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1.
Invest Ophthalmol Vis Sci ; 63(1): 7, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34989761

RESUMO

Purpose: Dry eye-induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye-induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. Methods: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α2δ-1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye-induced ocular neuropathic pain. Results: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α2δ-1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α2δ-1 subunit upregulation, and astrocyte activation. Conclusions: These results suggest that dry eye-induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α2δ-1 subunit. Here, we showed that pregabalin is effective for treating dry eye-induced ocular neuropathic pain even after chronic pain has been established.


Assuntos
Analgésicos/administração & dosagem , Modelos Animais de Doenças , Síndromes do Olho Seco/fisiopatologia , Dor Ocular/fisiopatologia , Pregabalina/administração & dosagem , Administração Oftálmica , Animais , Astrócitos/patologia , Canais de Cálcio Tipo L/metabolismo , Doença Crônica , Córnea/inervação , Síndromes do Olho Seco/tratamento farmacológico , Dor Ocular/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Microglia/patologia , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Soluções Oftálmicas , Ratos , Ratos Sprague-Dawley , Nervo Trigêmeo/metabolismo , Nervo Trigêmeo/patologia
2.
Sci Rep ; 11(1): 18549, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535707

RESUMO

Maladaptive adult neurogenesis in the mammalian brain has been associated with diverse behaviors including disrupted learning, negative mood disorders and psychiatric conditions. However, its functional role in the generation and maintenance of chronic pathological pain has not yet been elucidated. Using an inducible genetic deletion in vivo mouse model, different behavioural paradigms and home cage monitoring systems, we show that an absence of adult neurogenesis does not impact the development of neuropathic injury-induced peripheral nociceptive hypersensitivity, but rather promotes the recovery of pathological pain as well as improves parameters associated with the state of well-being of the injured mice. These results provide a mechanistic insight into the mechanisms of chronic pain and implicate neurogenic processes as a potential therapeutic target for reducing pain and improving the quality of life for patients.


Assuntos
Encéfalo/fisiopatologia , Dor Crônica/fisiopatologia , Neuralgia/fisiopatologia , Neurogênese , Adulto , Animais , Humanos , Masculino , Camundongos
3.
PLoS One ; 16(8): e0252781, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34403429

RESUMO

PURPOSE: Evaluation of symptoms and signs for the management of neuropathic cancer pain (NCP) is challenging. This study aimed to identify clinical predictors of NCP and symptoms and signs most relevant of those in Korean patients. METHODS: This nationwide, descriptive, cross-sectional, multicenter, observational study included 2,003 cancer patients aged ≥20 years who reported a visual analog scale (VAS) score ≥1 for pain and provided informed consent for participation. The Douleur Neuropathic (DN4) questionnaire (score ≥4) was used to determine symptoms and signs as well as the presence of NCP. RESULTS: The prevalence of NCP was associated with age <65 years [OR, 1.57; 95% CI, 1.270-1.934], disease duration >6 months (OR, 1.57; 95% CI, 1.232-2.012), stage IV cancer (OR, 0.75; 95% CI, 0.593-0.955), history of chemotherapy (OR, 1.74; 95% CI, 1.225-2.472), and moderate-to-severe cancer pain (OR, 2.05; 95% CI, 1.671-2.524) after multivariate analysis. The most common descriptive symptoms of NCP were tingling, electric shock, and pins and needles. For NCP patients in the presence or absence of the clinical predictors, pins and needles (p = 0.001) and painful cold (p<0.001) symptoms were significantly frequent in patients with moderate-to-severe pain. Tingling, numbness, and touch hypoesthesia (p = 0.022, 0.033, 0.024, respectively) were more frequent in those with longer cancer duration and hyperesthesia (p = 0.024) was more frequent in young patients. CONCLUSION: Age <65 years, disease duration >6 months, stage IV cancer, history of chemotherapy, and moderate-to-severe cancer pain, were identified as predictors of NCP. Some symptoms and signs of NCP were associated with these predictors. Further studies are warranted on the pathogenesis and management of NCP with respect to the symptoms and signs, and factors associated with pain severity in Korean patients.


