Search Results (514)

Background/Objectives: Pressure pain thresholds (PPTs) are commonly used to quantify mechanical hyperalgesia in migraine and tension-type headache (TTH), but the discriminatory performance of PPTs across neural and muscular sites remains unclear. This study compared nerve- and muscle-related PPTs between migraine and frequent episodic TTH and explored site-specific ROC-derived cut-off values as complementary classification markers. Methods: In this cross-sectional case-group discrimination study, participants with migraine (n = 33) and frequent episodic TTH (n = 31) underwent bilateral PPT assessment (electronic algometry) over the temporalis and tibialis anterior muscles, C5/C6 zygapophyseal joints, peripheral nerves (greater occipital, median, ulnar, radial, posterior tibial, common peroneal), and the second metacarpal region. Results: PPTs were generally lower in the migraine group than in the TTH group. After adjustment for sex and age, the most consistent between-group differences remained at the temporalis muscles bilaterally (left: adjusted mean difference 0.49 kg/cm², 95% CI 0.10 to 0.89, p = 0.015; right: 0.53 kg/cm², 95% CI 0.13 to 0.93, p = 0.011) and at the left tibialis anterior muscle (0.90 kg/cm², 95% CI 0.03 to 1.78, p = 0.044). In the main ROC analysis, the temporalis muscles showed the strongest discriminatory performance (left AUC = 0.733; right AUC = 0.707), whereas tibialis anterior and left posterior tibial nerve sites showed modest, below-threshold discrimination (AUCs < 0.70 despite statistical significance in some cases). Women-only ROC analyses showed a broadly similar pattern, with slightly improved metrics at some sites, particularly the temporalis muscles. Across most sites, likelihood ratios indicated only small-to-moderate shifts in post-test probability. Conclusions: Participants with migraine showed lower PPTs than those with frequent episodic TTH across most assessed sites, with the clearest differences at the temporalis muscles. ROC and PR analyses suggest that PPTs (especially at temporalis sites) may provide complementary, hypothesis-generating discriminatory information, but their overall stand-alone discriminative utility is modest. PPT assessment should therefore be interpreted as an adjunct to clinical evaluation rather than a replacement diagnostic test. Full article

The present study was to evaluate the analgesic activity of two newly synthesized 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione derivatives, designated DSZ-13 and DSZ-19. To achieve the desired result, the in vitro XTT cell proliferation assay, serotonin 5-HT_1A receptor affinity and COX-1 and COX-2 enzyme inhibition potential of the compounds were conducted by real-time qPCR. Non-compartmental analysis was used to estimate the pharmacokinetic parameters of the compounds in serum and brain tissue. The analgesic activity was evaluated using various in vivo pain models, encompassing acute pain (hot plate test), tonic pain (formalin test), neurogenic pain (capsaicin test), carrageenan-induced acute inflammation, and neuropathic pain models. Both compounds showed moderate affinity for serotonin 5-HT_1A receptors, a lack of cytotoxic activity, desirable pharmacokinetic parameters and slightly reduced mRNA expression for COX-1 and COX-2. Only the DSZ-19 revealed central/supraspinal analgesic activity and did not affect movement. Both compounds attenuated tonic and neurogenic pain, in the formalin and capsaicin tests, respectively. In addition, the involvement of the 5-HT_1A receptors in the formalin test was confirmed. Both compounds also showed antiallodynic activity in the oxaliplatin- and streptozotocin-induced neuropathy models. Slightly weaker than indomethacin, DSZ-13 and DSZ-19 attenuated carrageenan-induced inflammation (edema) and hyperalgesia in rat models. Full article

Background: Fibromyalgia is a chronic disease that predominantly affects women and lasts over several months, causing problems both for individuals and society. While several studies have demonstrated the potential of electroacupuncture (EA) to alleviate fibromyalgia pain in mice, further research is needed to investigate its underlying mechanisms. Programmed cell death ligand 1 (PD-L1)/PD-1 were first identified to be involved in cancer immunotherapy, and their application to pain management has not been yet investigated. Methods: In this study, we aimed to explore the mechanism underlying the action of PD-L1 on the PD-1 pathway in a mouse model of fibromyalgia. Results: We established such a mouse model using intermittent cold stress (ICS) and confirmed mechanical (D4: 2.02 ± 0.13 g, n = 9) and thermal (D4: 4.28 ± 0.21 s, n = 9) hyperalgesia. We found that EA, intracerebral ventricle (ICV) PD-L1 injection, and transient receptor potential vanilloid 1 (Trpv1) knockout effectively counteracted hyperalgesia. We observed low PD-1 expression in the cerebellum of fibromyalgia mice but increased expression of TRPV1 and pain-related kinases. These phenomena could be further reversed by EA, ICV PD-L1 injection, and Trpv1 knockout. To confirm that these effects were caused by PD-L1 release, we added PD-L1-neutralizing antibodies to the EA and PD-L1 treatment. The analgesic effects and EA and PD-L1 mechanisms were inhibited. Conclusions: Our results elucidate the role of the PD-L1/PD-1 pathway in EA treatment of fibromyalgia and reveal its potential value for fibromyalgia management. Full article

