunotherapy monitoring. The review discusses the immunological mechanisms of basophil activation, the role of CD63 and CD203c, methodological aspects of the assay, sensitivity and specificity data, and advantages and limitations compared with conventional diagnostic approaches. Particular attention is given to protocol standardization, interpretation criteria, and the problem of non-responder patients. Current evidence indicates that BAT demonstrates high specificity and provides functional assessment of clinically relevant allergic reactions. In addition, this review proposes practical clinical frameworks for integrating BAT into allergy diagnostic pathways and for managing inconclusive or non-responder BAT results. Further standardization, multiplex formats, and automated analytical approaches may expand its role in personalized allergy diagnostics. Full article

Neuropathic pain (NP) arises from diverse conditions, including peripheral nerve injury, spinal cord injury (SCI), and painful diabetic neuropathy, yet these disorders share oxidative stress, mitochondrial dysfunction, lipid dysregulation, and altered neuronal excitability. We investigated whether dietary omega-3 polyunsaturated fatty acids modulate ferroptotic stress-associated pathways, defined as lipid peroxidation susceptibility and impaired antioxidant defense rather than overt ferroptotic cell death. Female Sprague–Dawley rats received either a soy oil control diet (SOD) or fish oil omega-3-enriched diet (FOD) before chronic constriction injury (CCI). Behavioral outcomes were assessed using Hargreaves and CatWalk testing, followed by dorsal root ganglion (DRG) RNA sequencing, RT-PCR, and GPX4 ELISA. Previously generated SCI metabolomics and human diabetic serum metabolomic/lipidomic datasets were re-analyzed for shared pathways. FOD attenuated CCI-induced thermal hypersensitivity and improved gait parameters. DRG transcriptomics showed reduced injury-associated transcriptional disruption, enrichment of selenoamino acid metabolism, nonsense-mediated decay, and ribosomal quality-control pathways, and reduced mitochondrial dysfunction pathway activity. Omega-3 increased Gpx1/Gpx4 expression and GPX4 protein, reduced pain-associated genes including Scn10a, Piezo2, Trpa1, and Oprm1, and aligned with selenoamino acid enrichment in SCI and human datasets. Human lipidomics showed MG/DG/PC/PE pathway remodeling. These findings support ferroptotic stress as a plausible shared downstream mechanism modulated by omega-3 supplementation across NP models. Full article

Approximately 10% of the general population reports a penicillin allergy, making it one of the most commonly documented drug allergies in clinical practice. Yet formal evaluation confirms true hypersensitivity in fewer than 10% of these cases. This gap has practical consequences. Patients who carry an inaccurate allergy label are more likely to receive broader-spectrum alternative antibiotics, with downstream effects on cost, adverse drug events, and antimicrobial resistance. Although primary care physicians are often the first to record these labels and the ones who face their consequences most often in daily prescribing, they have remained peripheral to most systematic delabeling efforts. In this narrative review, we examine how antibiotic allergy labels arise, why they persist, and what they cost—clinically, economically, and from a stewardship perspective. We also discuss emerging approaches to reassessment in primary care, including risk stratification tools and international guideline recommendations, along with the possible role of digital health tools and patient education in improving the accuracy of allergy documentation. Full article

Migraines are a common neurological disorder that significantly reduces quality of life. The sensitization of trigeminal afferents is a key factor in the development of the pain syndrome associated with migraine. Carbon monoxide (CO) is produced endogenously by heme oxygenase (HO), widely expressed in structures involved in pain processing. In our study, the role of CO in an acute and chronic nitroglycerin (NTG)-induced rat migraine model was investigated using behavioral, electrophysiological, biochemical and histological methods. The repeated administration of a CO donor (CORM-2) or an HO-1 inducer (CoPP) decreased mechanical hypersensitivity and photophobia of rats in the NTG-induced migraine model. Additionally, CORM-2 and CoPP prevented an increase in trigeminal afferent excitability, which was evaluated by the frequency of action potentials in response to KCl application. Preliminary CORM-2 or CoPP injections promoted mast cell stability in the meninges and prevented NTG-induced CGRP elevation in blood plasma. Our results suggest that exogenously or endogenously produced CO has a protective potential in preventing inflammation and the sensitization of peripheral trigeminal afferents, the activity of which underlies the occurrence of pain in migraine. This could contribute to the development of new approaches for migraine prevention. Full article

