Mechanical Hyperalgesia Research Articles

Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat.

The CXC motif chemokine ligand 8 (CXCL8)-CXC motif chemokine receptor 1/2 (CXCR1/2) axis has been implicated in type 1 diabetes mellitus (T1DM). Its actions on non-immune cells may also contribute to T1DM-associated complications, including painful diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR). We assessed the efficacy of early (4-8 weeks) or late (8-12 weeks) daily ladarixin (LDX) for the treatment of streptozotocin (STZ)-induced T1DM and the related complications of DPN or DR in male rats. Early LDX mitigated STZ-induced dysmetabolism (i.e., blood glucose, insulin), inflammation in dorsal root ganglion/ sciatic nerve (interleukin-1β and tumor necrosis factor-α expression) and mechanical allodynia and thermal hyperalgesia, indicative of DPN. Moreover, vitreous citrullinated histone H3 (CitH3) and plasma GRO/CINC1 (CXCL8) increase were attenuated. Late LDX failed to reverse STZ-induced changes in metabolic parameters (i.e., blood glucose, insulin, C-peptide, pancreatic β-cell number and function). Strikingly, even in the absence of an effect on glycemic control, late LDX mitigated STZ-induced mechanical allodynia and thermal hyperalgesia and vitreous (CXCL8, CitH3) and retinal (CXCL8, CXCR1/2, myeloperoxidase, CitH3) inflammatory/pro-angiogenic (vascular endothelial growth factor, CD34) signs of DR. These data confirm the efficacy of LDX in STZ-induced T1DM and provide evidence of a protective effect also against DPN and onset of DR which is independent of its effect on β-cell functionality preservation and glycemic control.

A glutamatergic innervation from medial area of secondary visual cortex to lateral posterior thalamic nucleus facilitates nociceptive and neuropathic pain

Neuropathic pain involves complex cortical mechanisms, yet the role of the medial secondary visual cortex (V2M) remains poorly understood. We hypothesized that glutamatergic neurons in V2M (V2MGlu) contribute to pain modulation and explored their functional involvement in both normal and neuropathic pain states. Here, we found that V2MGlu could be activated by peripheral stimulation under normal conditions. Optical inhibition or activation of unilateral V2MGlu respectively decreased or increased bilateral nociceptive sensitivity, with activation also inducing aversive emotions. Tracing experiments revealed that V2MGlu sends dense synaptic projections to the lateral posterior thalamic nucleus (LP) and lateral dorsal thalamic nucleus (LD). Notably, only optical manipulation of V2MGlu terminals in LP, rather than LD, affected bilateral pain perception. Following partial sciatic nerve ligation (PSL), V2MGlu exhibited hyperactivity, including increased spontaneous spike frequency and heightened responses to stimulation. Inhibiting V2MGlu alleviated PSL-induced mechanical allodynia, thermal hyperalgesia, and negative affective states related to pain. Inhibition of V2MGlu terminals in LP mitigated neuropathic pain. Here, we identified V2MGlu and its circuits to LP as part of the endogenous pain modulatory network, hyperactive after peripheral nerve injury and contributing to neuropathic pain. Our findings support targeting V2MGlu and related circuits as potential therapeutic strategies for neuropathic pain.

Gut microbiome and serum metabolites in neuropathic pain: The PPARα perspective.

Gut microbiome and serum metabolites in neuropathic pain: The PPARα perspective.

Murraya koenigii Linn. Modulate diabetic neuropathy via attenuation of mechanical hyperalgesia and allodynia in STZ-induced diabetic rats

Murraya koenigii Linn. Modulate diabetic neuropathy via attenuation of mechanical hyperalgesia and allodynia in STZ-induced diabetic rats

Chronic Pain Induced by Social Defeat Stress in Juvenile Mice Depends on TLR4.