Nerve injury often results in neuropathic pain, marked by spontaneous pain, hyperalgesia, and allodynia. Current treatments have moderate efficacy and have side effects, prompting interest in alternative approaches. Mesenchymal stem cell (MSC) therapy has shown promise in preclinical studies for reducing neuropathic pain and inflammation. However, the precise mechanisms underlying MSC-mediated pain reduction remain unclear. Investigating these mechanisms is crucial for optimizing MSC-based therapies for neuropathic pain. This article provides a brief overview of the MSC administration, animal models of neuropathic pain, and treatment regimens used in 25 preclinical studies, focusing on the potential mechanisms of action underlying the neuropathic pain-reducing effect of MSCs. Importantly, 23 out of the 25 studies demonstrated a reduction in neuropathic pain following MSC therapy, despite differences in MSC sources and treatment regimens. Neuropathic pain relief was associated with decreased inflammation, suggesting that MSCs may act through immune modulation. However, the resolution of inflammation does not always correlate with complete neuropathic pain relief, indicating the involvement of additional mechanisms. Full article

Recently, complementary and alternative medicine (CAM) has been actively employed for patients experiencing symptoms unresponsive to Western medical treatments like drug therapy. The natural compounds carotenoids and astaxanthin (AST) have demonstrated various beneficial biological actions for human health in several studies. Given their broad pharmacological activities and reduced toxicity, ASTs possess significant potential as resources for the development of natural analgesic drugs. Given recent studies showing that AST can modulate neuronal excitability, including nociceptive sensory transmission through voltage-gated Ca²⁺ channels and the n-methyl-D-aspartate (NMDA) glutamate receptor, and inhibit the cyclooxygenase-2 cascade, AST holds promise as a CAM, particularly as a therapeutic agent for nociceptive and pathological pain. Based on the in vivo research findings from our laboratory presented in this review, we have confirmed that carotenoid ASTs possess: (i) an intravenous anesthetic effect on both nociceptive and inflammatory pain comparable to existing analgesics such as ketamine; and (ii) an anti-inflammatory effect on chronic pain with an efficacy almost equivalent to that of the commonly used non-steroidal anti-inflammatory drug (NSAID) celecoxib. Therefore, these findings suggest that, as natural compounds, ASTs contribute to the relief of nociceptive and inflammatory pain, implying their potential for clinical application. Full article

Huwentoxin-XI (HWTX-XI) is a 55-amino acid peptide belonging to the family of spider Kuntiz-type toxins (KTTs), isolated from the venom of the Chinese tarantula Cyriopagopus schmidti. Under whole-cell voltage-clamp conditions, HWTX-XI was found to block Kv1.1 potassium channels but had no effect on other potassium channel subunits (Kv1.4, Kv2.1, Kv3.1 and Kv4.2), sodium channels or calcium channels. In the present study, it was found that the substitution of Tyr379 by the valine in the filter region significantly decreased the affinity of toxin HWTX-XI by about 90-fold, indicating that the Kv1.1 filter region is a critical determinant of HWTX-XI potassium channel activity. After intrathecal or intraplantar injections, HWTX-XI decreased the mechanical nociceptive threshold (hyperalgesia) for a long-lasting period. HWTX-XI also significantly increased the firing frequency in mouse DRG neurons. The novel function of HWTX-XI makes it a new tool for studying the relationship between spider toxins and Kv1.1 channels and suggests that Kv1.1 channels might be a novel potential target for preventing and/or treating neuropathic pain. Full article