Peripheral nerve ischemia–reperfusion injury is considered to contribute to sensory disturbances that impair quality of life in patients with diabetic neuropathy and chemotherapy-induced neuropathy. However, the spinal mechanisms underlying these disturbances remain unclear, partly due to the lack of established animal models and evaluation systems. In the present study, we used a rat hindlimb ischemia–reperfusion model and in vivo extracellular recording to examine bidirectional changes in neuronal activity in the spinal dorsal horn. Ischemia was induced by tightly binding the rat ankle with a rubber band, followed by reperfusion. Behavioral analysis showed a significant increase in hindlimb licking behavior after reperfusion, indicating the development of sensory disturbance-like responses. Extracellular recordings from superficial dorsal horn neurons showed diverse patterns of spontaneous firing and responses to mechanical stimulation, with both hypersensitive and desensitized responses. Furthermore, mRNA expression levels of immediate early genes (Egr1, Egr3, and Fos) were upregulated in the spinal cord after reperfusion. These results suggest that this ischemia–reperfusion model reproduces complex neuronal responses relevant to peripheral neuropathy and provides a useful evaluation system for evaluating both increased and decreased neural activity. This approach may contribute to elucidating the mechanisms of sensory disturbances and to the development of new treatments for neuropathic conditions. Full article

Pharmacological approaches to tinnitus have remained peripheral within research, despite persistent patient demand and advances in auditory neuroscience. There is increasing consideration of whether these developments now justify renewed focus on pharmacological research in tinnitus and hyperacusis. This paper presents a narrative synthesis of perspectives arising from an international scientific meeting, based on invited contributions from speakers who expanded on themes related to their presentations, integrating insights from systems neuroscience, cellular and molecular mechanisms, animal and human models of auditory hypersensitivity, and patient-reported experience. Rather than summarising individual presentations, the analysis focuses on converging mechanistic explanations, biological heterogeneity, emerging therapeutic targets, and advances in objective measurement. Particular attention is given to how evolving mechanistic frameworks can support patient education and clinical communication, even in the absence of disease-modifying treatments. Taken together, these discussions reflect renewed examination of pharmacological approaches to tinnitus and hyperacusis, with attention to both emerging mechanistic rationales and the substantial challenges that remain. Integrating mechanistic insights, phenotype-informed care, and responsible communication may help clarify research priorities and support informed clinical and patient-facing discussions. Full article

Background/Objectives: Postoperative pain pharmacology is complex. We investigated the sensitivity of analgesic-like effects induced by morphine, ibuprofen, and their combination to peripheral opioid antagonism in a mouse laparotomy model. Methods: Mechanical hypersensitivity was assessed using von Frey filaments, and ongoing pain (abdominal licking and facial expressions) was evaluated using artificial intelligence algorithms. We tested the sensitivity of the analgesic treatments to the opioid antagonist naloxone or its peripherally restricted analog, naloxone methiodide. We also tested the effects of neutrophil depletion using an anti-Ly6G antibody. Gastrointestinal transit and pupillary diameter were measured to assess non-analgesic opioid effects. Results: Morphine reversed all pain-related behaviors; its effect on mechanical hypersensitivity was reversed by peripheral opioid antagonism, whereas its effects on ongoing pain were not. Ibuprofen reduced mechanical hypersensitivity and facial expressions but failed to alter licking. Interestingly, the ibuprofen effect on mechanical hypersensitivity depended on peripheral opioid receptors and neutrophils at the injury site. The morphine–ibuprofen combination produced synergistic analgesia across all endpoints without enhancing opioid-induced gastrointestinal inhibition or mydriasis. Peripheral opioid antagonism reversed the effect of the combination on mechanical hypersensitivity and facial expressions but not on licking. Conclusions: Our results replicate the key clinical phenomena relevant to the postoperative pain context, including the potentiation of morphine analgesia by ibuprofen without the exacerbation of adverse effects. Our results suggest that drug effects on different postoperative pain measures rely on distinct neurobiological mechanisms and are not interchangeable. Therefore, the use of a battery of complementary pain endpoints in preclinical pharmacology studies is advisable. Full article

