RESUMEN
OBJECTIVE: It is known that neuropathic pain frequently accompanies rheumatological diseases. In this study, neuropathic pain in Ankylosing Spondylitis(AS) and its relationship with disease activity were investigated. METHODS: Forty patients with AS were included. Laboratory data and disease status parameters were recorded. Neuropathic pain questionnaires were administered. Electrophysiological examination was performed on all patients. The relationship between neuropathic pain and disease activity parameters was investigated. RESULTS: According to the Pain Detect and LANSS questionnaire results, the rate of neuropathic pain was 57.5% and 42.5%. ASQoL, BASDAI, and ASDAS-ESH parameters are statistically significantly higher in the group with neuropathic pain according to the PainDetect (p:0.018, p:0.04, p:0.028). MASES, ASQoL, BASDAI, BASFI, and ASDAS-ESH parameters are statistically significantly higher in the group with neuropathic pain according to the LANSS (p:0.004, p:0.005, p: 0.001, p:0.005, p:0.02). Disease activity is higher in patients with neuropathic pain for both scales. Peripheral neuropathy is detected in nine patients. There is a positive correlation between disease activity parameters and neuropathic pain scales. A strong positive correlation was detected between ASQoL and BASDAI parameters and the Pain Detect questionnaire (r:0.533, r:0.606). CONCLUSIONS: The majority of patients with AS have a neuropathic pain. This condition is associated with high disease activity and adversely affects the patient's quality of life.
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Neuralgia , Espondilitis Anquilosante , Humanos , Neuralgia/etiología , Neuralgia/diagnóstico , Neuralgia/fisiopatología , Espondilitis Anquilosante/complicaciones , Espondilitis Anquilosante/fisiopatología , Masculino , Femenino , Estudios Transversales , Adulto , Persona de Mediana Edad , Dimensión del Dolor/métodos , Encuestas y Cuestionarios , Calidad de VidaRESUMEN
BACKGROUND: Individuals with spinal cord injury (SCI) often suffer from neuropathic pain which is often disabling and negatively affects function, participation, and quality of life (QoL). Pharmacological treatments lack efficacy in neuropathic pain reduction hence studying alternatives to drug treatment is necessary. Preclinical evidence of various aerobic exercises has shown positive effects on neuropathic pain but scientific studies investigating its effect in the SCI human population are limited. METHODOLOGY: This study is a double-blind, parallel, two-group, randomized controlled trial with an interventional study design that aims to evaluate the effectiveness of aerobic exercise program on neuropathic pain and quality of life (QoL) in individuals with chronic paraplegia. Thirty individuals with chronic paraplegia with the neurological level of injury from T2 to L2 will be recruited from the rehabilitation department at a super specialty hospital based on the inclusion criteria. Using a 1:1 allocation ratio, the participants will be randomly assigned to one of the two groups. The intervention group will perform high-intensity interval training (HIIT) aerobic exercise using an arm ergometer based on their peak heart rate, and the control group will perform free-hand arm aerobic exercise. In both groups, the intervention will be delivered as 30-min sessions, four times a week for 6 weeks. OUTCOME MEASURES: International Spinal Cord Injury Pain Basic Data Set Version 3.0 will be used for diagnosing and assessing neuropathic pain and its interference with day-to-day activities, mood, and sleep. The International Spinal Cord Society (ISCoS) QoL basic data set will be used to assess QoL, and 6-min push test distance will be used to assess peak heart rate and aerobic capacity. DISCUSSION: The effectiveness of the aerobic exercise program will be assessed based on the changes in neuropathic pain score and its interference with day-to-day activities, mood, sleep, QoL, and aerobic capacity after 3 weeks mid-intervention and after 6 weeks post-intervention. The trial will provide new knowledge about the effectiveness of the aerobic exercise program in improving neuropathic pain and QoL in individuals with chronic paraplegia. TRIAL REGISTRATION: Clinical Trials Registry-India CTRI/2023/08/056257. Registered on 8 August 2023.
