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Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.
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Chronic primary pain, characterized by overlapping symptoms of chronic pain, anxiety, and depression, is strongly associated with stress and is particularly prevalent among females. Recent research has convincingly linked epigenetic modifications in the medial prefrontal cortex (mPFC) to chronic pain and chronic stress. However, our understanding of the role of histone demethylation in the mPFC in chronic stress-induced pain remains limited. In this study, we investigated the function of lysine-specific histone demethylase 1A (KDM1A/LSD1) in the context of chronic overlapping pain comorbid with anxiety and depression in female mice. We employed a chronic variable stress model to induce pain hypersensitivity in the face and hindpaws, as well as anxiety-like and depression-like behaviors, in female mice. Our findings revealed that chronic stress led to a downregulation of KDM1A mRNA and protein expression in the mPFC. Notably, overexpressing KDM1A in the mPFC alleviated the pain hypersensitivity, anxiety-like behaviors, and depression-like behaviors in female mice, without affecting basal pain responses or inducing emotional distress. Conversely, conditional knockout of KDM1A in the mPFC exacerbated pain sensitivity and emotional distress specifically in females. In summary, this study highlights the crucial role of KDM1A in the mPFC in modulating chronic stress-induced overlapping pain, anxiety, and depression in females. Our findings suggest that KDM1A may serve as a potential therapeutic target for treating chronic stress-related overlap pain and associated negative emotional disorders.
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Dolor Crónico , Regulación hacia Abajo , Histona Demetilasas , Ratones Endogámicos C57BL , Corteza Prefrontal , Estrés Psicológico , Animales , Corteza Prefrontal/metabolismo , Femenino , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Ratones , Dolor Crónico/metabolismo , Dolor Crónico/psicología , Depresión/metabolismo , Depresión/etiología , Ansiedad/metabolismo , Ratones NoqueadosRESUMEN
OBJECTIVE: Temporomandibular disorders (TMD) affect the temporomandibular joint and associated structures. Despite its prevalence and impact on quality of life, the underlying mechanisms of TMD remain unclear. Magnetic resonance imaging studies suggest brain abnormalities in patients with TMD. However, these lines of evidence are essentially observational and cannot infer a causal relationship. This study employs Mendelian randomisation (MR) to probe causal relationships between TMD and brain changes. METHODS: Genome-wide association study (GWAS) summary statistics for TMD were collected, along with brain imaging-derived phenotypes (IDPs). Instrumental variables were selected from the GWAS summary statistics and used in bidirectional 2-sample MR analyses. The inverse-variance weighted analysis was chosen as the primary method. In addition, false discovery rate (FDR) correction of P value was used. RESULTS: Eleven IDPs related to brain imaging alterations showed significant causal associations with TMD (P-FDR < .05), validated through sensitivity analysis. In forward MR, the mean thickness of left caudal middle frontal gyrus (OR, 0.76; 95% CI, 0.67-0.87; P-FDR = 1.15 × 10-2) and the volume of right superior frontal gyrus (OR, 1.24; 95% CI, 1.10-1.39; P-FDR = 2.26 × 10-2) exerted significant causal effects on TMD. In the reverse MR analysis, TMD exerted a significant causal effect on 9 IDPs, including the mean thickness of the left medial orbitofrontal cortex (ß = -0.10; 95% CI, -0.13 to -0.08; P-FDR = 2.06 × 10-11), the volume of the left magnocellular nucleus (ß = -0.15; 95% CI, -0.22 to -0.09; P-FDR = 3.26 × 10-4), the mean intensity of the right inferior-lateral ventricle (ß = -0.09; 95% CI, -0.14 to -0.04; P-FDR = 2.23 × 10-2), the volume of grey matter in the anterior division of the left superior temporal gyrus (ß = 0.09; 95% CI, 0.04-0.14; P-FDR = 1.69 × 10-2), and so forth. CONCLUSIONS: This study provides genetic evidence supporting the bidirectional causal associations between TMD and brain IDPs, shedding light on potential neurobiological mechanisms underlying TMD development and its relationship with brain structure.