Assuntos
Dor do Câncer , Neoplasias , Neuralgia , Medição da Dor , Inquéritos e Questionários , Fatores Etários , Idoso , Dor do Câncer/diagnóstico , Dor do Câncer/epidemiologia , Dor do Câncer/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Neuralgia/fisiopatologia , Prevalência
5.
Curr Pain Headache Rep ; 25(9): 61, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34287719

RESUMO

PURPOSE OF REVIEW: Occipital neuralgia is a painful condition that affects the posterior aspect of the head and can be difficult to distinguish from other common forms of headaches. This article reviews the anatomy, pathophysiology, clinical presentation, differential diagnosis, diagnostic testing, and management approaches for occipital neuralgia. RECENT FINDINGS: Non-pharmacological treatments aim to alleviate muscle tension and improve posture. Acupuncture shows some promise. The occipital nerve block is considered the first line in a minimally invasive intervention, but the duration of relief may be short term. An onabotulinum toxin A injection may improve the sharp but not the dull component of the pain of occipital neuralgia. Radiofrequency ablation and occipital nerve stimulation may provide effective long-term relief in refractory patients. Surgical decompression, neurotomies, and neurolysis are last-resort treatment options. Occipital neuralgia is a debilitating condition that can be difficult to treat. Studies with larger sample sizes and randomized control trials are needed to further determine the effectiveness and safety of different therapies.


Assuntos
Cefaleia , Neuralgia , Diagnóstico Diferencial , Técnicas e Procedimentos Diagnósticos , Cefaleia/diagnóstico , Cefaleia/patologia , Cefaleia/fisiopatologia , Cefaleia/terapia , Humanos , Neuralgia/diagnóstico , Neuralgia/patologia , Neuralgia/fisiopatologia , Neuralgia/terapia
6.
J Sports Sci Med ; 20(2): 258-267, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34211318

RESUMO

Stretching is commonly used to increase range of motion and flexibility. Therefore, investigations are usually oriented towards the muscle-tendon unit. Limited evidence exists regarding potential effects of stretching on peripheral nerves which lie within muscles. The objective of this investigation will be to elucidate the responses of peripheral nerves to stretching. A literature search was performed using the following databases: Scopus, NLM Pubmed and ScienceDirect. Studies regarding the effects of stretching protocols on responses of peripheral nerves were retrieved for investigation. The NHLBI tool was used for quality assessment. Outcomes included nerve stiffness, nerve displacement, pain pressure thresholds and resistive torque. A total of 10 studies were considered eligible and were included in this investigation. The quality assessment of the studies revealed an overall "fair to good" methodological quality across the included studies. All studies except for one involved healthy participants. High heterogeneity of stretching protocols was retrieved. As a consequence of stretching, nerve stiffness (-15.6%) and pain pressure thresholds (-1.9kg) increased. Nerve displacements on each movement plane for all the considered nerves and nerve deformation were also frequently observed. Peripheral nerve responses to muscle stretching include decreased nerve stiffness and increased pain pressure thresholds. Nerve displacement also frequently occurs. It is still unclear if reduced nerve displacement may lead to clinical outcomes. There is a lack of longitudinal studies regarding peripheral nerve adaptations to stretching.


Assuntos
Exercícios de Alongamento Muscular/fisiologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Nervos Periféricos/fisiologia , Humanos , Neuralgia/fisiopatologia , Amplitude de Movimento Articular
7.
Clin Neurophysiol ; 132(10): 2702-2710, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34217600

