Search Results (126)

This study provides a comprehensive evaluation of the effects of environmental stressors and physical exertion on human nociceptive processing across multiple ecologically relevant conditions. Using a repeated-measures design, participants (N = 45) completed up to five controlled laboratory (thermoclimatic chamber) sessions (baseline, simulated altitude at 4200 m asl, heat at +42 °C, cold at −10 °C, and exertion). Participants were tested by using electrical stimuli. Linear mixed-effects models with participant-level random intercepts, alongside estimated marginal means and bootstrap derived effect sizes, enabled robust characterization of within-subject differences. Thermal stress emerged as the strongest modulator of nociception. Heat exposure significantly elevated sensory and pain thresholds compared with all other conditions, whereas tolerance thresholds peaked during cold exposure, yielding the largest observed effects. Altitude consistently produced the lowest thresholds across all modalities. These contrasts were confirmed statistically in the mixed-effects models, and effect-size analyses indicated substantial within-subject differences between the thermal extremes. By integrating three distinct nociceptive modalities and extreme environment simulations, this work offers novel and informative insights into how environmental stressors shape pain processing. The discovery of opposing thermal effects on sensory/pain versus tolerance thresholds—within the same cohort and design—reveals modality-specific patterns not previously documented and suggests that hypoxia may further modulate these responses. Full article

Background: The pain experienced by people with fibromyalgia (FM) is thought to be the result of altered nociceptive processing, impaired descending inhibition and reduced tolerance to physical load. However, the relationship between the amount of exercise and pain reduction remains unclear. Methods: This study synthesized randomized controlled trials of exercise interventions for FM to quantify the combined analgesic effects of different types of exercise. A secondary aim was to standardize exposure using metabolic equivalent of task (MET)-based metrics and examine the association between cumulative intervention dose (MET·h) and analgesic response (Hedges’ g) across intervention arms. Following the PRISMA guidelines, a search was conducted in PubMed for randomized controlled trials published up to 31 December 2025. After screening and a full-text assessment, 15 trials were included. The protocols were converted into MET-defined intensity and weekly MET·min exposure, and the cumulative dose was calculated as the total MET·h accrued over the intervention period. Random-effects models were used to estimate the pooled effects within modality subgroups. Results: Across modalities, exercise was associated with reductions in pain, with effects typically falling within the small-to-moderate range. Larger improvements were observed in structured or supervised programs. The dose-response scatter plot showed wide variability across the dose range, with overlapping confidence intervals. An exploratory fourth-degree polynomial fit explained limited variance (R² = 0.1615) and did not indicate a monotonic dose-response pattern. This suggests that cumulative workload alone is a weak proxy for therapeutic response. Conclusions: Based on these findings, a pain-responsive algorithm combining weekly Visual Analogue Scale (VAS), ΔVAS and Talk Test thresholds was implemented as a preliminary online calculator to support the prescription of exercise tailored to symptoms. Full article

The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory neuron subtypes that convey nociceptive and mechanosensory signals from the sinus mucosa remain incompletely defined. In this study, trigeminal ganglion (TG) neurons innervating the maxillary sinus (maxillary sinus TG neurons) were retrogradely labeled with the fluorescent dye DiD in mice and characterized using ex vivo patch-clamp electrophysiology and single-cell RT-PCR. Maxillary sinus TG neurons were found to be predominantly small-diameter, C-afferent nociceptors with electrophysiologic features including high thresholds, repetitive firing, and broad action potentials. Notably, maxillary sinus TG neurons formed a distinct molecular and functional subgroup: they expressed Nav1.9, while showing minimal Nav1.8 expression and limited overlap with Nav1.8-positive nociceptor populations. A majority of maxillary sinus TG neurons were mechanically responsive, generating mechanically activated currents with heterogeneous adaptation profiles, and a subset expressed the mechanoreceptor Piezo2. Collectively, these findings identify maxillary sinus TG neurons as a specialized population of Nav1.9-enriched C-afferent nociceptors with mechanosensitive properties, providing a mechanistic framework for pressure-evoked sinus pain. This work advances the neurobiological basis of sinus-related pain and suggests that Nav1.9 and mechanoreceptor pathways may be potential therapeutic targets for conditions in which sinus symptoms overlap with migraine and other craniofacial pain disorders. 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

Background/Objectives: Linezolid is an oxazolidinone antibiotic whose prolonged use is associated with peripheral neuropathy, hyperlactatemia, and metabolic acidosis. These adverse effects are primarily linked to the inhibition of mitochondrial protein synthesis, respiratory chain dysfunction, and oxidative stress. Given the central role of impaired energy metabolism and redox imbalance in drug-induced peripheral neuropathy, therapeutic strategies targeting mitochondrial function are of particular interest. Accordingly, this study aimed to comparatively evaluate the effects of adenosine triphosphate (ATP), coenzyme Q10 (CoQ10), pyridoxine, and thiamine pyrophosphate (TPP) on linezolid-induced peripheral neuropathic pain in rats. Methods: Sixty male albino Wistar rats were assigned to ten groups: healthy (HG); ATP-only (ATPG, 5 mg/kg, intraperitoneally); CoQ10-only (CQ10G, 10 mg/kg, orally); pyridoxine-only (PDXG, 50 mg/kg, orally); TPP-only (TPPG, 20 mg/kg, intraperitoneally); linezolid-only (LZDG, 125 mg/kg, orally); linezolid+ATP (ATLG); linezolid+CoQ10 (CQLG); linezolid+pyridoxine (PXLG); and linezolid+TPP (TPLG). Treatments were administered once daily for ATP, CoQ10, and TPP, and twice daily for linezolid and pyridoxine for 14 days. Oxidative stress indices (MDA, tGSH, SOD, CAT) were quantified in the sciatic nerve using ELISA. Serum lactate dehydrogenase (LDH) activity and blood lactate levels were determined to evaluate metabolic disturbances. Mechanical paw withdrawal thresholds were measured using the Randall–Selitto test both before and after treatment. Results: Linezolid significantly reduced paw withdrawal thresholds and induced oxidative stress, antioxidant depletion, increased LDH activity, and hyperlactatemia. Co-treatment with ATP and CoQ10 attenuated oxidative stress but did not significantly improve linezolid-induced reductions in nociceptive thresholds. In contrast, pyridoxine partially alleviated linezolid-induced neuropathic pain and improved biochemical parameters. Notably, TPP exerted the most robust protective effect, preserving nociceptive thresholds and effectively normalizing oxidative stress and metabolic indices. Conclusions: These findings identify TPP as a promising therapeutic strategy for mitigating linezolid-induced peripheral neuropathic pain by targeting mitochondrial energy metabolism and pyruvate–lactate homeostasis. Full article

Background and Object: Complex Regional Pain Syndrome Type I (CRPS-I) is a debilitating condition often triggered by trauma, with early pathophysiology driven by neuroinflammation and oxidative stress. Avocado/soybean unsaponifiables (ASU) possess potent anti-inflammatory and antioxidant properties but have never been tested for CRPS-I prevention. This study investigated the preventive effects of early systemic administration of ASU on the development of CRPS-I-like features in a validated rat model of tibial fracture and cast immobilization. Methods: Twenty adult male Wistar rats were randomized into two groups (n = 10/group): a CRPS-I (Vehicle) group receiving daily intraperitoneal saline, and a CRPS-I+ASU group receiving daily ASU (300 mg/kg/day). The model was induced via a right tibial fracture followed by 28 days of cast immobilization. Treatment began immediately post-fracture. Behavioral outcomes (mechanical allodynia via von Frey, paw edema, temperature asymmetry) were assessed pre-fracture and on day 29. Subsequently, levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and oxidative stress markers (TAS, TOS, OSI) were measured in the ipsilateral hind paw tissue. Results: ASU treatment significantly attenuated the development of CRPS-I-like manifestations. Compared to the vehicle group, the ASU group exhibited a markedly lower median percentage decrease in mechanical withdrawal threshold (30.20% [22.56–37.01] vs. 51.45% [47.84–61.11], p = 0.001), reduced temperature asymmetry (0.75 °C [0.55–1.00] vs. 1.95 °C [1.80–2.33], p < 0.001), and less paw edema (8.35% [7.06–11.29] vs. 14.75% [12.66–19.20], p = 0.004). Biochemically, ASU treatment significantly suppressed tissue levels of IL-1β, IL-6, and TNF-α (all p < 0.001), enhanced total antioxidant status (TAS), and reduced total oxidant status (TOS) and the oxidative stress index (OSI) (all p < 0.001). Conclusions: Early systemic administration of ASU significantly prevents the development of nociceptive, vascular, inflammatory, and oxidative disturbances in a rat model of CRPS-I. These findings highlight ASU’s multimodal protective effects at the tissue level and position it as a promising candidate for early preventive intervention in post-traumatic CRPS-I. Full article

Background and Objectives: Lumbar disk herniation with radiculopathy (LDHR) is a prevalent neuromusculoskeletal condition characterized by nociceptive and neuropathic pain components. Manual therapy (MT) is commonly used in its management, whereas Functional Magnetic Stimulation (FMS) represents an emerging modality with limited evidence in radiculopathy. The aim of this study was to examine the short-term effects of combining MT with FMS compared with MT alone on pain intensity, neuropathic pain features, neural mechanosensitivity, and functional disability in individuals with chronic LDHR. Materials and Methods: Forty adults with MRI-confirmed unilateral LDHR were randomly allocated to an MT + FMS group or an MT-only group. Both groups received ten treatment sessions over three weeks. Outcomes included lumbar and leg pain intensity (NPRS), functional disability (RMDQ), neuropathic pain symptoms (S-LANSS), and straight leg raise (SLR) range of motion. Measurements were obtained at baseline and at week 3. Group and time effects were examined using a two-way mixed ANOVA with significance set at p < 0.05. Results: Significant group × time interactions were observed for all outcomes (p < 0.01), indicating greater improvements in the MT + FMS group. Reductions in lumbar and leg pain, disability, and S-LANSS scores exceeded established MCID thresholds, while SLR gains surpassed published MDC values, reflecting both statistical and clinical relevance. Only the MT + FMS group improved below the neuropathic pain diagnostic cutoff (S-LANSS < 12). Conclusions: The findings of this trial suggest that incorporating FMS into a manual therapy program may provide additional short-term clinical benefits for individuals with chronic LDHR. Further research with larger samples, longer follow-up periods, and mechanistic assessments is needed to confirm these preliminary results and to better understand the underlying mechanisms. Full article

Previous in vivo studies have clearly demonstrated that the intravenous administration of the carotenoid astaxanthin (AST) suppresses the excitability of rat trigeminal spinal nucleus caudalis (SpVc) neurons. This action is hypothesized to be mediated through the inhibition of both voltage-gated Ca²⁺ (Cav) channels and excitatory glutamate receptor transmission. The objective of this study was to determine whether acute intravenous administration of AST alleviates the hyperexcitability of SpVc wide dynamic range (WDR) neurons in a rat model of inflammation. Neuronal responses to both nociceptive and non-nociceptive mechanical stimulation were evaluated using an in vivo electrophysiological model. One day following inflammation induced by Complete Freund’s Adjuvant (CFA), the mechanical escape threshold was significantly reduced compared to pre-injection baseline values. Subsequently, extracellular single-unit recordings were performed on SpVc WDR neurons in anesthetized, inflamed rats. The neuronal responses to both non-noxious and noxious orofacial mechanical stimuli were then analyzed. Acute intravenous administration of AST at 1 and 5 mM elicited a dose-dependent reduction in the mean firing frequency of SpVc WDR neurons in response to noxious mechanical stimuli. This inhibition peaked within 10 min and was fully reversed after approximately 25 min. Importantly, AST preferentially inhibited the discharge frequency of SpVc WDR neurons in response to noxious stimulation, exhibiting a significantly greater effect than on the response evoked by non-noxious stimulation (41.5 ± 3.0% vs. 20.7 ± 4.2%, p < 0.05). Collectively, these findings demonstrate that acute intravenous administration of AST effectively suppresses noxious synaptic transmission within the SpVc during inflammation. We propose that this suppressive effect is mediated by the inhibition of upregulated Cav channels and glutamate receptors. Consequently, AST is implicated as a promising therapeutic candidate for the management of trigeminal inflammatory pain, given its potential for a favorable safety profile compared to conventional treatments. Full article

Five years after the onset of the SARS-CoV-2 pandemic, post-COVID-19 condition continues to affect millions of subjects with persistent symptoms that significantly impair quality of life. Post-COVID-19 pain, particularly in women, has emerged as a frequent yet underestimated symptom. The validation and identification of animal models that reproduce persistent symptoms after an acute SARS-CoV-2 infection is crucial for a better understanding of the underlying mechanisms. The aim of the current study was to evaluate thermal nociception, biomarkers of inflammation, and nerve tissue damage in a female animal model of post-COVID-19 condition. A SARS-CoV-2 infection model was established by intranasal administration of the Omicron variant (BA.1.17 lineage) in transgenic female C57BL/6 mice expressing the human ACE2 receptor (hACE2). Nociception was assessed using the hot-plate test for 28 days post-infection. Afterwards, animals were sacrificed to analyze plasma inflammatory biomarkers by multiplex analysis. In addition, IL-6, IL-18, and IL-1β expression were evaluated by immunohistochemistry to analyze neural inflammation in the saphenous nerve. The results revealed that heat nociceptive thresholds in infected mice did not significantly differ from those of non-infected, but a trend toward lower thresholds was observed in the infected group (days 14 and 28 post-infection). In addition, a slight modification in pro- and anti-inflammatory cytokines/chemokines in plasma was detected, but no changes in the expression of IL-6, IL-1β, or IL-18 were observed in the saphenous nerve. Based on all the analyses conducted, infection with the Omicron variant of SARS-CoV-2 did not induce thermal sensitization in animals nor alterations in the expression of inflammatory biomarkers in the saphenous nerve. Finally, a slight state of systemic inflammation was present in the infected animals. The absence of detectable changes in this animal model underscores the need for further research to clarify the discrepancies observed in human patients and to explore alternative pathways potentially involved in post-COVID-19 pain syndromes. Full article

Background/Objectives: Wound-related pain is a common, yet inadequately managed condition, and new therapeutic strategies are warranted. Limited data suggests that phytocannabinoids and cannabis may alleviate wound-related pain; however, further studies are required. This study investigated the effects of systemic administration of cannabidiol (CBD) on nociceptive behaviour following dorsum incision and on the endocannabinoid system. Methods: Male Sprague-Dawley rats (150–200 g on arrival, n = 9/group) underwent a 1.2 cm incision on the hairy skin of the dorsum or sham procedure. Back and hind paw mechanical withdrawal thresholds were assessed at baseline and post-surgery/sham days (PSDs) 1, 4, 7, and 8 using manual and electronic von Frey tests, respectively. On PSD 8, the effect of a single acute administration of CBD (3, 10, or 30 mg/kg, i.p.) on mechanical hypersensitivity in the dorsum and hind paws was assessed. The levels of endocannabinoids and N-acylethanolamines in the plasma and discrete brain regions following CBD administration were analysed. Results: Robust mechanical hypersensitivity was evident in the dorsum and hind paws following the incision. CBD (3 mg/kg) partially attenuated primary mechanical hypersensitivity in the dorsum, in a site- and dose-specific manner. CBD had no effect on secondary mechanical hypersensitivity. CBD did not alter the levels of endocannabinoids or N-acylethanolamines, but in rats that received CBD (3 mg/kg), levels of 2-AG were lower in the contralateral amygdala and levels of AEA were higher in the contralateral lumbar spinal cord, compared to the ipsilateral sides. Conclusions: These data provide evidence for antinociceptive effects of CBD in a model of incisional wound-related pain. Further research on CBD’s mechanism(s) of action is warranted. The potential antinociceptive effects of other phytocannabinoids in this model should also be investigated. Full article

Introduction: Migraine is featured by altered nociceptive processing and the presence of cognitive impairments. No study has previously investigated the influence of neurocognitive performance and executive functions in descending pain processing in this population. Aim: To assess the influence of neurocognitive processes and executive functions in conditioned pain modulation (CPM) activation in women with migraine. Methods: A cross-sectional case–control study including 140 women with migraine (50% chronic) and 70 control women was conducted. Clinical migraine features, neurocognitive processes (e.g., attention), and executive functions (memory, mental inhibition, speed of processing) were evaluated. Pressure pain thresholds (PPTs) were bilaterally assessed at the temporalis muscle, lateral epicondyle, and tibialis anterior muscle. Heat (HPT) and cold (CPT) pain thresholds were assessed at the frontalis (trigeminal area) muscle. Thus, CPM was evaluated with the cold pressor test paradigm by analyzing changes in mechanical/thermal stimuli after a conditioned stimulus. Results: Significant group*time interactions not associated with neurocognitive process/executive function, educational level, and employment status were found for PPTs at the temporalis muscle (Wilk’s λ = 0.588, F[2,199] = 69.756, p < 0.001, n²p = 0.412, 1 − β = 0.999), lateral epicondyle (Wilk’s λ = 0.674, F[2,200] = 48.331, p < 0.001, n²p = 0.326, 1 − β = 0.999), and tibialis anterior (Wilk’s λ = 0.751, F[2,200] = 33.110, p < 0.001, n²p= 0.249, 1 − β = 0.999): PPTs were higher after the conditioned stimulus in all points in control women (increases ranging from 11% to 17%), whereas PPTs were lower after the conditioned stimulus in women with migraine (decrease from −7.5% to −0.1%) when compared with PPTs at baseline. Changes in HPT and CPT were small and not significant, ranging from 0.1% to 0.5%. Conclusion: This study revealed that women with episodic or chronic migraine showed CPM deficits particularly against mechanical stimuli when compared with pain-free women. Neurocognitive (e.g., attention) processes or executive functions (e.g., working memory, mental inhibition) did not modulate CPM activity in women with migraine. 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

Migraine is characterized by severe pain and somatic symptoms like allodynia and photophobia, driven by neuroinflammation that sensitizes the trigeminal vascular system (TVS). This study investigated how neuroinflammation induced by systemic lipopolysaccharide (LPS) affects migraine-related nociceptive signaling. Using a chronic migraine model in rats with nitroglycerin (NTG), we compared prenatal and acute postnatal LPS administration. Rats with prenatal LPS exhibited lower mechanical thresholds and enhanced allodynia and photophobia after NTG. Acute LPS also increased allodynia, but not photophobia. Both LPS groups showed increased mast cell degranulation in the dura mater. Plasma CGRP after NTG administration was elevated in the acute LPS group. Electrophysiology revealed enhanced trigeminal afferent responses to serotonin in both acutely and prenatally LPS-treated rats. Calcium imaging demonstrated increased neuronal responses to serotonin and capsaicin, suggesting an upregulation of serotonin and TRPV1 receptors. Our findings show that LPS-induced neuroinflammation, whether prenatal or acute, promotes sensitization of peripheral and central nociceptive pathways, involving serotoninergic mechanisms. Full article

Mechanical allodynia is the predominant symptom of neuropathic pain following peripheral nerve injury (PNI) and is characterized by pain evoked by innocuous sensory signals transmitted through low-threshold mechanoreceptive primary afferents, including Aβ fibers. However, the underlying neural mechanisms remain insufficiently understood. Previous studies have suggested that the pathological conversion of tactile input into nociceptive signals involves maladaptive alterations in neural circuits and function within the spinal dorsal horn (SDH). Somatosensory processing and transmission in the SDH are regulated not only by local neuronal circuits but also by descending inputs from the brainstem and higher cortical regions. In this study, we show that chemogenetic silencing of descending neurons projecting directly from the primary somatosensory (S1) cortex to the SDH (S1^→SDH neurons) suppresses both PNI-induced allodynia-like behavior and c-FOS expression in the superficial SDH observed in male rats where touch-sensing Aβ fibers were optogenetically activated. S1^→SDH neurons were excitatory and preferentially targeted excitatory SDH neurons (^S1→SDH neurons) broadly distributed across laminae I–V. ^S1→SDH neurons in the superficial laminae also received excitatory inputs from both Aβ fibers and inhibitory inputs from neuropeptide Y promoter active SDH neurons (NpyP⁺ neurons). Furthermore, loss of inhibition from NpyP⁺ neurons induced Aβ fiber-derived allodynia, which was attenuated by suppressing descending signaling from S1^→SDH neurons to the SDH. Moreover, silencing ^S1→SDH neurons alleviated neuropathic allodynia. These findings identify a new corticospinal mechanism that contributes to Aβ fiber-mediated neuropathic allodynia and highlight the S1→SDH pathway as a potential therapeutic target. Full article

Snakebite envenomation by Bothrops species is a neglected tropical disease and a major cause of local tissue damage and disability in Latin America. Antivenom therapy is effective against systemic effects but fails to prevent local myonecrosis, inflammation, and pain. This study evaluated photobiomodulation therapy (PBMT) using infrared (808 nm) alone or in combination with red (660 nm) laser in a murine model of Bothrops leucurus envenomation. A single PBMT session was applied, and animals were evaluated at 24 and 72 h. Combined treatment significantly reduced edema, hyperthermia, plasma CK and LDH, restored nociceptive thresholds, and improved motor recovery compared with infrared alone. Principal component analysis demonstrated clustering of combined-treatment animals with negative controls, supporting a synergistic therapeutic effect. These findings highlight dual-wavelength PBMT as a promising adjunctive approach to antivenom, directly targeting local venom-induced pathology. Full article