Central to the linkage of pain circuitry with the limbic system is its initial NAα2-mediated antinociceptive effect in acute pain models, followed by contradictory pronociceptive activation by the locus coeruleus seen in chronic pain models. Rats with a stable, long-term (>10 weeks) inflammatory compression of the trigeminal infraorbital nerve (FRICT-ION) preclinical model were given daily doxazosin, a slow-release NAα1 receptor antagonist, in weeks 8–10. Facial hypersensitivity was reversed back to baseline in male and female rats, but anxiety was only reduced in male animals. Doxazosin-decreased astrocytic activation was indicated by a decrease in both intracranial cathepsin B imaging in vivo and GFAP immunostaining in the somatosensory cortex and hippocampus. Doxazosin reduction in NAα1 receptor activation diminished glial-neuronal interactions, resulting in downstream reduction in pain-related behaviors. Other significant differences by sex included improved elevated zero maze anxiety measures only in males, and improved novel recognition scores only in females. Elevated thymus chemokine CXCL7 levels were reduced by doxazosin but only in male rats. These sexually dimorphic contradictions further complicate the understanding of the noradrenergic system’s involvement in nociception. The findings indicate that by reducing NAα1 receptor drive with doxazosin, the role of the locus coeruleus can be shifted back to NAα2-receptor-mediated pain inhibition. Full article

Background and Objectives: Hyaluronic acid (HA) is extensively used in dermo-aesthetic medicine for its hydrating and tissue-repairing properties. Beyond cosmetic use, HA has shown therapeutic effects in inflammatory skin diseases such as seborrheic, radiation-induced, and atopic dermatitis (AD). However, HA-based aesthetic formulations such as Profhilo^®, a hybrid complex of high- and low-molecular weight HA, have not been tested in immunologically driven models of AD. This study aimed to investigate the therapeutic effects of intradermal Profhilo^® injections in a recently developed ovalbumin (OVA)-induced murine model of AD. Specific objectives included assessing changes in skin inflammation, pain sensitivity, and spinal cord pathology. Materials and Methods: Twenty-eight adult female ICR-CD1 mice were sensitized and exposed to OVA via intraperitoneal, subcutaneous, and topical routes over 49 days to induce AD-like lesions. Control animals received saline. On day 50, mice were subdivided into four groups receiving intradermal injections of Profhilo^® or saline. Skin inflammation was evaluated using the SCORAD index on days 49 and 57, and nociceptive responses were measured using the plantar thermal hyperalgesia test. On day 57, dorsal skin and thoracic spinal cord samples were collected for histological and immunohistochemical analysis, including assessments of epidermal and dermal thickness, mast cell density, collagen content, CGRP immunoreactivity, and microglial activation. Results: OVA-treated mice developed significant skin inflammation (p < 0.0001) and thermal hyperalgesia. Intradermal HA injection significantly reduced SCORAD scores (p < 0.01) and mast cell density (p < 0.05) while increasing dermal thickness (p < 0.05). In the spinal cord, HA treatment reduced CGRP immunoreactivity and microglial activation (p < 0.01 and p < 0.05, respectively), especially in OVA-treated animals. Conclusions: Intradermal Profhilo^® alleviated both cutaneous inflammation and neurogenic pain in an OVA-induced AD model. These findings suggest that HA not only improves local skin pathology but also modulates central neuroimmune responses, supporting its therapeutic potential for inflammatory skin conditions involving peripheral and central sensitization. Full article

Background: A debilitating complication of diabetes is diabetic peripheral neuropathy (DPN), for which effective therapy remains limited. In this research, we evaluated the effects of quercetin, pioglitazone, insulin, and a novel thiazolidine-2,4-dione derivative (TZDd) on the nerve functions in a streptozotocin (STZ)-induced rat model of DPN. Methods: In the experimental groups, STZ (60 mg/kg) was administered to Wistar rats to induce type 1 diabetic neuropathy, and the control and experimental DPN groups were treated with quercetin, pioglitazone, insulin, or TZDd for 5 weeks. The sensory and motor symptoms of DPN were evaluated via behavioral tests, nerve conduction velocity measurements, and electrophysiological assessment, and the synthesized TZDd was evaluated in silico for its pharmacokinetic, toxicological, and drug-likeness properties. Results: The diabetic rats developed DPN after 2 weeks of STZ administration, as evidenced by the significant reduction in the sensory and motor nerve conduction velocities (SNCVs and MNCVs) and increased mechanical hyperalgesia; on the other hand, quercetin, pioglitazone, insulin, and TZDd administration ameliorated the nerve functions of the DPN rats. In the in silico predictions, the novel TZDd exhibited no toxicity risks and demonstrated drug-like properties. Conclusions: Quercetin, pioglitazone, insulin, and TZDd showed neuroprotective effects that enhanced functional recovery in experimental DPN. These findings highlight that TZDd may represent a valuable compound with neuroprotective effects that could be used in DPN therapy and management. Full article