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Encéfalo , Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética , Fenotipo , Trastornos de la Articulación Temporomandibular , Humanos , Trastornos de la Articulación Temporomandibular/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Análisis de la Aleatorización Mendeliana , NeuroimagenRESUMEN
Temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) may present as comorbid conditions, but treatment options are ineffective. The purpose of this study was to investigate whether valproate (VPA) attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress, which represents a model of pain associated with TMD and FMS comorbidity, and to explore the potential mechanisms. The results showed that VPA inhibited somatic hyperalgesia induced by orofacial inflammation combined with stress, and down-regulated the interleukin-6 (IL-6) expression in the L4-L5 spinal dorsal horn of female rats. The anti-nociceptive effect of VPA was blocked by single or 5 consecutive day intrathecal administration of recombinant rat IL-6. Orofacial inflammation combined with stress up-regulated the ratio of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) to STAT1 (p-STAT1/STAT1) in the spinal cord. VPA did not affect the STAT1 expression, while it down-regulated the ratio of p-STAT1/STAT1. The expression of STAT3 and the ratio of p-STAT3/STAT3 were not affected by orofacial inflammation combined with stress and VPA treatment. Intrathecal administration of exogenous IL-6 up-regulated the ratio of p-STAT1/STAT1. These data indicate that VPA attenuated somatic hyperalgesia induced by orofacial inflammation combined with stress via inhibiting spinal IL-6 in female rats, and the mechanism may involve the alteration of activation status of spinal STAT1. Thus, VPA may be a new candidate analgesic that targets IL-6 and STAT1 for the treatment of pain associated with the comorbidity of TMD and FMS.
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Hiperalgesia , Ácido Valproico , Femenino , Ratas , Animales , Hiperalgesia/metabolismo , Ácido Valproico/efectos adversos , Interleucina-6/metabolismo , Fosforilación , Ratas Sprague-Dawley , Factor de Transcripción STAT1/metabolismo , Dolor/metabolismo , Médula Espinal/metabolismo , Inflamación/metabolismo , Factores Inmunológicos/farmacologíaRESUMEN
Autophagy, switched by the AMPK/mTOR signaling, has been revealed to contribute greatly to traumatic brain injury (TBI). Electroacupuncture (EA) is a promising therapeutic method for TBI, however, the underlying mechanism is still unclear. Herein, we hypothesize that the therapeutic effect of EA on TBI is associated with its inhibition on AMPK/mTOR-mediated autophagy. Sprague-Dawley rats were randomly divided into three groups: sham, TBI, and TBI + EA. TBI model was established by using an electronic controlled cortical impactor. Rats were treated with EA at 12 h after modeling, 15 min daily for 14 consecutive days. EA was applied at the acupuncture points Quchi (LI 11), Hegu (LI4), Baihui (GV20), Guanyuan (CV4), Zusanli (ST36) and Yongquan (KI1), using dense-sparse wave, at frequencies of 1 Hz, and an amplitude of 1 mA. After 3, 7 and 14 days of modeling, the modified neurological severity scale (mNSS), rota rod system, and Morris Water Maze (MWM) test showed that EA treatment promoted neurological function recovery in TBI rats. Moreover, EA treatment alleviated brain edema, pathological damage, neuronal apoptosis in TBI rats. EA improved abnormal ultrastructure, including abnormal mitochondrial morphology and increased autophagosomes, in the brain neurons of TBI rats, as measured by transmission electron microscopy, and the concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Western blot and immunohistochemistry (IHC) assays were performed to measure the protein levels of interleukin 10 (IL-10), autophagy-related proteins and key proteins in the AMPK/mTOR signaling pathway. EA treatment increased IL-10 production, inhibited the AMPK/mTOR signaling, and inhibited excessive autophagy in TBI rats. Additionally, AMPK inhibitor Compound C treatment had similar effects to EA. Both AMPK agonist AICAR and IL-10 neutralizing antibody treatments reversed the effects of EA on the related protein levels of autophagy and the AMPK/mTOR signaling pathway, and abolished the protective effects of EA on TBI rats. In conclusion, EA treatment promoted neurological function recovery and alleviated pathological damage and neuronal apoptosis in TBI rats through inhibiting excessive autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway.