A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. The components of the nervous system that link stress and pain in early life remain unclear. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLRs), as critical for inducing long-term anxiety and pain-like behaviors in social defeat stress (SDS) models. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL/6J or Tlr4-/-) underwent six social defeat sessions with adult aggressor (CD1) mice. In WT mice, SDS promotes chronic mechanical allodynia and thermal hyperalgesia assessed via von Frey testing and the Hargreaves test, respectively. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4-/--stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases in TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating TLR4 activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord.

Spinal KCC2 Mediates the Modulation Effect of HDAC2 on Bone Cancer Pain in Rats.

Bone cancer pain is a global medical concern with limited treatment options that significantly reduce the quality of life for cancer patients. Therefore, identifying a promising therapeutic target for bone cancer pain is urgently needed. Our previous research indicated that KCC2 may be associated with the modulation of HDAC2 in a rat model of bone cancer pain. The current study aimed to investigate whether KCC2 in the lumbar spinal cord is a key downstream molecule in the modulation of HDAC2 related to bone cancer pain. In this study, we assessed the expression levels of KCC2 and HDAC2 in the lumbar spinal cord of rats with bone cancer pain using Western blotting and RT-PCR. Mechanical hyperalgesia was evaluated using Von Frey hairs, and immunofluorescence was employed to localize KCC2 in central nervous system cells. The expression of KCC2 was down-regulated in a time-dependent manner in the lumbar spinal cord of rats with bone cancer pain. Furthermore, the use of an RNA-interfering lentivirus targeting HDAC2 restored KCC2 expression and alleviated mechanical hyperalgesia in these rats. Notably, the analgesic effect of the HDAC2-targeting lentivirus was completely reversed by the KCC2 inhibitor VU0240551. KCC2 in the lumbar spinal cord mediated the modulation of HDAC2 in rat models of bone cancer pain, suggesting that KCC2 could be a promising therapeutic target for treating bone cancer pain.

TNF-α Enhanced Activity of Sympathetic Neurons in Superior Cervical Ganglion to Promote Chronic Sleep Deprivation-Related Hyperalgesia.

The mechanisms underlying the association between sleep deprivation (SD) and hyperalgesia remain incompletely understood. In this study, the Modified Horizontal Platform Method was employed to induce chronic SD. Neuropathic pain was induced using chronic constriction injury of the sciatic nerve. Pain-like behaviors were assessed through measurements of mechanical allodynia and thermal hyperalgesia, while gait analysis was used to evaluate motor function. Immunofluorescence and western blot analyses were conducted to examine the expression of TNF-α, Iba-1, TH, neurons and c-Fos. Apoptosis was assessed using TUNEL staining. To explore anatomical connections, anterograde and retrograde tracer viruses were injected into the superior cervical ganglion (SCG) and the spinal cord, respectively. Local injection of 6-OHDA was used to ablate sympathetic neurons in the SCG, and R-7050 was administrated to block the TNF-α receptor. We found that chronic SD induced hyperalgesia in both normal and neuropathic pain model, accompanied by significant infiltration of microglia in the dorsal horn. TH expression and apoptotic cells were increased in the SCG following chronic SD. Viral tracer results demonstrated the existence of anatomical connections between the SCG and the spinal cord. Ablation of sympathetic innervation improved pain-like behaviors and reduced microglia, without affecting movement. Furthermore, chronic SD led to increased expression of TNF-α in sympathetic neurons, which was associated with heightened SCG activity. Blocking the TNF-α receptor ameliorated pain-like behaviors, decreased microglia, reduced apoptosis, lowered SCG activity. In conclusion, TNF-α enhanced the activity of sympathetic neurons in the SCG, promoting hyperalgesia related to chronic SD.

Anterior Cingulate Cortex-Anterior Insular Cortex Circuit Mediates Hyperalgesia in Adolescent Mice Experiencing Early Life Stress.