Effective pain management is central to anesthesia, critical care, and perioperative medicine, and opioids remain essential agents for moderate-to-severe pain despite ongoing concerns regarding their safety and misuse. This narrative review synthesizes the current knowledge on opioid mechanisms, clinical indications, safety considerations, and evolving strategies aimed at optimizing their use. Opioids exert their analgesic effects primarily through μ-, δ-, and κ-opioid receptors, which modulate central and peripheral nociceptive pathways. They maintain a well-established role in acute postoperative and cancer-related pain, whereas their use in chronic non-cancer pain remains controversial. Contemporary evidence suggests that physiological dependence and addiction are less frequent in appropriately selected and monitored patients, although the risk increases in the presence of psychological comorbidity, prior substance use, or adverse social determinants of health. Unequal access, prescribing variability, and persistent disparities further complicate global opioid management strategies. Recent advances, including partial agonists such as buprenorphine, dual-mechanism agents such as tapentadol, individualized titration, opioid rotation, and the integration of multimodal analgesia, support safer and more tailored prescribing. Non-pharmacological interventions, including behavioral and physical therapies, increasingly complement pharmacological strategies to minimize opioid exposure and improve functional outcomes. Clinicians must balance analgesic efficacy with adverse effects, such as tolerance, opioid-induced hyperalgesia, sedation, and respiratory depression, particularly in perioperative and critically ill populations. Opioids remain indispensable for selected indications but should be incorporated into a comprehensive, patient-centered, multimodal analgesic approach that prioritizes safety, ongoing reassessment, and individualized risk mitigation. Full article

Background/Objectives: The present study investigated the local analgesic effect of a novel synthetic cyclohexanone derivative, 2,6-bis-4-(hydroxyl-3-methoxybenzilidine)-cyclohexanone, or BHMC, in a mouse model of peripheral nociception. Methods: Local administration of BHMC (0.5–60 µg/paw) intra-plantarly in the hindpaws of mice exhibited significant inhibition in carrageenan-induced paw hyperalgesia. Intra-plantar pretreatment of naloxone (non-selective opioid receptor blocker), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP, selective µ-opioid receptor blocker), and nor-binaltorphimine (nor-BNI, selective κ-opioid receptor blocker), but not naltrindole hydrochloride (selective δ-opioid receptor blocker), reversed the anti-nociceptive effect of BHMC. The peripheral analgesic effect of BHMC was also reversed by intra-plantar pretreatment of methylene blue (soluble guanosyl cyclase blocker), but not N^G-nitro-L-arginine (L-NAME, nitric oxide synthase blocker). Involvement of the potassium channel in the local analgesic effect of BHMC was shown through the reversed analgesic effect by intra-plantar pretreatment of glibenclamide (ATP-sensitive potassium channel blocker), but not by charybdotoxin (large-conductance calcium-sensitive potassium channel blocker), apamin (small-conductance calcium-sensitive potassium ion channel blocker), or tetraethylammonium (voltage-sensitive potassium channel blocker). Results: Taken together, the present study demonstrated that the local administration of BHMC attenuated nociception, with possible mechanisms that may involve the desensitization of inflammatory mediators’ receptors, opioid receptor activation, and nitric oxide-independent cyclic guanosine monophosphate activation of ATP-sensitive potassium ion channel opening. Conclusions: The current findings may further support the exploration of BHMC as a new therapeutic agent for pain and inflammation, for the betterment of human health. Full article

Perioperative pain remains a major clinical challenge, with many surgical patients experiencing inadequate analgesia and progression to chronic postsurgical pain. Conventional opioid-centered strategies are limited by narrow therapeutic windows, systemic toxicity, tolerance, opioid-induced hyperalgesia, and poor efficacy in neuroimmune-driven pain states. Advances in molecular neuroscience and biomedical engineering have catalyzed the development of nonpharmacologic analgesic technologies that modulate pain pathways through biophysical rather than receptor–ligand mechanisms. This narrative review synthesizes emerging nonpharmacologic analgesic platforms relevant to anesthesiology, integrating molecular, cellular, and systems-level mechanisms with clinical evidence. It examines how peripheral sensitization, spinal dorsal horn plasticity, glial and neuroimmune activation, and supraspinal network dysfunction create ideal targets for device-based interventions. Electrical neuromodulation strategies, including peripheral and central techniques, are discussed alongside temperature-based, photonic, and focused-energy modalities. These include cryoneurolysis, radiofrequency techniques, photobiomodulation, and low-intensity focused ultrasound. Clinical integration within enhanced recovery pathways, patient selection, workflow considerations, and limitations of the current human evidence base are reviewed. While many of these technologies are established in chronic pain management, this review emphasizes available human perioperative data and discusses how chronic pain evidence informs perioperative translation within opioid-sparing multimodal anesthesia care. Collectively, these technologies support a mechanism-based, systems-level approach to pain modulation, with perioperative relevance varying by modality and strength of available human evidence. Full article