RESUMO

OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent "theta-burst" stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain. METHODS: Forty-six patients received 20 Hz-rTMS and/or iTBS protocols and 39 of them underwent the full two procedures in a random cross-over design. They rated pain intensity, sleep quality, fatigue and general health status daily during 5 consecutive weeks. RESULTS: Pain relief during the month following stimulation was superior after 20 Hz-rTMS relative to iTBS (F(1,38) = 4.645; p = 0.037). Correlation between respective levels of maximal relief showed a significant deviation toward the 20 Hz-rTMS effect. A greater proportion of individuals responded to 20 Hz-rTMS (52% vs 32%, 95 %CI[0.095-3.27]; p = 0.06), and reports of fatigue significantly improved after 20 Hz-rTMS relative to iTBS (p = 0.01). General health and sleep quality scores did not differentiate both techniques. CONCLUSIONS: High-frequency rTMS appeared superior to iTBS for neuropathic pain relief. SIGNIFICANCE: Adequate matching between the oscillatory activity of motor cortex and that of rTMS may increase synaptic efficacy, thus enhancing functional connectivity of motor cortex with distant structures involved in pain regulation.


Assuntos
Neuralgia/fisiopatologia , Neuralgia/terapia , Plasticidade Neuronal/fisiologia , Manejo da Dor/métodos , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiologia , Neuralgia/diagnóstico
8.
Sci Rep ; 11(1): 12688, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135363

RESUMO

Electrical stimulation of the cerebral cortex (ESCC) has been used to treat intractable neuropathic pain for nearly two decades, however, no standardized approach for this technique has been developed. In order to optimize targeting and validate the effect of ESCC before placing the permanent grid, we introduced initial assessment with trial stimulation, using a temporary grid of subdural electrodes. In this retrospective study we evaluate the role of electrode location on cerebral cortex in control of neuropathic pain and the role of trial stimulation in target-optimization for ESCC. Location of the temporary grid electrodes and location of permanent electrodes were evaluated in correlation with the long-term efficacy of ESCC. The results of this study demonstrate that the long-term effect of subdural pre-motor cortex stimulation is at least the same or higher compare to effect of subdural motor or combined pre-motor and motor cortex stimulation. These results also demonstrate that the initial trial stimulation helps to optimize permanent electrode positions in relation to the optimal functional target that is critical in cases when brain shift is expected. Proposed methodology and novel results open a new direction for development of neuromodulation techniques to control chronic neuropathic pain.


Assuntos
Dor Crônica/terapia , Estimulação Encefálica Profunda , Córtex Motor/fisiologia , Neuralgia/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Dor Crônica/fisiopatologia , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/fisiopatologia , Manejo da Dor , Estudos Retrospectivos
9.
PLoS Comput Biol ; 17(6): e1009097, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34101729

RESUMO

The amygdala is a brain area involved in emotional regulation and pain. Over the course of the last 20 years, multiple researchers have studied sensory and motor connections within the amygdala in trying to understand the ultimate role of this structure in pain perception and descending control of pain. A number of investigators have been using cell-type specific manipulations to probe the underlying circuitry of the amygdala. As data have accumulated in this research space, we recognized a critical need for a single framework to integrate these data and evaluate emergent system-level responses. In this manuscript, we present an agent-based computational model of two distinct inhibitory neuron populations in the amygdala, those that express protein kinase C delta (PKCδ) and those that express somatostatin (SOM). We utilized a network of neural links to simulate connectivity and the transmission of inhibitory signals between neurons. Type-specific parameters describing the response of these neurons to noxious stimuli were estimated from published physiological and immunological data as well as our own wet-lab experiments. The model outputs an abstract measure of pain, which is calculated in terms of the cumulative pro-nociceptive and anti-nociceptive activity across neurons in both hemispheres of the amygdala. Results demonstrate the ability of the model to produce changes in pain that are consistent with published studies and highlight the importance of several model parameters. In particular, we found that the relative proportion of PKCδ and SOM neurons within each hemisphere is a key parameter in predicting pain and we explored model predictions for three possible values of this parameter. We compared model predictions of pain to data from our earlier behavioral studies and found areas of similarity as well as distinctions between the data sets. These differences, in particular, suggest a number of wet-lab experiments that could be done in the future.


Assuntos
Núcleo Central da Amígdala/fisiologia , Modelos Neurológicos , Dor/fisiopatologia , Animais , Núcleo Central da Amígdala/lesões , Núcleo Central da Amígdala/fisiopatologia , Biologia Computacional , Modelos Animais de Doenças , Dominância Cerebral/fisiologia , Fenômenos Eletrofisiológicos , Humanos , Técnicas In Vitro , Masculino , Camundongos , Rede Nervosa/fisiologia , Rede Nervosa/fisiopatologia , Neuralgia/fisiopatologia , Neurônios/classificação , Neurônios/fisiologia , Proteína Quinase C-delta/metabolismo , Somatostatina/metabolismo , Análise de Sistemas
10.
Medicine (Baltimore) ; 100(25): e26500, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160466

RESUMO

ABSTRACT: This study aimed to perform cluster analysis in patients with chronic pain to extract groups with similar circadian rhythms and compare neuropathic pain and psychological factors among these groups to identify differences in pain-related outcomes. A total of 63 community-dwellers with pain lasting at least 3 months and Numerical Rating Scale scores of ≥2 were recruited from 3 medical institutions. Their pain circadian rhythms were evaluated over 7 days by measuring pain intensity at 6-time points per day using a 10-cm visual analog scale. Cluster analysis was performed using 6 variables with standardized visual analog scale values at 6-time points for individual participants to extract groups with similar pain circadian rhythms. The results of the Neuropathic Pain Symptom Inventory and psychological evaluations in each group were compared using the Kruskal-Wallis test. The results revealed 3 clusters with different circadian rhythms of pain. The total and evoked pain subscale Neuropathic Pain Symptom Inventory scores differed among the 3 clusters. The results suggest that a thorough understanding of circadian pain rhythms in chronic pain patients may facilitate the performance of activities of daily living and physical exercise from the perspective of pain management.


Assuntos
Dor Crônica/diagnóstico , Ritmo Circadiano/fisiologia , Neuralgia/diagnóstico , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Dor Crônica/terapia , Cronoterapia/métodos , Terapia por Exercício/métodos , Feminino , Humanos , Vida Independente , Masculino , Pessoa de Meia-Idade , Neuralgia/fisiopatologia , Neuralgia/psicologia , Neuralgia/terapia , Manejo da Dor/métodos , Medição da Dor/estatística & dados numéricos , Psicometria , Estatísticas não Paramétricas , Inquéritos e Questionários/estatística & dados numéricos
11.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066977

RESUMO

Oxaliplatin is a third-generation platinum-based anticancer drug that is widely used as first-line treatment for colorectal carcinoma. Patients treated with oxaliplatin develop an acute peripheral pain several hours after treatment, mostly characterized by cold allodynia as well as a long-term chronic neuropathy. These two phenomena seem to be causally connected. However, the underlying mechanisms that trigger the acute peripheral pain are still poorly understood. Here we show that the activity of the transient receptor potential melastatin 8 (TRPM8) channel but not the activity of any other member of the TRP channel family is transiently increased 1 h after oxaliplatin treatment and decreased 24 h after oxaliplatin treatment. Mechanistically, this is connected with activation of the phospholipase C (PLC) pathway and depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) after oxaliplatin treatment. Inhibition of the PLC pathway can reverse the decreased TRPM8 activity as well as the decreased PIP2-concentrations after oxaliplatin treatment. In summary, these results point out transient changes in TRPM8 activity early after oxaliplatin treatment and a later occurring TRPM8 channel desensitization in primary sensory neurons. These mechanisms may explain the transient cold allodynia after oxaliplatin treatment and highlight an important role of TRPM8 in oxaliplatin-induced acute and neuropathic pain.


Assuntos
Ativação do Canal Iônico , Oxaliplatina/efeitos adversos , Canais de Cátion TRPM/metabolismo , Doença Aguda , Animais , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/patologia , Neuralgia/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismo
12.
J Neurosci ; 41(26): 5595-5619, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34031166

RESUMO

Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aß slowly adapting type I (SAI) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aß SAI LTMR action potentials that are transmitted to the CNS, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Using a genetic Merkel cell KO mouse model, we subsequently examined the importance of intact Merkel cell-Aß complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that, in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Aß afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex-dependent manner.SIGNIFICANCE STATEMENT Merkel discs or Merkel cell-Aß afferent complexes are mechanosensory end organs in mammalian skin. Yet, it remains unknown whether Merkel cells or their associated sensory neurons play a role in the mechanical hypersensitivity caused by peripheral nerve injury. We found that male mice genetically lacking Merkel cell-Aß afferent complexes exhibited a reduction in mechanical allodynia after nerve injury. Interestingly, this behavioral phenotype was not observed in mutant female mice. Our study will facilitate understanding of mechanisms underlying neuropathic pain.


Assuntos
Hiperalgesia/fisiopatologia , Células de Merkel/fisiologia , Neuralgia/fisiopatologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Caracteres Sexuais , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/etiologia , Neurônios Aferentes/fisiologia , Traumatismos dos Nervos Periféricos/complicações , Pele/inervação , Nervo Sural/lesões
13.
Neurology ; 97(4): e389-e402, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34011572

RESUMO

OBJECTIVE: To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms. METHODS: We analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury [PNI], postherpetic neuropathy [PHN], radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area. RESULTS: Among 424 patients (PNI n = 256, PHN n = 78, radiculopathy n = 90), contralateral sensory abnormalities were frequent in both painful (n = 383) and painless (n = 41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical nonpainful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology, and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function. CONCLUSION: Mechanisms of sensory loss seem to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the 2 ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain but not yet in human patients.


Assuntos
Hiperalgesia/fisiopatologia , Neuralgia/fisiopatologia , Percepção da Dor/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Radiculopatia/fisiopatologia , Feminino , Humanos , Hiperalgesia/complicações , Masculino , Neuralgia/etiologia , Medição da Dor , Limiar da Dor/fisiologia , Traumatismos dos Nervos Periféricos/complicações , Estimulação Física , Radiculopatia/complicações
14.
Sci Rep ; 11(1): 9735, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958647

RESUMO

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.


Assuntos
Córtex Motor/fisiopatologia , Neuralgia/terapia , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/fisiopatologia , Manejo da Dor/métodos
15.
Neurochem Res ; 46(8): 2143-2153, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34014488

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable non-selective cation channel that is involved in the development of neuropathic pain. P2X7 receptor (P2X7) belongs to a class of ATP-gated nonselective cation channels that plays an important role in neuropathic pain. Nevertheless, little is known about the interaction between them for neuropathic pain. In this paper, we investigated role of TRPV4-P2X7 pathway in neuropathic pain. We evaluated the effect of TRPV4-P2X7 pathway on neuropathic pain in a chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) model. We analyzed the effect of P2X7 on mechanical and thermal hyperalgesia mediated by TRPV4 in CCD. Furthermore, we assessed the effect of TRPV4 on the expression of P2X7 and the release of IL-1ß and IL-6 in DRG after CCD. We found that intraperitoneal injection of TRPV4 agonist GSK-1016790A led to a significant increase of mechanical and thermal hyperalgesia in CCD, which was partially suppressed by P2X7 blockade with antagonist Brilliant Blue G (BBG). Then, we further noticed that GSK-1016790A injection increased the P2X7 expression of CCD, which was decreased by TRPV4 blockade with antagonist RN-1734 and HC-067047. Furthermore, we also discovered that the expressions of IL-1ß and IL-6 were upregulated by GSK-1016790A injection but reduced by RN-1734 and HC-067047. Our results provide evidence that P2X7 contributes to development of neuropathic pain mediated by TRPV4 in the CCD model, which may be the basis for treatment of neuropathic pain relief.


Assuntos
Gânglios Espinais/metabolismo , Síndromes de Compressão Nervosa/fisiopatologia , Neuralgia/fisiopatologia , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/fisiologia , Canais de Cátion TRPV/metabolismo , Animais , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Morfolinas/farmacologia , Síndromes de Compressão Nervosa/tratamento farmacológico , Neuralgia/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirróis/farmacologia , Ratos Wistar , Corantes de Rosanilina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores
16.
Mol Pain ; 17: 17448069211011326, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33906495