Understanding neurobiological mechanisms underlying changes in behavior and neural activity caused by early life stress (ELS) is essential for improving these adverse outcomes in individuals. ELS incited by exposure to maternal separation (MS) can be defined as a form of social pain, but little is known about the neural mechanism in adolescents with ELS-induced pain sensitization. Employing an MS-induced ELS paradigm in mice, we reported here that both male and female MS mice aged 1-2 months exhibited mechanical and thermal hyperalgesia using paw-withdrawal and hot/cold plate tests. The increased high gamma (γhigh) oscillations accompanied by the activation of parvalbumin-positive interneurons (PVINs) in the anterior insular cortex (AIC), but not the anterior cingulate cortex (ACC), were shown in MS mice. Moreover, ACC-driven AIC connectivity was enhanced in MS mice, characterized by amplified phase coherence in the delta (δ) and theta (θ) bands and an escalation in the coupling of the ACC θ phase and AIC γ amplitude. Chemogenetic inactivation of AIC PVINs relieved hyperalgesia and altered the ACC-AIC connectivity in MS mice. The observed increase in δ-θ synchronization and PVIN activation in the ACC-AIC circuit indicates this pathway is a therapeutic target for ELS-induced hyperalgesia.

GDF11 Mitigates Neuropathic Pain via Regulation of Microglial Polarization and Neuroinflammation through TGF-βR1/SMAD2/NF-κB Pathway in Male Mice.

Spinal microglial activation and the polarization towards the M1 phenotype are implicated in the pathological process of neuropathic pain. Extensive research has elucidated that growth and differentiation factor 11 (GDF11), a constituent of the transforming growth factor-β (TGF-β) superfamily, exerts inhibitory effects on macrophage activation and mitigates inflammatory responses via the activation of TGF-β receptor type I (TGF-βR1). Nonetheless, the influence of GDF11 on spinal microglial polarization and its role in neuropathic pain remains to be ascertained. In the present investigation, a neuropathic pain model was induced via a spared nerve injury (SNI) procedure on the sciatic nerve in male mice. The impact of GDF11 on microglial polarization and neuropathic pain in SNI-subjected mice was evaluated through pain behavior assessments, WB, IF, qRT-PCR, and ELISA. Our findings revealed a significant downregulation of spinal GDF11 and TGF-βR1 expression levels in microglia of mice subjected to SNI. Furthermore, GDF11 treatment notably reversed the mechanical allodynia and thermal hyperalgesia, inhibited M1 microglial polarization, and attenuated neuroinflammatory processes by modulating the SMAD2/NF-κB in SNI mice. However, the analgesic effects of GDF11 on pain hypersensitivity and its modulatory influence on spinal microglial polarization were abrogated by the application of a specific antagonist of TGF-βR1, or the TGF-βR1 siRNA. In summary, GDF11 effectively ameliorated mechanical allodynia and thermal hyperalgesia, suppressed M1 microglial polarization, and alleviated neuroinflammation via the regulation of the TGF-βR1/SMAD2/NF-κB pathway in mice with SNI. These findings suggest that GDF11 holds promise as a therapeutic modality for the management of neuropathic pain.

The cannabinoid CB2 receptor mediates the analgesic effects of Cannabis sativa extract in a rat model of neuropathic pain.

The cannabinoid CB2 receptor mediates the analgesic effects of Cannabis sativa extract in a rat model of neuropathic pain.

Electroacupuncture Modulates Programmed Cell Death 1 Ligand 1 on Peripheral and Central Nervous Systems in a Mouse Fibromyalgia Pain Model.