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Lesiones Traumáticas del Encéfalo , Electroacupuntura , Ratas , Animales , Ratas Sprague-Dawley , Proteínas Quinasas Activadas por AMP , Interleucina-10 , Lesiones Traumáticas del Encéfalo/terapia , Transducción de Señal , Autofagia , Serina-Treonina Quinasas TORRESUMEN
This study aims to explore whether selenium (Se) concentration correlates with arseniasis in a high-arsenic coal area in the southern Shaanxi Province, China. Herein, an epidemiological investigation was conducted among 100 arsenic (As)-poisoned patients in Ziyang County, an area with high soil As and Se levels. Fifty healthy subjects were selected from areas without endemic As poisoning. The subjects in the high-As coal area were diagnosed with either normal, suspicious, mild, moderate, or severe As poisoning. Local coal, water, soil, corn, and pepper samples, as well as hair, blood, and urine samples of subjects and patients were collected and analyzed for their As and Se contents. The contents of As and Se in coal, soil, corn, pepper, and hair samples from Ziyang County were significantly higher than those in the control area. The As content of hair in Ziyang County positively correlated with As poisoning, whereas the Se content of hair and urine negatively correlated with As poisoning. The Se content in the body was negatively correlated with the degree of As poisoning, indicating that Se may accelerate the metabolism and decumulation of As and antagonize As toxicity.
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Recent studies have shown that the incidence of chronic primary pain including temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently reported that central sensitization and descending facilitation system contributed to the development of somatic pain hypersensitivity induced by orofacial inflammation combined with stress. The purpose of this study was to explore whether TMD caused by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and whether the cholecystokinin (CCK) receptor-mediated descending facilitation system promotes hypersensitivity through neuron-glia cell signaling cascade. UAC evoked thermal and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked at week 4 post UAC. The expression levels of CCK1 receptors, interleukin-18 (IL-18) and IL-18 receptors (IL-18R) were significantly up-regulated in the L4 to L5 spinal dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent with neurons. These findings indicate that the signaling transduction between neurons and glia at the spinal cord level contributes to the descending pain facilitation through CCK1 receptors during the development of the comorbidity of TMD and FMS. PERSPECTIVE: CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade, providing novel therapeutic targets for the clinical treatment of TMD and FMS comorbidities.
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Dolor Crónico , Maloclusión , Dolor Nociceptivo , Receptor de Colecistoquinina B , Animales , Colecistoquinina/metabolismo , Dolor Crónico/metabolismo , Hiperalgesia/metabolismo , Interleucina-18/metabolismo , Maloclusión/metabolismo , Neuroglía/fisiología , Neuronas , Dolor Nociceptivo/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina B/metabolismo , Receptores de Interleucina-18/metabolismo , Transducción de Señal/fisiología , Médula Espinal , Asta Dorsal de la Médula Espinal/metabolismoRESUMEN
Oxytocin (OT) is recognized as a critical neuropeptide in pain-related disorders. Chronic pain caused by the comorbidity of temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) is common, but whether OT plays an analgesic role in the comorbidity of TMD and FMS is unknown. Female rats with masseter muscle inflammation combined with 3-day forced swim (FS) stress developed somatic hypersensitivity, which modeled the comorbidity of TMD and FMS. Using this model, the effects of spinal OT administration on mechanical allodynia and thermal hyperalgesia in hindpaws were examined. Furthermore, the protein levels of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn were analyzed by Western blot. The OT receptor antagonist atosiban and 5-HT2A receptor antagonist ritanserin were intrathecally injected prior to OT injection in the separate groups. Intrathecal injection of 0.125 µg and 0.5 µg OT attenuated the hindpaw hyperalgesia. The expression of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn significantly increased following intrathecal injection of 0.5 µg OT. Intrathecal administration of either the OT receptor antagonist atosiban or 5-HT2A receptor antagonist ritanserin blocked the analgesic effect of OT. These results suggest that OT may inhibit hindpaw hyperalgesia evoked by orofacial inflammation combined with stress through OT receptors and/or 5-HT2A receptors, thus providing a therapeutic prospect for drugs targeting the OT system and for patients with comorbidity of TMD and FMS.