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Terapia por Ejercicio , Neuralgia , Paraplejía , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Traumatismos de la Médula Espinal , Humanos , Neuralgia/terapia , Neuralgia/fisiopatología , Neuralgia/psicología , Paraplejía/rehabilitación , Paraplejía/fisiopatología , Paraplejía/psicología , Método Doble Ciego , Terapia por Ejercicio/métodos , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/psicología , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Masculino , Femenino , Ejercicio Físico , Dimensión del Dolor , Factores de Tiempo , Adulto JovenAsunto(s)
Dolor de la Región Lumbar , Extremidad Inferior , Radiculopatía , Humanos , Dolor de la Región Lumbar/fisiopatología , Dolor de la Región Lumbar/etiología , Radiculopatía/fisiopatología , Extremidad Inferior/fisiopatología , Calidad del Sueño , Neuralgia/fisiopatología , Neuralgia/etiologíaRESUMEN
Increasing evidence is present to enable pain measurement by using frontal channel EEG-based signals with spectral analysis and phase-amplitude coupling. To identify frontal channel EEG-based biomarkers for quantifying pain severity, we investigated band-power features to more complex features and employed various machine learning algorithms to assess the viability of these features. We utilized a public EEG dataset obtained from 36 patients with chronic pain during an eyes-open resting state and performed correlation analysis between clinically labelled pain scores and EEG features from Fp1 and Fp2 channels (EEG band-powers, phase-amplitude couplings (PAC), and its asymmetry features). We also conducted regression analysis with various machine learning models to predict patients' pain intensity. All the possible feature sets combined with five machine learning models (Linear Regression, random forest and support vector regression with linear, non-linear and polynomial kernels) were intensively checked, and regression performances were measured by adjusted R-squared value. We found significant correlations between beta power asymmetry (r = -0.375), gamma power asymmetry (r = -0.433) and low beta to low gamma coupling (r = -0.397) with pain scores while band power features did not show meaningful results. In the regression analysis, Support Vector Regression with a polynomial kernel showed the best performance (R squared value = 0.655), enabling the regression of pain intensity within a clinically usable error range. We identified the four most selected features (gamma power asymmetry, PAC asymmetry of theta to low gamma, low beta to low/high gamma). This study addressed the importance of complex features such as asymmetry and phase-amplitude coupling in pain research and demonstrated the feasibility of objectively observing pain intensity using the frontal channel-based EEG, that are clinically crucial for early intervention.
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Biomarcadores , Dolor Crónico , Electroencefalografía , Neuralgia , Humanos , Electroencefalografía/métodos , Masculino , Femenino , Persona de Mediana Edad , Dolor Crónico/fisiopatología , Dolor Crónico/diagnóstico , Neuralgia/fisiopatología , Neuralgia/diagnóstico , Adulto , Aprendizaje Automático , Anciano , Dimensión del Dolor/métodos , Descanso/fisiologíaRESUMEN
BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.
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Núcleos Talámicos Ventrales , Animales , Ratones , Masculino , Neuralgia del Trigémino/fisiopatología , Neuralgia/fisiopatología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Optogenética , Umbral del Dolor/fisiologíaRESUMEN
Approximately 50 million Americans suffer from chronic pain, and nearly a quarter of chronic pain patients have reported misusing opioid prescriptions. Repeated drug seeking is associated with reactivation of an ensemble of neurons sparsely scattered throughout the dorsomedial prefrontal cortex (dmPFC). Prior research has demonstrated that chronic pain increases intrinsic excitability of dmPFC neurons, which may increase the likelihood of reactivation during drug seeking. We tested the hypothesis that chronic pain would increase oxycodone-seeking behaviour and that the pain state would differentially increase intrinsic excitability in dmPFC drug-seeking ensemble neurons. TetTag mice self-administered intravenous oxycodone. After 7 days of forced abstinence, a drug-seeking session was performed, and the ensemble was tagged. Mice received spared nerve injury (SNI) to induce chronic pain during the period between the first and second seeking session. Following the second seeking session, we performed electrophysiology on individual neurons within the dmPFC to assess intrinsic excitability of the drug-seeking ensemble and non-ensemble neurons. SNI had no impact on sucrose seeking or intrinsic excitability of dmPFC neurons from these mice. In females, SNI increased oxycodone seeking and intrinsic excitability of non-ensemble neurons. In males, SNI had no impact on oxycodone seeking or neuron excitability. Data from females are consistent with clinical reports that chronic pain can promote drug craving and relapse and support the hypothesis that chronic pain itself may lead to neuroadaptations which promote opioid seeking.