Background: Fibromyalgia, a chronic condition that causes long-lasting pain over several months, is a global medical issue with both personal and societal implications. It is one of the hardest types of pain to heal, given the lack of objective parameters for diagnosis and progression evaluation. The main symptoms of fibromyalgia are long-lasting widespread pain alongside with anxiety, fatigue, sleep disorders, cognitive dysfunction, and obesity. Programmed cell death 1 ligand 1 (PD-L1) has been used as a target in cancer immunotherapy. It can inhibit acute and chronic pain by suppressing nociceptive neuron activity via PD-1 receptors. Methods: The current study aimed to investigate the role of PD-L1/PD1 in a mouse fibromyalgia pain model. Mice were exposed to intermittent cold stress (ICS) to produce a murine fibromyalgia model characterized using von Frey and Hargreaves tests. Results: The ICS-induced mice fibromyalgia pain model showed mechanical (2.26 ± 0.18 g) and thermal (4.36 ± 0.31 s) hyperalgesia. Nociceptive responses could be relieved with electroacupuncture, intracerebral PD-L1 injection, or Trpv1 deletion. We also identified a lower PD-1 level in the dorsal root ganglion, spinal cord, thalamus, and somatosensory cortex. In contrast, levels of pain-related kinases increased after fibromyalgia induction, an effect which could be reversed by EA, PD-L1, or Trpv1 deletion. Conclusions: Our findings shed light on the contribution of PD-L1/PD1 to EA and fibromyalgia pain, indicating its potential as a treatment target for fibromyalgia.

P2Y12-mediated HIV gp120 and ddC-induced neuropathic pain improved by esculin.

We studied whether esculin (ES) has the effect of alleviating peripheral neuropathic pain (NP) in rat models of HIV glycoprotein 120 (gp120) together with zalcitabine (2',3'-dideoxycytidine; ddC) treatment and explored the possible mechanism of it. The rats pain behaviors were evaluated by observing the paw withdrawal threshold (PWT) and the paw withdrawal latency (PWL). The rats were divided into a control group, sham group, gp120 combined with a ddC treatment group (gp120& ddC group), gp120&ddC combined with ES treatment group (gp120&ddC+ES group), which ES was administered intragastrically, and gp120&ddC combined with short hair RNA of P2Y12 receptor (rP2Y12) treatment group (gp120&ddC+shP2Y12 group), which shRNA of rP2Y12 was injected intrathecally with a dose of 25 µg/20 µl for every rat, and a negative control plasmid was administered to the gp120&ddC+nc group. Western blotting was used to measure the protein expression levels of the rP2Y12, the nuclear factor of activated T-cells type c1 (NFATc1), phospho-NFATc1 and the C-C motif chemokine ligand 3 (CCL3) in the L4-L6 dorsal root ganglia (DRG). Real-time quantitative PCR (RT-qPCR) was used to test the mRNA expression level of the CCL3. Double-labeling immunofluorescence was used to identify the co-localization of the rP2Y12 with glial fibrillary acidic protein (GFAP) in DRG. Fluorescence imaging with calcium indicator fluo-3 AM (7.5 μM) was performed to observe the change of intracellular calcium concentration ([Ca2+]i). Molecular docking was performed to identify the interaction between rP2Y12 and the ligand ES. We found that accompanied by the attenuation of mechanical allodynia and thermal hyperalgesia, rP2Y12 expression in the gp120+ddC+ES group of rats was downregulated compared with the gp120+ddC ones, as was the coexpression of the rP2Y12 and GFAP of satellite glial cells (SGCs) in DRG, and the CCL3 mRNA levels and protein expression were both decreased. In addition, mechanistic studies have found that there is a docking pocket between ES and the rP2Y12 protein, which causes ES to decrease the [Ca2+]i, thus increasing the phosphorylation level of NFATc1. Taken together, the results suggest that ES can combine with the rP2Y12, inhibit DRG SGCs activation caused by gp120&ddC, reduce [Ca2+]i, and prevent the NFATc1-mediated gene transcription of CCL3, finally relieving NP in rats treated with gp120&ddC.

NFAT1 Signaling Contributes to Bone Cancer Pain by Regulating IL-18 Expression in Spinal Microglia.