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Hiperalgesia , Oxitocina , Analgésicos/uso terapéutico , Animales , Femenino , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/complicaciones , Hiperalgesia/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Oxitocina/farmacología , Oxitocina/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Ritanserina/efectos adversos , Serotonina , Médula Espinal/metabolismoRESUMEN
Epigenetic regulation of gene expression has been implicated in the development of chronic pain. However, little is known about whether this regulation is involved in the development and treatment of chronic pain comorbidities such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), a comorbidity predominantly occurring among women. Here we explored the impact of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on somatic hyperalgesia induced by stress or stress combined with orofacial inflammation, which mimicked the comorbidity of FMS and TMD in rats. Our data showed that somatic thermal hyperalgesia and mechanical allodynia induced by both conditions were completely prevented by intrathecal injection of SAHA, which upregulated 5-HT2C receptors but downregulated 5-HT3 receptors in the spinal dorsal horn. Subsequent spinal administration of RS102221 to inhibit 5-HT2C receptors or SR57227 to activate 5-HT3 receptors reversed the analgesic effect of SAHA under both conditions. These results indicate that SAHA attenuates the pro-nociceptive effects of stress combined with orofacial inflammation and the effects of stress alone. This likely occurs through epigenetic regulation of spinal 5-HT2C and 5-HT3 receptor expression, suggesting that SAHA has potential therapeutic value in FMS or comorbid FMS-TMD patients with somatic hyperalgesia.
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Epigénesis Genética , Hiperalgesia , Animales , Femenino , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina , Médula Espinal , Vorinostat/farmacología , Vorinostat/uso terapéuticoRESUMEN
In some chronic primary pain conditions such as temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS), mild or chronic stress enhances pain. TMD and FMS often occur together, but the underlying mechanisms are unclear. The purpose of this study was to investigate the role of cholecystokinin (CCK) in the spinal cord in somatic hyperalgesia induced by orofacial inflammation combined with stress. Somatic hyperalgesia was detected by the thermal withdrawal latency and mechanical withdrawal threshold. The expression of CCK1 receptors, CCK2 receptors, ERK1/2 and p-ERK1/2 in the spinal cord was examined by Western blot. After the stimulation of orofacial inflammation combined with 3 day forced swim, the expression of CCK2 receptors and p-ERK1/2 protein in the L4-L5 spinal dorsal horn increased significantly, while the expression of CCK1 receptors and ERK1/2 protein remained unchanged. Intrathecal injection of the CCK2 receptor antagonist YM-022 or mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 blocked somatic hyperalgesia induced by orofacial inflammation combined with stress. Intrathecal administration of the MEK inhibitor blocked somatic sensitization caused by the CCK receptor agonist CCK8. The CCK2 receptor antagonist YM-022 significantly reduced the expression of p-ERK1/2. These data indicate that upregulation of CCK2 receptors through the MAPK pathway contributes to somatic hyperalgesia in this comorbid pain model. Thus, CCK2 receptors and MAPK pathway may be potential targets for the treatment of TMD comorbid with FMS.
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Colecistoquinina/metabolismo , Dolor Crónico/inmunología , Dolor Facial/inmunología , Hiperalgesia/inmunología , Estrés Psicológico/complicaciones , Animales , Dolor Crónico/patología , Modelos Animales de Enfermedad , Dolor Facial/patología , Femenino , Humanos , Hiperalgesia/patología , Inflamación/inmunología , Inflamación/patología , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina B/metabolismo , Asta Dorsal de la Médula Espinal/inmunología , Asta Dorsal de la Médula Espinal/patología , Estrés Psicológico/inmunología , Estrés Psicológico/psicologíaRESUMEN
Temporomandibular disorders (TMD) are a group of diseases in the oral and maxillofacial region that can manifest as acute or chronic persistent pain, affecting millions of people worldwide. Although hundreds of studies have explored mechanisms and treatments underlying TMD, multiple pathogenic factors and diverse clinical manifestations make it still poorly managed. Appropriate animal models are helpful to study the pathogenesis of TMD and explore effective treatment measures. At present, due to the high cost of obtaining large animals, rodents and rabbits are often used to prepare TMD animal models. Over the past decade, various animal models have been intensively developed to understand neurobiological and molecular mechanisms of TMD, and seek effective treatments. Although these models cannot carry out all clinical features, they are valuable in revealing the mechanisms of TMD and creating curative access. Currently, there are multitudinous animal models of TMD research. They can be constructed in different means and summarized into four ways according to the various causes and symptoms, including chemical induction (intra-articular injection of ovalbumin, collagenase, formalin, vascular endothelial growth factor, intramuscular injection of complete Freund's adjuvant, etc.), mechanical stress stimulation (passive mouth opening, change of chewing load), surgical operation (partial disc resection, joint disc perforation) and psychological stress induction. Here, we summarize and discuss different approaches of animal models for determining neurophysiological and mechanical mechanisms of TMD and assess their advantages and limitations, respectively.