Numerous research works have tried to evaluate the correlation between inflammation and the onset of prostate cancer. Given the in vitro antioxidant power and the anti-proliferative effects on human prostate cancer cells shown by a Juglans regia L. fresh fruit extract, the aim of this work was the evaluation of its potential in the acute and chronic inflammatory states in vivo, revealing a strong anti-inflammatory activity. In the zymosan-induced edema formation assay, a light and non-significant edema reduction was shown. On the contrary, in the zymosan-induced thermal hyperalgesia assay, the reversion of hyperalgesia after the extract administration was determined. Moreover, in the formalin test, the extract caused a significant decrease in the licking time caused by the aldehyde, especially in the late phase. In silico, quercetin showed the best fit into the enzymatic pocket of AChE (docking score: −11.306 Kcal/mol). Neochlorogenic acid and ellagic acid gave the best docking scores on BChE (−10.292 Kcal/mol and −10.054 Kcal/mol, respectively). Abscisic acid showed a high binding affinity for the glucocorticoid receptor. Finally, quercetin and abscisic acid were quantified to complete the data by HPLC-DAD, giving 0.246 ± 0.003 mg/g of dried extract and 0.036 ± 0.004 mg/g of dried extract, respectively. Full article

Neuropathic pain (NPP) remains therapeutically challenging, with oxidative/nitrosative stress and neuroinflammation—amplified by nitric oxide (NO)—as key drivers. This study investigated geraniin (GRN), a naturally occurring hydrolyzable ellagitannin widely distributed in various plant species, including Phyllanthus spp. and Nephelium lappaceum (rambutan), in a rat model of sciatic nerve chronic constriction injury (CCI), focusing on NO-pathway involvement. Male Wistar rats (n = 8/group) received intraperitoneal GRN (3, 10, 30, or 100 mg/kg) or vehicle (1% DMSO in saline) daily for 21 days. Behavioral (thermal hyperalgesia, mechanical allodynia, sciatic functional index), electrophysiological (nerve conduction velocity), and biochemical markers—oxidative/nitrosative stress (nitrite, MDA), antioxidant defenses (GSH, SOD, CAT), inflammation (TNF-α, IL-1β, IL-6, MPO), and apoptosis (caspase-3)—were quantified. L-arginine or L-NAME was co-administered to probe NO signaling. GRN at 30 and 100 mg/kg produced significant antinociceptive and neuroprotective effects; 30 mg/kg was selected for detailed analysis. By day 21, GRN improved pain thresholds and nerve conduction, enhanced antioxidant capacity, suppressed inflammatory mediators, and reduced caspase-3 activity. L-arginine reversed, whereas L-NAME potentiated these effects, confirming NO-dependent modulation. Collectively, GRN mitigates CCI-induced NPP via coordinated antioxidant, anti-inflammatory, and anti-apoptotic actions, supporting its potential as a multi-target candidate for pharmacokinetic and translational development. Full article

Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain due to a lack of effective and safe analgesics. In this study, we investigated the role of spinal TLR7 in the pathogenesis of chronic pain using female MRL lupus prone (MRL/lpr) mice, a SLE mouse model. We found that from 11 weeks of age, MRL/lpr mice exhibited thermal hypersensitivity in the hind paw, which reached plateau between 14 and 16 weeks. MRL/lpr mice with thermal hypersensitivity had increased expression of TLR7 in the spinal dorsal horn. TLR7 was located in microglia in this region. Intrathecal administration of a TLR7 antagonist attenuated the thermal hypersensitivity in MRL/lpr mice, while administration of the TLR7 agonist induced thermal hypersensitivity in control mice. Pharmacological activation of spinal TLR7 in control mice recapitulated molecular, synaptic, and cellular changes in the spinal dorsal horn of MRL/lpr mice with thermal hyperalgesia. These alterations included activation of microglia and astrocytes, increased production of IL-1β and IL-18, upregulated expression of N-type voltage-gated calcium channels (Cav2.2), enhanced glutamatergic synaptic activity, and elevated neuronal activation. Our findings suggest that targeting TLR7 or downstream effectors may represent a promising strategy to alleviate chronic pain induced by SLE. Full article