This study aimed to test the hypothesis that nuclear factor of activated T cells 1 (NFAT1) signaling contributes to bone cancer pain by regulating interleukin (IL)-18 expression in spinal microglia. This study was performed on male mice using a Lewis lung carcinoma-induced bone cancer pain model. Nociceptive behaviors were evaluated by measuring mechanical allodynia, thermal hyperalgesia, and spontaneous pain. Expression levels were measured via real-time quantitative polymerase chain reaction, western blotting, and immunofluorescence analysis. The effect of pharmacologic intervention of spinal NFAT1/IL-18 signaling on bone cancer pain was the primary outcome. NFAT1 expression was upregulated in the spinal microglia after tumor inoculation. Pharmacological inhibition of NFAT1 upregulation prevented and reversed bone cancer-related pain behaviors. In spinal microglia, NFAT1 inhibition decreased p38 MAPK phosphorylation and IL-18 production. Blocking NFAT1 signaling suppressed tumor-induced neuronal sensitization and microglial activation as well as activation of the N-methyl-D-aspartate receptor and the subsequent Ca2+-dependent signaling. Microglia NFAT1-p38 signaling contributes to bone cancer pain through IL-18-mediated central sensitization in spinal microglia. NFAT1 could be a potential target for therapeutic intervention to prevent bone cancer pain.

Effects of Combined Shinbaro and Celecoxib in a Complete Freund's Adjuvant-Induced Inflammatory Pain Mouse Model.

Persistent inflammation resulting from injury, infection, or arthritis contributes to both peripheral and central sensitization. Various combinations of natural extracts have been explored to minimize the side effects associated with conventional medications. Shinbaro, which has traditionally been used in Eastern medicine to treat inflammatory conditions, was chosen due to its known anti-inflammatory properties. However, previous studies have not yet investigated the combined administration of celecoxib and Shinbaro for their anti-inflammatory and analgesic effects. In this study, we examined the anti-inflammatory and analgesic effects of combining celecoxib with Shinbaro in a complete Freund's adjuvant (CFA)-induced inflammatory pain model. We randomly assigned 66 mice to 6 groups (n = 11 per group) and administered intraplantar injections of 100μL CFA or saline into their right hind paw, followed by oral administration of Shinbaro (100 mg/kg), celecoxib (15 or 30 mg/kg), or both 30minutes later. Behavioral assessments were conducted blindly at baseline and on days 1, 3, and 7 post-injection. The right hind paw and spinal cord were harvested 3 days post-injection to examine the molecular mechanisms, including macrophage infiltration in the right hind paw, as well as glial cell activation and inflammatory cytokine levels in the spinal cord. Statistical analysis was performed using Tukey's post-hoc test. The combination of Shinbaro (100 mg/kg) and celecoxib (15 mg/kg) synergistically reduced mechanical hyperalgesia and paw edema by preventing the conversion of monocytes to macrophages and inhibiting macrophage infiltration. Moreover, it decreased the expression of pro-inflammatory cytokines and mediators in the spinal cord by inhibiting spinal microglial activation. The combination of Shinbaro and celecoxib demonstrates significant anti-inflammatory and analgesic effects, suggesting its potential for managing inflammatory pain with fewer side effects than conventional therapies.

High energy diet-induced prediabetic neuropathic pain is mediated by reduction of SIRT6 negative control of both spinal and peripheral neuroinflammation.

High energy diet-induced prediabetic neuropathic pain is mediated by reduction of SIRT6 negative control of both spinal and peripheral neuroinflammation.

Accumulation of advanced oxidative protein products exacerbate satellite glial cells activation and neuropathic pain

BackgroundNeuropathic pain (NP) is a debilitating condition caused by lesion or dysfunction in the somatosensory nervous system. Accumulation of advanced oxidation protein products (AOPPs) is implicated in mechanical hyperalgesia. However, the effects of AOPPs on NP remain unclear.MethodsA rat model of NP was established by chronic constriction injury (CCI) and employed to evaluate the changes of mechanical withdrawal threshold, thermal and cold withdrawal latency, as well as AOPPs levels. The effects of AOPPs on the activation of satellite glial cells (SGCs) in the dorsal root ganglion (DRG), receptor for advanced glycation end-products (RAGE) expression, and NF-κB signaling pathway activation were also investigated using western blotting, immunofluorescence, and the Fluo4-AM fluorescence probe for calcium signaling. Additionally, oxidative stress levels and inflammatory cytokine production in SGCs, triggered by AOPPs exposure, were measured through the DCFH-DA probe for ROS detection and ELISA kits for cytokine quantification.ResultsCCI significantly elevated the AOPPs levels in the plasma and sciatic nerve and caused AOPPs accumulation in the DRG. Exogenous AOPPs activated SGCs, increased reactive oxygen species and inflammatory response, upregulated the RAGE, and activated NF-κB signaling. The RAGE inhibitor FPS-ZM1 effectively inhibited AOPPs-induced SGC activation. Additionally, AOPPs intervention worsened CCI-induced hyperalgesia and neuroinflammation in vivo.ConclusionThese results indicate that AOPPs exacerbate the SGC activation and NP following nerve injury, and AOPPs accumulation might play an important role in the pathogenesis of NP.

Rapid weight loss and combat athletes: a study on psychological resilience and mechanical hyperalgesia.

The study investigates the effects of Rapid Weight Loss (RWL) on the levels of psychological resilience and mechanical pain sensitivity in elite kickboxers. The primary aim was to examine changes in psychological resilience subdimensions and pressure pain threshold (PPT) values in the thoracolumbar region before and after a one-month RWL period leading up to competition. Hypotheses included expectations of significant reductions in PPT values due to biomechanical and physiological changes during RWL, along with improvements in psychological resilience subdimensions due to structured routines and social support. Thirty-seven elite male athletes (age: 22.94 ± 1.98) participated in the study. Psychological resilience was assessed using the Psychological Resilience Scale for Adults, and mechanical pain sensitivity was evaluated through Pressure Pain Threshold (PPT) measurements. Measurements were conducted before and after the RWL period, spanning one month prior to competition. The results revealed significant PPT values across all thoracolumbar segments after RWL (p < 0.001). Cohen's d values indicated large effect sizes for these changes (d = 2.10-2.36). The L5 segment exhibited the largest PPT decrease (t = -10.45, d = 2.36), while the Th1 segment showed the smallest decrease (t = -8.23, d = 2.10). Measurements taken at 4 cm from the spine midline also demonstrated significant PPT reductions (p < 0.001), with the highest change recorded in the L5 segment (t = -9.78, d = 2.30). Psychological resilience subdimensions, including "structured style," "social competence," "future orientation," and "social resources," improved significantly after RWL (p < 0.05), while "family cohesion" and "personal strength" did not show significant changes. Athletes who previously ranked in tournaments exhibited higher psychological resilience, potentially due to enhanced self-confidence. These findings align with literature suggesting that competitive success and optimism play crucial roles in resilience development. Personality traits and perceived social support further contributed to the observed resilience levels. This study highlights the multidimensional impact of RWL, emphasizing its detrimental effects on pain sensitivity and its mixed outcomes on psychological resilience. RWL-associated increases in mechanical hyperalgesia, especially in the lumbar region, were attributed to biomechanical and neurophysiological factors. Enhanced psychological resilience observed in certain subdimensions underscores the importance of structured and social support systems in mitigating RWL-induced stress. Future research should explore interventions to optimize resilience and manage pain during RWL periods, focusing on individualized support strategies for athletes. These findings contribute to understanding the interplay between psychological and physiological factors during RWL, practical insights for athletic training.

Long-term effects of linear versus macrocyclic GBCAs on gene expression in the central nervous system of mice

BackgroundWe examined chronic gadolinium retention impact on gene expression in the mouse central nervous system (CNS) after injection of linear or macrocyclic gadolinium-based contrast agents (GBCAs).MethodsFrom 05/2022 to 07/2023, 36 female mice underwent weekly intraperitoneal injections of gadodiamide (2.5 mmol/kg, linear), gadobutrol (2.5 mmol/kg, macrocyclic), or saline. Mice were sacrificed on day 29 or 391 after a 1-year washout. Assessments included magnetic resonance imaging (MRI), mechanical hyperalgesia tests, and inductively coupled plasma mass spectrometry to measure gadolinium levels. Ribonucleic acid (RNA) sequencing and bioinformatic analyses identified differentially expressed genes (DEGs), with validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB).ResultsPost-gadodiamide, MRI showed increased signal intensity in the deep cerebellar nuclei (pre, 0.997 ± 0.006 versus post, 1.086 ± 0.013, p < 0.001). Mechanical hyperalgesia tests indicated transient sensory changes. After 1-year, gadolinium retention was noted in the brain (5.92 ± 0.32 nmol/kg) and spinal cord (1.23 ± 0.66 nmol/kg) with gadodiamide, compared to saline controls (0.06 ± 0.02 nmol/kg in brains and 0.28 ± 0.06 nmol/kg in spinal cords). RNA sequencing identified 17 shared DEGs between brain and spinal cord in the gadodiamide group on day 391, with altered Hmgb2 and Sgk1 expression confirmed by qRT-PCR and WB. Reactome pathway analysis showed enrichment in neuroinflammation pathways. No DEGs were detected in brains on day 29.ConclusionChronic gadolinium deposition from repeated linear GBCA but not macrocyclic administration causes significant gene expression alterations in the mouse CNS, particularly affecting neuroinflammation pathways.Relevance statementThis study examined the long-term impact of chronic gadolinium retention on gene expression in the mouse CNS, uncovering significant changes associated with neuroinflammation pathways after repeated administration of linear GBCA, but not with macrocyclic GBCA. These findings highlight the importance of further research on the long-term safety of linear GBCA in medical imaging.Key PointsChronic gadolinium retention alters gene expression in the mouse central nervous system.Significant neuroinflammatory pathway changes were observed after linear gadodiamide exposure.MRI showed increased signal intensity in deep cerebellar nuclei after gadodiamide injection.Graphical

Clavulanic acid prevents paclitaxel-induced neuropathic pain through a systemic and central anti-inflammatory effect in mice.

Clavulanic acid prevents paclitaxel-induced neuropathic pain through a systemic and central anti-inflammatory effect in mice.

A novel approach to completely alleviate peripheral neuropathic pain in human patients: insights from preclinical data.

Neuropathic pain is a pervasive health concern worldwide, posing significant challenges to both clinicians and neuroscientists. While acute pain serves as a warning signal for potential tissue damage, neuropathic pain represents a chronic pathological condition resulting from injury or disease affecting sensory pathways of the nervous system. Neuropathic pain is characterized by long-lasting ipsilateral hyperalgesia (increased sensitivity to pain), allodynia (pain sensation in response to stimuli that are not normally painful), and spontaneous unprovoked pain. Current treatments for neuropathic pain are generally inadequate, and prevention remains elusive. In this review, we provide an overview of current treatments, their limitations, and a discussion on the potential of capsaicin and its analog, resiniferatoxin (RTX), for complete alleviation of nerve injury-induced neuropathic pain. In an animal model of neuropathic pain where the fifth lumbar (L5) spinal nerve is unilaterally ligated and cut, resulting in ipsilateral hyperalgesia, allodynia, and spontaneous pain akin to human neuropathic pain. The application of capsaicin or RTX to the adjacent uninjured L3 and L4 nerves completely alleviated and prevented mechanical and thermal hyperalgesia following the L5 nerve injury. The effects of this treatment were specific to unmyelinated fibers (responsible for pain sensation), while thick myelinated nerve fibers (responsible for touch and mechanoreceptor sensations) remained intact. Here, we propose to translate these promising preclinical results into effective therapeutic interventions in humans by direct application of capsaicin or RTX to adjacent uninjured nerves in patients who suffer from neuropathic pain due to peripheral nerve injury, following surgical interventions, diabetic neuropathy, trauma, vertebral disc herniation, nerve entrapment, ischemia, postherpetic lesion, and spinal cord injury.