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Chronic Overlapping Pain Conditions, including irritable bowel syndrome (IBS) and temporomandibular disorder (TMD), represent a group of idiopathic pain conditions that likely have peripheral and central mechanisms contributing to their pathology, but are poorly understood. These conditions are exacerbated by stress and have a female predominance. The presence of one condition predicts the presence or development of additional conditions, making this a significant pain management problem. The current study was designed to determine if the duration and magnitude of peripheral sensitization and spinal central sensitization differs between restraint stress-induced visceral hypersensitivity (SIH) and chronic comorbid pain hypersensitivity (CPH; stress during pre-existing orofacial pain). SIH in female rats, as determined by the visceromotor response, persisted at least four but resolved by seven weeks. In contrast, CPH persisted at least seven weeks. Surprisingly, colonic afferents in both SIH and CPH rats were sensitized at seven weeks. CPH rats also had referred pain through seven weeks, but locally anesthetizing the colon only attenuated the referred pain through four weeks, suggesting a transition to colonic afferent independent central sensitization. Different phenotypes of dorsal horn neurons were sensitized in the CPH rats seven weeks post stress compared to four weeks or SIH rats. The current study suggests differential processing of colonic afferent input to the lumbosacral spinal cord contributes to visceral hypersensitivity during comorbid chronic pain conditions. PERSPECTIVE: Chronic Overlapping Pain Conditions represent a unique challenge in pain management. The diverse nature of peripheral organs hinders a clear understanding of underlying mechanisms accounting for the comorbidity. This study highlights a mismatch between the condition-dependent behavior and peripheral and spinal mechanisms that contribute to visceral pain hypersensitivity.
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Dolor Crónico/fisiopatología , Colon/inervación , Dolor Facial/fisiopatología , Hiperalgesia/fisiopatología , Dolor Referido/fisiopatología , Células del Asta Posterior/fisiología , Células Receptoras Sensoriales/fisiología , Estrés Psicológico/fisiopatología , Dolor Visceral/fisiopatología , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Hiperalgesia/etiología , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/complicaciones , Dolor Visceral/etiologíaRESUMEN
Temporomandibular disorder (TMD) is commonly comorbid with fibromyalgia syndrome (FMS). The incidence of these pain conditions is prevalent in women and prone to mental stress. Chronic pain symptoms in patients with FMS and myofascial TMD (mTMD) are severe and debilitating. In the present study, we developed a new animal model to mimic the comorbidity of TMD and FMS. In ovariectomized female rats, repeated forced swim (FS) stress induced mechanical allodynia and thermal hyperalgesia in the hindpaws of the 17ß-estradiol (E2) treated rats with orofacial inflammation. Subcutaneous injection of E2, injection of complete Freund's adjuvant (CFA) into masseter muscles or FS alone did not induce somatic hyperalgesia. We also found that the somatic hyperalgesia was accompanied by upregulation of GluN1 receptor and serotonin (5-hydroxytryptamine, 5-HT)3A receptor expression in the dorsal horn of spinal cord at L4-L5 segments. Intrathecal injection of N-methyl-D-aspartic acid receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid (APV) or 5-HT3 receptor antagonist Y-25130 blocked stress-induced wide-spreading hyperalgesia. These results suggest that NMDAR-dependent central sensitization in the spinal dorsal horn and 5-HT-dependent descending facilitation contribute to the development of wide-spreading hyperalgesia in this comorbid pain model.