RESUMO

Microglia activation following peripheral nerve injury has been shown to contribute to central sensitization of the spinal cord for the development of neuropathic pain. In a recent study, we reported that the amount of nerve damage does not necessarily correlate with chronic pain development. Here we compared the response of spinal microglia, using immunohistochemistry as a surrogate of microglial activation, in mice with two different types of crush injury of the sciatic nerve. We confirmed that incomplete crush of the sciatic nerve (partial crush injury, PCI) resulted in tactile hypersensitivity after the recovery of sensory function (15 days after surgery), whereas the hypersensitivity was not observed after the complete crush (full crush injury, FCI). We observed that immunoreactivity for Iba-1, a microglial marker, was greater in the ipsilateral dorsal horn of lumbar (L4) spinal cord of mice 2 days after FCI compared to PCI, positively correlating with the intensity of crush injury. Ipsilateral Iba-1 reactivity was comparable between injuries at 7 days with a significant increase compared to the contralateral side. By day 15 after injury, ipsilateral Iba-1 immunoreactivity was much reduced compared to day 7 and was not different between the groups. Our results suggest that the magnitude of the early microgliosis is dependent on injury severity, but does not necessarily correlate with the long-term development of chronic pain-like hypersensitivity after peripheral nerve injury.


Assuntos
Gliose/fisiopatologia , Hiperalgesia/fisiopatologia , Microglia/fisiologia , Neuralgia/fisiopatologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Nervo Isquiático/lesões , Medula Espinal/fisiopatologia , Animais , Gliose/complicações , Hiperalgesia/etiologia , Camundongos , Compressão Nervosa , Neuralgia/etiologia , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático/fisiopatologia
17.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33808020

RESUMO

Neuropathic pain is difficult to cure and is often accompanied by emotional and psychological changes. Exploring the mechanisms underlying neuropathic pain will help to identify a better treatment for this condition. The insular cortex is an important information integration center. Numerous imaging studies have documented increased activity of the insular cortex in the presence of neuropathic pain; however, the specific role of this region remains controversial. Early studies suggested that the insular lobe is mainly involved in the processing of the emotional motivation dimension of pain. However, increasing evidence suggests that the role of the insular cortex is more complex and may even be related to the neural plasticity, cognitive evaluation, and psychosocial aspects of neuropathic pain. These effects contribute not only to the development of neuropathic pain, but also to its comorbidity with neuropsychiatric diseases. In this review, we summarize the changes that occur in the insular cortex in the presence of neuropathic pain and analgesia, as well as the molecular mechanisms that may underlie these conditions. We also discuss potential sex-based differences in these processes. Further exploration of the involvement of the insular lobe will contribute to the development of new pharmacotherapy and psychotherapy treatments for neuropathic pain.


Assuntos
Córtex Cerebral , Neuralgia , Plasticidade Neuronal , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Humanos , Neuralgia/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia
18.
Front Immunol ; 12: 660203, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912189

RESUMO

Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.


Assuntos
Citocinas/imunologia , Mediadores da Inflamação/imunologia , Neuralgia/imunologia , Neuroimunomodulação/imunologia , Células Receptoras Sensoriais/imunologia , Pele/imunologia , Animais , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Modelos Imunológicos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Nociceptores/imunologia , Nociceptores/metabolismo , Células Receptoras Sensoriais/metabolismo , Pele/inervação , Pele/metabolismo
19.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925121

RESUMO

Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10-15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.


Assuntos
Analgésicos/farmacologia , Curcumina/farmacologia , Neuralgia/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Analgésicos/química , Analgésicos/farmacocinética , Animais , Curcuma/química , Curcumina/química , Curcumina/farmacocinética , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Neuralgia/fisiopatologia , Dor Pós-Operatória/fisiopatologia , Fitoterapia
20.
Int J Mol Sci ; 22(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919338

RESUMO

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer's disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.


Assuntos
Astrócitos/metabolismo , Encefalopatias/metabolismo , Receptor de Endotelina B/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Astrócitos/fisiologia , Encefalopatias/fisiopatologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Endotelina-1/metabolismo , Humanos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Receptor de Endotelina B/fisiologia
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