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor (GPCR) expressed in both the peripheral and central nervous systems. It plays a pivotal role in mediating neuroimmune interactions, particularly in the context of inflammation and pain. Upon activation by proteases, PAR2 modulates nociception through signaling cascades that influence key ion channels, including transient receptor potential (TRP) ion channels vanilloid 1 and 4 (TRPV1 and TRPV4), ankyrin 1 (TRPA1), acid-sensing ion channel 3 (ASIC3), P2X purinoceptor 3 (P2X3), Cav3.2 (T-type Ca²⁺ channel), and potassium Kv7 (M-current) channels, altering their expression and function. Through this crosstalk, PAR2 contributes to heightened neuronal excitability and pain hypersensitivity in various inflammatory conditions. In this narrative review, we highlight and discuss the mechanistic and functional interplay between PAR2 and nociceptive ion channels, which might be contributing to the pathogenesis of inflammatory pain. Targeting these specific molecular interactions between PAR2 and nociceptive ion channels may offer a promising therapeutic strategy for treating inflammatory pain. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting adverse effect of paclitaxel and is characterized by cold and mechanical allodynia. Effective therapeutic strategies for CIPN remain limited. This study evaluated the analgesic potential of Corydalis yanhusuo (CY) and Evodia rutaecarpa (ER), as well as their major alkaloids tetrahydropalmatine (THP) and rutaecarpine, in a mouse model of paclitaxel-induced neuropathic pain. Methods: Neuropathic pain was induced by paclitaxel administration (2 mg/kg, i.p., four injections). CY and ER extracts were orally administered at doses of 100 or 300 mg/kg, either alone or in combination, and cold and mechanical allodynia were assessed from days 0 to 8. The analgesic effects of THP and rutaecarpine were also examined. Gene and protein expression analyses were performed to evaluate the involvement of TRPV1 and TRPM8 signaling pathways, and high-performance liquid chromatography (HPLC) was used to confirm the presence of THP in CY and rutaecarpine in ER. Results: Paclitaxel reliably induced robust cold and mechanical hypersensitivity. Oral administration of CY or ER significantly alleviated allodynia in a dose-dependent manner, with greater efficacy at 300 mg/kg. Combined CY–ER treatment produced stronger anti-allodynic effects than either extract alone. THP and rutaecarpine also exhibited dose-dependent analgesic effects, and their co-administration yielded the most pronounced inhibition of paclitaxel-evoked hypersensitivity. Molecular analyses confirmed the involvement of TRPV1- and TRPM8-related pathways in these analgesic effects. Collectively, these findings indicate that CY, ER, and their representative alkaloids effectively attenuate paclitaxel-induced neuropathic pain and highlight CY–ER-based natural products as promising candidates for managing CIPN through modulation of TRPV1/TRPM8 signaling. Full article

Neuropathic pain represents a critical challenge in medical research and clinical practice. Enhanced peripheral nerve activity and spinal dorsal horn neuronal firing are thought to contribute to the nociceptive hypersensitivities that are observed in chronic pain conditions, including those modeled by partial sciatic nerve ligation (PSNL). However, the detailed in vivo neuronal response dynamics and underlying mechanisms in the PSNL model remain to be fully clarified. To better understand these mechanisms, we evaluated dorsal root ganglion (DRG) and spinal dorsal horn neuronal activity in the PSNL model using in vivo approaches. Von Frey testing revealed sustained mechanical allodynia in PSNL animals; withdrawal thresholds were significantly reduced up to day 14 post-surgery. Immunohistochemistry revealed a stimulation-dependent increase in phosphorylated extracellular signal-regulated kinase (pERK)-positive neurons in the DRG, thereby indicating heightened peripheral nerve activity. Additionally, electrophysiological recordings demonstrated the enhanced firing of spinal dorsal horn neurons in response to the same stimuli. Notably, DRG pERK expression changes correlated with spinal neuronal firing frequency. Together, these findings suggest that peripheral nerve activity drives spinal neuronal sensitization, thus elucidating both pain mechanisms in the PSNL model and activity-dependent signaling in neuropathic pain. Full article