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Sensibilización del Sistema Nervioso Central , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Inflamación/fisiopatología , Boca/patología , Estrés Psicológico/complicaciones , Animales , Cara/patología , Femenino , Inflamación/patología , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Natación , TemperaturaRESUMEN
Patients suffering with functional somatic pain syndromes such as temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) have some similar symptoms, but the underlying cause is still unclear. The purpose of this study was to investigate whether 5-HT2A and 5-HT2C receptors in the spinal cord contribute to somatic hyperalgesia induced by orofacial inflammation combined with different modes of stress. Ovariectomized rats were injected subcutaneously with estradiol and bilateral masseter muscles were injected with complete Freund's adjuvant followed by stress. Somatic sensitivity was assessed with thermal and mechanical stimulation. The anxiety- and depression-like behaviors were measured by immobility time, sucrose preference, elevated plus maze and open field tests. The expression of 5-HT2A and 5-HT2C receptors in the spinal cord was examined by Western blot. Orofacial inflammation combined with 11â¯day forced swim stress (FSS) induced persistent mechanical allodynia for 15â¯days and thermal hyperalgesia for 2â¯days. The mechanical and thermal hyperalgesia lasted for 43â¯days and 30â¯days respectively following orofacial inflammation combined with 11â¯day heterotypic stress. Orofacial inflammation combined with stress induced anxiety- and depression-like behaviors. The expression of 5-HT2A and 5-HT2C receptors significantly decreased in the orofacial inflammation combined with stress groups. Intrathecal injection of 5-HT2A or 5-HT2C receptor agonist reversed somatic hyperalgesia. The results suggest that down-regulation of 5-HT2A and 5-HT2C receptors in the spinal cord contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress, indicating that 5-HT2A and 5-HT2C receptors may be potential targets in the treatment of TMD comorbid with FMS.
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Hiperalgesia , Serotonina , Animales , Regulación hacia Abajo , Adyuvante de Freund/toxicidad , Humanos , Hiperalgesia/inducido químicamente , Inflamación/inducido químicamente , Ratas , Receptor de Serotonina 5-HT2ARESUMEN
Sodium valproate (VPA) has analgesic effects in clinical and experimental studies, but the mechanisms are still unclear. The present study examined the effects of VPA on stress-induced somatic hyperalgesia and visceral hypersensitivity and the role of 5-HT2C receptors in the spinal cord. Repeated 3 day forced swim (FS) significantly reduced the thermal withdrawal latency and mechanical withdrawal threshold, and increased the magnitude of the visceromotor response to colorectal distention compared to the baseline values in rats. The somatic hyperalgesia and visceral hypersensitivity were accompanied by significant down-regulation of 5-HT2C receptor expression in the L4-L5 and L6-S1 dorsal spinal cord. Intraperitoneal administration of VPA (300 mg/kg) before each FS and 1 day post FS prevented the development of somatic hyperalgesia and visceral hypersensitivity induced by FS stress, as well as down-regulation of 5-HT2C receptors in the spinal cord. The reversal of somatic hyperalgesia and visceral hypersensitivity by VPA in FS rats was blocked by intrathecal administration of the selective 5-HT2C receptor antagonist RS-102221 (30 µg/10 µL) 30 min after each VPA injection. The results suggest that VPA attenuates FS-induced somatic hyperalgesia and visceral hypersensitivity by restoring down-regulated function of 5-HT2C receptors in the spinal cord.