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Analgésicos Opioides , Comportamiento de Búsqueda de Drogas , Neuralgia , Neuronas , Oxicodona , Corteza Prefrontal , Animales , Oxicodona/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Ratones , Neuralgia/fisiopatología , Neuronas/efectos de los fármacos , Masculino , Femenino , Analgésicos Opioides/farmacología , Autoadministración , Dolor Crónico/fisiopatología , Factores SexualesRESUMEN
Chronic neuropathic pain and chronic tinnitus have been likened to phantom percepts, in which a complete or partial sensory deafferentation results in a filling in of the missing information derived from memory. 150 participants, 50 with tinnitus, 50 with chronic pain and 50 healthy controls underwent a resting state EEG. Source localized current density is recorded from all the sensory cortices (olfactory, gustatory, somatosensory, auditory, vestibular, visual) as well as the parahippocampal area. Functional connectivity by means of lagged phase synchronization is also computed between these regions of interest. Pain and tinnitus are associated with gamma band activity, reflecting prediction errors, in all sensory cortices except the olfactory and gustatory cortex. Functional connectivity identifies theta frequency connectivity between each of the sensory cortices except the chemical senses to the parahippocampus, but not between the individual sensory cortices. When one sensory domain is deprived, the other senses may provide the parahippocampal 'contextual' area with the most likely sound or somatosensory sensation to fill in the gap, applying an abductive 'duck test' approach, i.e., based on stored multisensory congruence. This novel concept paves the way to develop novel treatments for pain and tinnitus, using multisensory (i.e. visual, vestibular, somatosensory, auditory) modulation with or without associated parahippocampal targeting.
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Electroencefalografía , Neuralgia , Acúfeno , Acúfeno/fisiopatología , Humanos , Neuralgia/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Electroencefalografía/métodos , Adulto , Encéfalo/fisiopatología , Anciano , Dolor Crónico/fisiopatologíaRESUMEN
OBJECTIVE: The present study aimed to investigate whether subjective and objective measures of pain habituation can be used as potential markers for central sensitization across various chronic pain patients. METHODS: Two blocks of contact-heat stimuli were applied to a non-painful area in 93 chronic pain patients (low back pain, neuropathic pain, and complex regional pain syndrome) and 60 healthy controls (HC). Habituation of pain ratings, contact-heat evoked potentials (CHEP), and sympathetic skin responses (SSR) was measured. RESULTS: There was no significant difference in any measure of pain habituation between patients and HC. Even patients with apparent clinical signs of central sensitization showed no reduced pain habituation. However, prolonged baseline CHEP and SSR latencies (stimulation block 1) were found in patients compared to HC (CHEP: Δ-latency = 23 ms, p = 0.012; SSR: Δ-latency = 100 ms, p = 0.022). CONCLUSION: Given the performed multimodal neurophysiological testing protocol, we provide evidence indicating that pain habituation may be preserved in patients with chronic pain and thereby be of limited use as a sensitive marker for central sensitization. These results are discussed within the framework of the complex interactions between pro- and antinociceptive mechanism as well as methodological issues. The prolonged latencies of CHEP and SSR after stimulation in non-painful areas may indicate subclinical changes in the integrity of thermo-nociceptive afferents, or a shift towards antinociceptive activity. This shift could potentially affect the relay of ascending signals. SIGNIFICANCE: Our findings challenge the prevailing views in the literature and may encourage further investigations into the peripheral and central components of pain habituation, using advanced multimodal neurophysiological techniques.
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Dolor Crónico , Habituación Psicofisiológica , Humanos , Masculino , Dolor Crónico/fisiopatología , Femenino , Habituación Psicofisiológica/fisiología , Persona de Mediana Edad , Adulto , Anciano , Dimensión del Dolor/métodos , Neuralgia/fisiopatología , Calor , Umbral del Dolor/fisiología , Sensibilización del Sistema Nervioso Central/fisiologíaRESUMEN
Implantable devices interfacing with peripheral nerves exhibit limited longevity and resolution. Poor nerve-electrode interface quality, invasive surgical placement and development of foreign body reaction combine to limit research and clinical application of these devices. Here, we develop cuff implants with a conformable design that achieve high-quality and stable interfacing with nerves in chronic implantation scenarios. When implanted in sensorimotor nerves of the arm in awake rats for 21 days, the devices record nerve action potentials with fascicle-specific resolution and extract from these the conduction velocity and direction of propagation. The cuffs exhibit high biocompatibility, producing lower levels of fibrotic scarring than clinically equivalent PDMS silicone cuffs. In addition to recording nerve activity, the devices are able to modulate nerve activity at sub-nerve resolution to produce a wide range of paw movements. When used in a partial nerve ligation rodent model, the cuffs identify and characterise changes in nerve C fibre activity associated with the development of neuropathic pain in freely-moving animals. The developed implantable devices represent a platform enabling new forms of fine nerve signal sensing and modulation, with applications in physiology research and closed-loop therapeutics.
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Potenciales de Acción , Nervios Periféricos , Animales , Nervios Periféricos/fisiología , Ratas , Potenciales de Acción/fisiología , Masculino , Electrodos Implantados , Neuralgia/fisiopatología , Neuralgia/terapia , Ratas Sprague-Dawley , Prótesis e Implantes , Conducción Nerviosa/fisiologíaRESUMEN
BACKGROUND: Central neuropathic poststroke pain (CNPSP) affects up to 12% of patients with stroke in general and up to 18% of patients with sensory deficits. This pain syndrome is often incapacitating and refractory to treatment. Brain computed tomography and magnetic resonance imaging (MRI) are widely used methods in the evaluation of CNPSP. OBJECTIVE: The present study aims to review the role of neuroimaging methods in CNPSP. METHODS: We performed a literature review of the main clinical aspects of CNPSP and the contribution of neuroimaging methods to study its pathophysiology, commonly damaged brain sites, and possible differential diagnoses. Lastly, we briefly mention how neuroimaging can contribute to the non-pharmacological CNPSP treatment. Additionally, we used a series of MRI from our institution to illustrate this review. RESULTS: Imaging has been used to explain CNPSP pathogenesis based on spinothalamic pathway damage and connectome dysfunction. Imaging locations associated with CNPSP include the brainstem (mainly the dorsolateral medulla), thalamus (especially the ventral posterolateral/ventral posteromedial nuclei), cortical areas such as the posterior insula and the parietal operculum, and, more recently, the thalamocortical white matter in the posterior limb of the internal capsule. Imaging also brings the prospect of helping search for new targets for non-pharmacological treatments for CNPSP. Other neuropathic pain causes identified by imaging include syringomyelia, multiple sclerosis, and herniated intervertebral disc. CONCLUSION: Imaging is a valuable tool in the complimentary evaluation of CNPSP patients in clinical and research scenarios.
ANTECEDENTES: A dor neuropática central pós-acidente vascular cerebral (DNPAVC) afeta até 12% dos pacientes com AVC em geral e até 18% dos pacientes com déficits sensoriais. Essa síndrome dolorosa costuma ser incapacitante e refratária ao tratamento. A tomografia computadorizada e a ressonância magnética do cérebro são métodos amplamente utilizados na avaliação da DNPAVC. OBJETIVO: Este estudo tem como objetivo revisar o papel dos métodos de neuroimagem na DNPAVC. MéTODOS: Realizamos uma revisão da literatura sobre os principais aspectos clínicos da DNPAVC e a contribuição dos métodos de neuroimagem para estudar a fisiopatologia da DNPAVC, locais cerebrais comumente lesados na DNPAVC e possíveis diagnósticos diferenciais. Por fim, mencionamos brevemente como a neuroimagem pode contribuir no tratamento não farmacológico da DNPAVC. Além disso, utilizamos uma série de imagens de ressonância magnética da nossa instituição para ilustrar esta revisão. RESULTADOS: Os exames de imagem têm sido usados para explicar a patogênese da DNPAVC com base no dano da via espinotalâmica e na disfunção do conectoma. Os locais de imagem associados à DNPAVC incluem o tronco cerebral (principalmente o bulbo dorsolateral), o tálamo (especialmente os núcleos ventral posterolateral/ventral posteromedial), áreas corticais como a ínsula posterior e o opérculo parietal e, mais recentemente, a substância branca tálamo-cortical no membro posterior da cápsula interna. Os exames de imagem também trazem a perspectiva de auxiliar na busca de novos alvos para tratamentos não farmacológicos para DNPAVC. Outras causas de dor neuropática identificadas por exames de imagem incluem siringomielia, esclerose múltipla e hérnia de disco intervertebral. CONCLUSãO: Os exames de imagem são uma ferramenta valiosa na avaliação complementar de pacientes com DNPAVC em cenários clínicos e de pesquisa.
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Imagen por Resonancia Magnética , Neuralgia , Neuroimagen , Accidente Cerebrovascular , Humanos , Neuroimagen/métodos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Neuralgia/diagnóstico por imagen , Neuralgia/etiología , Neuralgia/fisiopatología , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatologíaRESUMEN
Neuropathic pain (NP) is pain resulting from lesions or disease of the somatosensory system. A cardinal feature of NP is tactile allodynia (a painful response to normally innocuous stimulation). In 2003, a breakthrough strategy for inducing NP was proposed in which microglia of the spinal dorsal horn (SDH) are activated after peripheral nerve injury (PNI) to overexpress P2X4 receptor (P2X4R) and play an important role in inducing tactile allodynia. In 2005, it was reported that stimulation of microglial P2X4Rs evokes the release of brain-derived neurotrophic factor (BDNF), which causes a depolarizing shift of the anion reversal potential (Eanion) of secondary sensory neurons. These findings and other facts suggest the mechanism by which innocuous touch stimuli cause severe pain and the important role of microglia in the mechanism.
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Factor Neurotrófico Derivado del Encéfalo , Microglía , Neuralgia , Receptores Purinérgicos P2X4 , Microglía/metabolismo , Neuralgia/metabolismo , Neuralgia/fisiopatología , Humanos , Animales , Receptores Purinérgicos P2X4/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Traumatismos de los Nervios Periféricos/metabolismoRESUMEN
BACKGROUND: Disorders of the trigeminal nerve, a sensory nerve of the orofacial region, often lead to complications in dental practice, including neuropathic pain, allodynia, and ectopic pain. Management of these complications requires an understanding of the cytoarchitecture of the trigeminal ganglion, where the cell bodies of the trigeminal nerve are located, and the mechanisms of cell-cell interactions. HIGHLIGHTS: In the trigeminal ganglion, ganglion, satellite, Schwann, and immune cells coexist and interact. Cell-cell interactions are complex and occur through direct contact via gap junctions or through mediators such as adenosine triphosphate, nitric oxide, peptides, and cytokines. Interactions between the nervous and immune systems within the trigeminal ganglion may have neuroprotective effects during nerve injury or may exacerbate inflammation and produce chronic pain. Under pathological conditions of the trigeminal nerve, cell-cell interactions can cause allodynia and ectopic pain. Although cell-cell interactions that occur via mediators can act at some distance, they are more effective when the cells are close together. Therefore, information on the three-dimensional topography of trigeminal ganglion cells is essential for understanding the pathophysiology of ectopic pain. CONCLUSIONS: A three-dimensional map of the somatotopic localization of trigeminal ganglion neurons revealed that ganglion cells innervating distant orofacial regions are often apposed to each other, interacting with and potentially contributing to ectopic pain. Elucidation of the complex network of mediators and their receptors responsible for intercellular communication within the trigeminal ganglion is essential for understanding ectopic pain.
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Comunicación Celular , Neuralgia , Ganglio del Trigémino , Ganglio del Trigémino/patología , Ganglio del Trigémino/metabolismo , Humanos , Neuralgia/patología , Neuralgia/fisiopatología , Neuralgia/metabolismo , Animales , Dolor Facial/fisiopatología , Dolor Facial/patología , Dolor Facial/metabolismoRESUMEN
BACKGROUND: Following peripheral nerve damage, various non-neuronal cells are activated, triggering accumulation in the peripheral and central nervous systems, and communicate with neurons. Evidence suggest that neuronal and non-neuronal cell communication is a critical mechanism of neuropathic pain; however, its detailed mechanisms in contributing to neuropathic orofacial pain development remain unclear. HIGHLIGHT: Neuronal and non-neuronal cell communication in the trigeminal ganglion (TG) is believed to cause neuronal hyperactivation following trigeminal nerve damage, resulting in neuropathic orofacial pain. Trigeminal nerve damage activates and accumulates non-neuronal cells, such as satellite cells and macrophages in the TG and microglia, astrocytes, and oligodendrocytes in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). These non-neuronal cells release various molecules, contributing to the hyperactivation of TG, Vc, and C1-C2 nociceptive neurons. These hyperactive nociceptive neurons release molecules that enhance non-neuronal cell activation. This neuron and non-neuronal cell crosstalk causes hyperactivation of nociceptive neurons in the TG, Vc, and C1-C2. Here, we addressed previous and recent data on the contribution of neuronal and non-neuronal cell communication and its involvement in neuropathic orofacial pain development. CONCLUSION: Previous and recent data suggest that neuronal and non-neuronal cell communication in the TG, Vc, and C1-C2 is a key mechanism that causes neuropathic orofacial pain associated with trigeminal nerve damage.
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Dolor Facial , Neuralgia , Dolor Facial/fisiopatología , Dolor Facial/patología , Neuralgia/fisiopatología , Neuralgia/patología , Humanos , Animales , Ganglio del Trigémino/patología , Comunicación Celular , Microglía/patología , Microglía/metabolismo , Astrocitos/patología , Macrófagos/metabolismo , Oligodendroglía/patología , Traumatismos del Nervio Trigémino/patología , Traumatismos del Nervio Trigémino/fisiopatología , Nociceptores/fisiología , Células Satélites Perineuronales/metabolismoRESUMEN
INTRODUCTION: Following amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. METHODS: Twenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. RESULTS: Male and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. CONCLUSION: This novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.
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Modelos Animales de Enfermedad , Hiperalgesia , Neuralgia , Neuroma , Animales , Masculino , Neuroma/patología , Neuralgia/fisiopatología , Neuralgia/patología , Neuralgia/etiología , Femenino , Hiperalgesia/fisiopatología , Hiperalgesia/patología , Ratas Sprague-Dawley , Ratas , Nervio Tibial/patología , Nervio Tibial/fisiopatología , Dimensión del Dolor/métodosRESUMEN
The ventrolateral periaqueductal gray (vlPAG) serves as a central hub for descending pain modulation. It receives upstream projections from the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), and projects downstream to the locus coeruleus (LC) and the rostroventral medulla (RVM). While much research has focused on upstream circuits and the LC-RVM connection, less is known about the PAG-LC circuit and its involvement in neuropathic pain. Here we examined the intrinsic electrophysiological properties of vlPAG-LC projecting neurons in Sham and spared nerve injury (SNI) operated mice. Injection of the retrotracer Cholera Toxin Subunit B (CTB-488) into the LC allowed the identification of LC-projecting neurons in the vlPAG. Electrophysiological recordings from CTB-488 positive cells revealed that both GABAergic and glutamatergic cells that project to the LC exhibited reduced intrinsic excitability after peripheral nerve injury. By contrast, CTB-488 negative cells did not exhibit alterations in firing properties after SNI surgery. An SNI-induced reduction of LC projecting cells was confirmed with c-fos labeling. Hence, SNI induces plasticity changes in the vlPAG that are consistent with a reduction in the descending modulation of pain signals.
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Locus Coeruleus , Ratones Endogámicos C57BL , Neuronas , Sustancia Gris Periacueductal , Animales , Sustancia Gris Periacueductal/fisiopatología , Sustancia Gris Periacueductal/fisiología , Locus Coeruleus/fisiopatología , Locus Coeruleus/patología , Locus Coeruleus/fisiología , Neuronas/fisiología , Masculino , Ratones , Potenciales de Acción/fisiología , Vías Nerviosas/fisiopatología , Neuralgia/fisiopatología , Neuralgia/patología , Traumatismos de los Nervios Periféricos/fisiopatología , Traumatismos de los Nervios Periféricos/patología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
OBJECTIVE: Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in the local circuits of the central nervous system following CCI remain unclear. This study aimed to identify the changes following CCI in Thy1-GCaMP6s transgenic mice. METHODS: Neural activity in the primary somatosensory cortex (S1) and motor cortex (M1) following whisker stimulation was assessed using in vivo Ca2+ imaging. CCI-induced changes in responses were analyzed. RESULTS: Before CCI, whisker stimulation induced a greater Ca2+ response in the contralateral S1 than in the ipsilateral S1 and contralateral M1. The peak Ca2+ response amplitude in the bilateral S1 and contralateral M1 decreased two days after CCI compared to before CCI. Decreased Ca2+ response amplitude in these regions was observed until four days after CCI. Seven days after CCI, the Ca2+ response amplitude in the contralateral S1 decreased, whereas that in the ipsilateral S1 and contralateral M1 recovered to control levels. CONCLUSION: These results suggest that neural activity in regions receiving excitatory inputs via corticocortical pathways recovers earlier than in regions receiving thalamocortical inputs. (185/250 words).
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Calcio , Modelos Animales de Enfermedad , Ratones Transgénicos , Corteza Motora , Corteza Somatosensorial , Vibrisas , Animales , Corteza Motora/fisiopatología , Corteza Somatosensorial/fisiopatología , Vibrisas/inervación , Vibrisas/fisiología , Ratones , Calcio/metabolismo , Masculino , Neuralgia/fisiopatología , Neuralgia del Trigémino/fisiopatología , Neuralgia del Trigémino/metabolismoRESUMEN
Altered functional connectivity has been demonstrated in key brain regions involved in pain processing in painful diabetic peripheral neuropathy. However, the impact of neuropathic pain treatment on functional connectivity does not appear to have been investigated. Sixteen participants underwent resting state functional MRI when optimally treated for neuropathic pain during their involvement in the Optimal Pathway for Treating Neuropathic Pain in Diabetes Mellitus trial and 1 week following withdrawal of treatment. On discontinuation of pain treatment, there was an increase in functional connectivity between the left thalamus and primary somatosensory cortex (S1) and the left thalamus and insular cortex, key brain regions that are involved in cerebral processing of pain. The changes in functional connectivity between scans also correlated with measures of pain (baseline pain severity and Neuropathic Pain Symptom Inventory). Moreover, when participants were stratified into higher- and lower-than-average baseline pain subgroups, the change in thalamic-S1 cortical functional connectivity between scans was significantly greater in those with high baseline pain compared with the lower-baseline-pain group. This study shows that thalamo-cortical functional connectivity has the potential to act as an objective biomarker for neuropathic pain in diabetes for use in clinical pain trials.
Asunto(s)
Neuropatías Diabéticas , Imagen por Resonancia Magnética , Neuralgia , Tálamo , Humanos , Neuropatías Diabéticas/fisiopatología , Neuropatías Diabéticas/diagnóstico por imagen , Masculino , Tálamo/fisiopatología , Tálamo/diagnóstico por imagen , Femenino , Persona de Mediana Edad , Neuralgia/fisiopatología , Corteza Somatosensorial/fisiopatología , Corteza Somatosensorial/diagnóstico por imagen , Anciano , Privación de Tratamiento , Adulto , Corteza Insular/diagnóstico por imagen , Corteza Insular/fisiopatologíaRESUMEN
Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.
Asunto(s)
Modelos Animales de Enfermedad , Neuralgia , Nervios Espinales , Animales , Neuralgia/patología , Neuralgia/fisiopatología , Neuralgia/etiología , Ligadura/métodos , Ligadura/efectos adversos , Ratas , Ratones , Hiperalgesia/fisiopatología , Dimensión del Dolor/métodos , MasculinoRESUMEN
Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we addressed the role of small-conductance Ca2+-activated potassium (SK) channels in pain-related amygdala plasticity. The facilitatory effects of the intra-CeA application of an SK channel blocker (apamin) on the pain behaviors of control rats were lost in a neuropathic pain model, whereas an SK channel activator (NS309) inhibited pain behaviors in neuropathic rats but not in sham controls, suggesting the loss of the inhibitory behavioral effects of amygdala SK channels. Brain slice electrophysiology found hyperexcitability of CeA neurons in the neuropathic pain condition due to the loss of SK channel-mediated medium afterhyperpolarization (mAHP), which was accompanied by decreased SK2 channel protein and mRNA expression, consistent with a pretranscriptional mechanisms. The underlying mechanisms involved the epigenetic silencing of the SK2 gene due to the increased DNA methylation of the CpG island of the SK2 promoter region and the change in methylated CpG sites in the CeA in neuropathic pain. This study identified the epigenetic dysregulation of SK channels in the amygdala (CeA) as a novel mechanism of neuropathic pain-related plasticity and behavior that could be targeted to control abnormally enhanced amygdala activity and chronic neuropathic pain.
Asunto(s)
Amígdala del Cerebelo , Epigénesis Genética , Neuralgia , Canales de Potasio de Pequeña Conductancia Activados por el Calcio , Animales , Masculino , Ratas , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiopatología , Conducta Animal/efectos de los fármacos , Metilación de ADN/genética , Neuralgia/metabolismo , Neuralgia/genética , Neuralgia/fisiopatología , Neuronas/metabolismo , Ratas Sprague-Dawley , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genéticaRESUMEN
OBJECTIVE: To explore and characterize somatosensory dysfunction in patients with post-polio syndrome and chronic pain, by conducting examinations with Quantitative Sensory Testing. DESIGN: A cross-sectional, descriptive, pilot study conducted during 1 month. SUBJECTS/PATIENTS: Six patients with previously established post-polio syndrome and related chronic pain. METHODS: All subjects underwent a neurological examination including neuromuscular function, bedside sensory testing, a thorough pain anamnesis, and pain drawing. Screening for neuropathic pain was done with 2 questionnaires. A comprehensive Quantitative Sensory Testing battery was conducted with z-score transformation of obtained data, enabling comparison with published reference values and the creation of sensory profiles, as well as comparison between the study site (more polio affected extremity) and internal control site (less affected extremity) for each patient. RESULTS: Derived sensory profiles showed signs of increased prevalence of sensory aberrations compared with reference values, especially Mechanical Pain Thresholds, with significant deviation from reference data in 5 out of 6 patients. No obvious differences in sensory functions were seen between study sites and internal control sites. CONCLUSION: Post-polio syndrome may be correlated with a mechanical hyperalgesia/allodynia and might be correlated to a somatosensory dysfunction. With lack of evident side-to-side differences, the possibility of a generalized dysfunction in the somatosensory system might be considered.