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Analgésicos/administración & dosificación , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Receptor de Serotonina 5-HT2C/metabolismo , Estrés Psicológico/complicaciones , Ácido Valproico/administración & dosificación , Animales , Femenino , Hiperalgesia/etiología , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
BACKGROUND: Wastewater involving a lot of contaminants like organic dyes from the textile finishing industry causes a greater adverse impact on human beings. There are many patents on nanofibers involved metallic oxides, this paper studies photocatalytic degradation of free-pollution Zinc Oxide (ZnO) nanomaterials on dye decontamination. OBJECTIVE: Polyacrylonitrile (PAN) nanofibrous membranes loaded with Zinc Oxide (ZnO) nanowires were fabricated and evaluated for photocatalytic degradation. METHODS: In this work, Polyacrylonitrile (PAN) nanofibrous membranes loaded with ZnO seeds were prepared by electrospinning PAN/Zn (Ac)2 solution followed by a thermal decomposition process. ZnO nanowires were hydrothermally grown on the surface of PAN nanofibers. The effects of the ratio of PAN and zinc acetate in a solution, decomposition temperature and ammonia (NH4OH) on the morphologies of ZnO nanowires were observed. ZnO nanowires showed the optimum morphologies when the ratio of PAN/Zn (Ac)2 was 10:1.5. The decomposition temperature was 150oC, and NH4OH was added in the hydrothermal reaction. The photocatalytic degradation of Rhodamine B solution under UV irradiation was used as a model reaction. The photodegradation ability of the ZnO @PAN membrane doped with cerium (Sm) was also investigated. RESULTS: Slight Sm doping increased the photocatalytic degradation rate from 57% to 89% under ultraviolet light irradiation for 2h. After 5 times of cycling under the same conditions, it still maintained the dye decolorization rate that was above 65%. CONCLUSION: Sm doped ZnO nanowires @PAN nanofibrous membranes were easily produced and could provide a novel process for the degradation of dye decontamination.
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Stress-induced hyperalgesia is a problematic condition that lacks an effective therapeutic measure, and hence impairs health-related quality of life. The regulation of stress by oxytocin (OT) has overlapping effects on pain. OT can alleviate pain directly mainly at the spinal level and the peripheral tissues. Additionally, OT plays an analgesic role by dealing with stress and fear learning. When OT relieves stress by targeting the prefrontal brain regions and the hypothalamic-pituitary-adrenal axis, the body's sensitivity to pain is attenuated. Meanwhile, OT facilitates fear learning and may, in turn, enhance the anticipatory actions to painful stimulation. The unique therapeutic value of OT in patients suffering from stress and stress-related hyperalgesia conditions is worth considering. We reviewed recent advances in animal and human studies involving the effects of OT on stress and pain, and discussed the possible targets of OT within the descending and ascending pathways in the central nervous system. This review provides an overview of the evidence on the role of OT in alleviating stress-induced hyperalgesia.
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Encéfalo/efectos de los fármacos , Hiperalgesia/tratamiento farmacológico , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Oxitocina/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Analgésicos/farmacología , Animales , Encéfalo/metabolismo , Humanos , Hiperalgesia/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismoAsunto(s)
Hiperalgesia/etiología , Hiperalgesia/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Femenino , Hiperalgesia/tratamiento farmacológico , Masculino , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Neuralgia/metabolismo , Ovariectomía , Oxazinas/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Estrés FisiológicoRESUMEN
Electroacupuncture (EA) has been used to treat numerous diseases, including hypertension. This study aimed to investigate the long-term effect and underlying mechanisms of EA stimulation at the LI11 point on the hypertension and sympathetic nerve activity in two-kidney, one-clip (2K1C) hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied to the acupoints LI11 overlying the deep radial nerve once a day for 6 weeks. The mean arterial pressure (MAP) and heart rate (HR) were determined by radiotelemetry, and the sympathetic nerve activity was evaluated by telemetric analyses of the low-frequency component of blood pressure (BP) and by plasma epinephrine and norepinephrine levels. The results showed 6 weeks of EA significantly lowered the increased BP effectively, inhibited the enhanced sympathetic nerve activities and attenuated cardiac hypertrophy in 2K1C hypertensive rats. The level of orexin receptor-1 (OX1R) in the rostral ventrolateral medulla (RVLM) after EA treatment was markedly reduced in 2K1C rats, while there was no difference in the RVLM expression of orexin receptor-2 (OX2R) in 2K1C and 2K1C+EA rats. Moreover, the increased pressor and depressor responses to microinjection of orexin A or OX1R antagonist SB408124 into the RVLM of 2K1C rats were significantly blunted by the EA treatment. These findings suggest that BP-lowering effect of EA on renovascular hypertension may be through inhibition of central sympathetic activities and modulation of functional orexin receptors in the RVLM.
RESUMEN
Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients.