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1.
Internist (Berl) ; 61(6): 617-620, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32342114

RESUMO

The case of a 72-year-old female patient with exanthem and concomitant neuropathy of the instep of the foot and progressive ipsilateral lower leg pain is reported. Sonographically, a superficial vein thrombosis with extension into the deep venous system originating from the exanthem was observed. On the basis of the clinical picture as well as the serological and electrophysiological findings, a rare diagnosis of acrodermatitis chronica atrophicans with peripheral neuropathy was made, which could significantly promote the local development of venous thrombosis.


Assuntos
Acrodermatite/diagnóstico , Exantema/complicações , Doença de Lyme/complicações , Trombose Venosa/complicações , Acrodermatite/etiologia , Idoso , Feminino , Humanos , Hiperalgesia , Doença de Lyme/diagnóstico , Neuralgia/complicações , Dor , Tromboflebite/diagnóstico
2.
Arch Biochem Biophys ; 685: 108330, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32156533

RESUMO

Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.


Assuntos
Neuropatias Diabéticas/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Animais , Linhagem Celular , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Janus Quinase 2/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/complicações , Ratos Sprague-Dawley , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/fisiologia , Estreptozocina
5.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835716

RESUMO

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.


Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Somatostatina/agonistas , Administração Oral , Analgésicos/química , Animais , Células CHO , Doença Crônica , Cricetinae , Cricetulus , Diterpenos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Inflamação/patologia , Ligantes , Masculino , Camundongos , Simulação de Dinâmica Molecular , Neuralgia/complicações , Neuralgia/patologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/química , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores de Somatostatina/metabolismo
6.
J Pak Med Assoc ; 69(12): 1907-1909, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31853127

RESUMO

Chronic neuropathic pain is secondary to other musculoskeletal pain. The following study aimed to determine the frequency of chronic neuropathic pain and its association with depression in the elderly. A crosssectional survey was carried out on 306 participants at the National Institute of Rehabilitation Medicine (NIRM) Hospital, in Islamabad over a period of 6 months from September 2017 to February 2018. Population of ? 60 years of age with chronic pain for >6 months were included, whereas patients with malignant origin of pain, intermittent pain and psychological pain were excluded. Data was collected by using DN4 and DASS Questionnaires were analysed by SPSS. Of the 271 participants with the mean age of 66 } 5.8 years, 216 (79.9%) were male. The frequency of patients suffering from chronic neuropathic pain was 53.9%. Data showed among the elderly a strong association of chronic neuropathic pain with anxiety and stress (P<0.05), but not with depression (P>0.05).


Assuntos
Dor Crônica , Depressão , Neuralgia , Idoso , Ansiedade , Dor Crônica/complicações , Dor Crônica/epidemiologia , Estudos Transversais , Depressão/complicações , Depressão/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/complicações , Neuralgia/epidemiologia , Paquistão/epidemiologia , Estresse Psicológico
7.
Rev Med Suisse ; 15(670): 2039-2043, 2019 Nov 06.
Artigo em Francês | MEDLINE | ID: mdl-31696679

RESUMO

Polyneuropathies occur frequently (> 30 %) among elderly people and can result in increased morbidity and impaired quality of life. Diabetes, chronic kidney disease, water-soluble vitamins deficiencies, drugs and alcohol side effects are the major etiologies after a systematic assessment. Neurologist referral is indicated when the diagnosis remains unclear and therapeutic options exist. Treatment strategies focus on reversal of underlying conditions, prevention, stabilization and alleviation of symptoms, especially neuropathic pain and maintain the best autonomy.


Assuntos
Polineuropatias/terapia , Idoso , Humanos , Neuralgia/complicações , Polineuropatias/complicações , Qualidade de Vida , Insuficiência Renal Crônica/complicações
8.
Biomed Res Int ; 2019: 3467121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737660

RESUMO

Spinal cord injury (SCI) is a highly debilitating disease and is increasingly being recognized as an important global health priority. However, the mechanisms underlying SCI have not yet been fully elucidated, and effective therapies for SCI are lacking. Long noncoding RNAs (lncRNAs), which form a major class of noncoding RNAs, have emerged as novel targets for regulating several physiological functions and mediating numerous neurological diseases. Notably, gene expression profile analyses have demonstrated aberrant changes in lncRNA expression in rats or mice after traumatic or nontraumatic SCI. LncRNAs have been shown to be associated with multiple pathophysiological processes following SCI including inflammation, neural apoptosis, and oxidative stress. They also play a crucial role in the complications associated with SCI, such as neuropathic pain. At the same time, some lncRNAs have been found to be therapeutic targets for neural stem cell transplantation and hydrogen sulfide treatment aimed at alleviating SCI. Therefore, lncRNAs could be promising biomarkers for the diagnosis, treatment, and prognosis of SCI. However, further researches are required to clarify the therapeutic effects of lncRNAs on SCI and the mechanisms underlying these effects. In this study, we reviewed the current progress of the studies on the involvement of lncRNAs in SCI, with the aim of drawing attention towards their roles in this debilitating condition.


Assuntos
Inflamação/genética , Neuralgia/genética , RNA Longo não Codificante/genética , Traumatismos da Medula Espinal/genética , Apoptose/genética , Regulação da Expressão Gênica , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Neuralgia/complicações , Neuralgia/fisiopatologia , Estresse Oxidativo/genética , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Transcriptoma
10.
Orv Hetil ; 160(27): 1047-1056, 2019 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-31264469

RESUMO

Orofacial pain is the common name of a variety of disorders from inflammatory diseases to neuropathic pain syndromes. This condition is quite common, it may involve 7% of the whole population. Patients (and doctors) are not aware of the origin of their complaints, therefore initial management falls among the variety of healthcare professionals. The aim of our review was to summarize the current evidence of chronic orofacial pain including diagnosis, management and pitfalls. Orv Hetil. 2019; 160(27): 1047-1056.


Assuntos
Dor Crônica/diagnóstico , Dor Crônica/terapia , Dor Facial/diagnóstico , Dor Facial/terapia , Neuralgia/complicações , Medição da Dor/métodos , Dor Crônica/etiologia , Depressão , Dor Facial/etiologia , Humanos , Comunicação Interdisciplinar , Resultado do Tratamento
11.
Eur J Pharmacol ; 857: 172450, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202805

RESUMO

Many areas of the brain along with neurotransmitters involve in processing of nociceptive, emotional and cognitive dimensions of neuropathic pain. Brian neuronal histamine through H1, H2, H3 and H4 receptors mediates many physiological functions such as cognition, emotion and pain. In the present study we investigated the effects of intra-agranular insular cortex microinjection of histamine and its H3 receptor agonist and antagonist on sensory and affective aspects of neuropathic pain. Spared nerve injury model of neuropathic pain was used. Two guide cannulas were surgically implanted in the right and left sides of agranular insular cortex. Sensory component (mechanical hyperalgesia) was recorded by application of von Frey filaments onto the plantar surface of the hind paw. Area under curve of mechanical hyperalgesia was calculated. Affective aspect (place escape avoidance paradigm) was recorded using an inverse white/black chamber. Histamine (0.5, 1 and 2 µg/site) and thioperamide (a histamine H3 receptor antagonist, 4 µg/site) decreased, whereas immepip (a histamine H3 receptor agonist, 2 µg/site) increased the percentages of paw withdrawal frequency and time spent in white side of white/black box. Prior administration of thioperamide (4 µg/site) increased the suppressive effects induced by histamine and inhibited immepip (2 µg/site)-induced hyperalgesia and aversion. Based on the present results, it is concluded that histamine and its H3 receptor at the agranular insular cortex level may involve in modulation of sensory and affective components of neuropathic pain.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Receptores Histamínicos H3/metabolismo , Animais , Histamina/administração & dosagem , Histamina/uso terapêutico , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/uso terapêutico , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/uso terapêutico , Hiperalgesia/complicações , Masculino , Microinjeções , Neuralgia/complicações , Neuralgia/metabolismo , Ratos , Ratos Wistar , Sensação/efeitos dos fármacos
12.
Cell Mol Neurobiol ; 39(8): 1081-1092, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31209627

RESUMO

Lidocaine is one of the typical local anesthetics that are frequently used in the peripheral nerve blocks and pain management. Emerging evidence have shown that lidocaine may exert anti-inflammatory effect involving neuropathic pain. However, the effect and underlying mechanism of lidocaine in suppressing neuroinflammation in neuropathic pain are incompletely revealed. In this study, effects of lidocaine on the suppressors of cytokine-signaling protein 3 (SOCS3) in microglia are investigated in chronic constriction injury (CCI) rat model and lipopolysaccharide (LPS)-stimulated BV-2 cells. It was shown that intrathecal injection of lidocaine substantially alleviated CCI-induced neuropathic pain, as reflected by the decreased thermal latency and mechanical threshold. Lidocaine reduced the CCI-evoked spinal injury and cell apoptosis. CCI induced an significant increase of IBA1+ microglia accompanied by the increase of inflammatory cytokines IL-6 and IL-1ß, which were suppressed after lidocaine administration. SOCS3 expression in IBA1+ microglia was notably upregulated in response to lidocaine injection, which presented in a similar pattern in LPS-activated BV-2 cells. Furthermore, lidocaine upregulated SOCS3 expression dependent of pCREB, and CREB silencing greatly discounted this effect. The intrathecal injection of lentiviral vectors LV-SOCS3 efficiently alleviated CCI-evoked neuropathic pain and reduced spinal IBA1+ microglia. SOCS3 overexpression contributed to the inhibition of neuroinflammation by decreasing the expression and activation of p38 MAPK and NF-κB stimulated by LPS. Collectively, lidocaine promoted the SOCS3 expression in microglia, in turn leading to suppression of IBA1+ microglia accumulation and p38 MAPK and NF-κB, which may expand our understanding on lidocaine in suppressing neuroinflammation and neuropathic pain.


Assuntos
Inflamação/tratamento farmacológico , Lidocaína/uso terapêutico , Microglia/patologia , Neuralgia/tratamento farmacológico , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Doença Crônica , Constrição Patológica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inflamação/complicações , Inflamação/patologia , Injeções Espinhais , Lidocaína/administração & dosagem , Lidocaína/farmacologia , Masculino , Camundongos , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Neuralgia/complicações , Neuralgia/patologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Temperatura , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Mol Med Rep ; 20(2): 1279-1287, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173269

RESUMO

Obesity is associated with increased sensitivity to pain, including neuropathic pain, but the precise mechanisms are not fully understood. Recent evidence has revealed that AMP­activated protein kinase (AMPK) in the central nervous system (CNS) regulates the neuropeptide calcitonin gene­related peptide (CGRP), a principal neurotransmitter of the class C nerve fiber, which serves an important role in initiating and maintaining neuropathic pain. AMPK has been demonstrated to be downregulated in the CNS in obesity. The present study hypothesized that obesity may lead to increased sensitivity to neuropathic pain by downregulating AMPK and upregulating CGRP expression levels in the CNS. Sprague­Dawley rats consuming a high­fat diet (HF) for 12 weeks developed obesity; they exhibited significantly decreased levels of phospho (p)­AMPK and increased CGRP expression levels in the spinal cord (SC) and dorsal root ganglion (DRG), respectively, compared with rats consuming a low­fat (LF) diet. HF­fed rats that underwent spared nerve injury (SNI) also exhibited lower p­AMPK and higher CGRP expression levels in the SC and DRG, compared with the corresponding LF­diet rats. The 50% paw withdrawal threshold (PWT; as measured by Von Frey testing) was significantly lower in HF­fed compared with LF­fed rats, with or without SNI. Through intrathecal treatment, the AMPK activator 5­aminoimidazole­4­carboxamide riboside (AICAR) or the CGRP antagonist CGRP8­37 decreased CGRP expression levels and increased the 50% PWT; however, the AMPK inhibitor dorsomorphin augmented CGRP expression levels and further reduced the 50% PWT in HF­fed rats, but not LF­fed rats, with or without SNI. The results indicated that blocking the AMPK­CGRP pathway may enhance neuropathic pain in HF­induced obesity, with or without nerve injury. Targeting AMPK in the CNS may be a novel strategy for the prevention and treatment of obesity­associated neuropathic pain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Sistema Nervoso Central/metabolismo , Dieta Hiperlipídica , Tecido Nervoso/lesões , Neuralgia/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Peso Corporal , Sistema Nervoso Central/patologia , Hiperalgesia/complicações , Masculino , Camundongos Obesos , Tecido Nervoso/metabolismo , Tecido Nervoso/patologia , Neuralgia/complicações , Obesidade/complicações , Limiar da Dor , Fosforilação , Ratos Sprague-Dawley
14.
Mol Neurobiol ; 56(11): 7408-7419, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31037647

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) adversely impacts quality of life and a challenge to treat with existing drugs used for neuropathic pain. Losartan, an angiotensin II type 1 receptor (AT1R) antagonist widely used to treat hypertension, has been reported to have analgesic effects in several pain models. In this study, we assessed losartan's analgesic effect on paclitaxel-induced neuropathic pain (PINP) in rats and its mechanism of action in dorsal root ganglion (DRG). Rats received intraperitoneal injections of 2 mg/kg paclitaxel on days 0, 2, 4, and 6 and received single or multiple intraperitoneal injections of losartan potassium dissolved in phosphate-buffered saline at various times. The mechanical thresholds, protein levels of inflammatory cytokines, and cellular location of AT1R and interleukin 1ß (IL-1ß) in the DRG were assessed with behavioral testing, Western blotting, and immunohistochemistry, respectively. Data were analyzed by two-way repeated-measures analysis of variance for the behavioral test or the Mann-Whitney U test for the Western blot analysis and immunohistochemistry. Single and multiple injections of losartan ameliorated PINP, and losartan delayed the development of PINP. Paclitaxel significantly increased, and losartan subsequently decreased, the expression levels of inflammatory cytokines, including IL-1ß and tumor necrosis factor α (TNF-α), in the lumbar DRG. AT1R and IL-1ß were expressed in both neurons and satellite cells and losartan decreased the intensity of IL-1ß in the DRG. Losartan ameliorates PINP by decreasing inflammatory cytokines including IL-1ß and TNF-α in the DRG. Our findings provide a new or add-on therapy for CIPN patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Citocinas/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Losartan/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/complicações , Hiperalgesia/patologia , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Losartan/farmacologia , Masculino , NF-kappa B/metabolismo , Neuralgia/complicações , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Paclitaxel/efeitos adversos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley
15.
BMC Neurosci ; 20(1): 16, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975083

RESUMO

BACKGROUND: Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. RESULTS: Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light-dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. CONCLUSIONS: Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.


Assuntos
Ansiedade/fisiopatologia , Cognição , Depressão/fisiopatologia , Neuralgia/fisiopatologia , Nervo Isquiático/lesões , Animais , Ansiedade/complicações , Antígeno B7-H1/genética , Comportamento Animal/fisiologia , Constrição Patológica , Depressão/complicações , Hiperalgesia/fisiopatologia , Hiperalgesia/psicologia , Masculino , Camundongos , Camundongos Knockout , Neuralgia/complicações , Fatores de Tempo
16.
J Neuroinflammation ; 16(1): 84, 2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-30981281

RESUMO

BACKGROUND: The G protein-coupled receptor 40 (GPR40), broadly expressed in various tissues such as the spinal cord, exerts multiple physiological functions including pain regulation. This study aimed to elucidate the mechanisms underlying GPR40 activation-induced antinociception in neuropathic pain, particularly related to the spinal glial expression of IL-10 and subsequent ß-endorphin. METHODS: Spinal nerve ligation-induced neuropathic pain model was used in this study. ß-Endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Double immunofluorescence staining of ß-endorphin with glial and neuronal cellular biomarkers was also detected in the spinal cord and cultured primary microglia, astrocytes, and neurons. RESULTS: GPR40 was expressed on microglia, astrocytes, and neurons in the spinal cords and upregulated by spinal nerve ligation. Intrathecal injection of the GPR40 agonist GW9508 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in neuropathic rats, with Emax values of 80% and 100% MPE and ED50 values of 6.7 and 5.4 µg, respectively. Its mechanical antiallodynia was blocked by the selective GPR40 antagonist GW1100 but not GPR120 antagonist AH7614. Intrathecal GW9508 significantly enhanced IL-10 and ß-endorphin immunostaining in spinal microglia and astrocytes but not in neurons. GW9508 also markedly stimulated gene and protein expression of IL-10 and ß-endorphin in cultured primary spinal microglia and astrocytes but not in neurons, originated from 1-day-old neonatal rats. The IL-10 antibody inhibited GW9508-stimulated gene expression of the ß-endorphin precursor proopiomelanocortin (POMC) but not IL-10, whereas the ß-endorphin antibody did not affect GW9508-stimulated IL-10 or POMC gene expression. GW9508 increased phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and its stimulatory effects on IL-10 and POMC expression were blocked by each MAPK isoform inhibitor. Spinal GW9508-induced mechanical antiallodynia was completely blocked by intrathecal minocycline, IL-10 neutralizing antibody, ß-endorphin antiserum, and µ-opioid receptor-preferred antagonist naloxone. CONCLUSIONS: Our results illustrate that GPR40 activation produces antinociception via the spinal glial IL-10/ß-endorphin antinociceptive pathway.


Assuntos
Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Interleucina-10/metabolismo , Neuralgia , Neuroglia/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/fisiologia , beta-Endorfina/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Interleucina-10/genética , Masculino , Metilaminas/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/complicações , Neuralgia/metabolismo , Neuralgia/patologia , Medição da Dor , Propionatos/uso terapêutico , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
17.
Ear Nose Throat J ; 98(8): 500-503, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30995862

RESUMO

Superior laryngeal nerve neuralgia (SLNN) is an anterior neck pain syndrome that is underrecognized and, as a result, is often misdiagnosed. We present a series of patients who were diagnosed with and subsequently treated for SLNN. Nineteen patients were treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs) and/or a therapeutic neck injection with 2% lidocaine and 40% triamcinolone acetonide. All patients completed a visual analog scale (VAS) to rate the level of pain before and after treatment. Four patients rated their pain as mild, 14 as moderate, and 1 as severe according to the VAS. Of the 19 patients, 8 chose to proceed with a 2-week course of NSAIDs and only 1 of them had complete resolution of their symptoms. A total of 18 patients underwent therapeutic neck injections, with a complete response to injection therapy in 10 patients. Five patients described a minimal residual foreign body sensation and 3 patients complained of mild residual pain. In this study, we found that therapeutic neck injections are effective not only in confirming the diagnosis but also in treating pain.


Assuntos
Anestésicos Locais/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Nervos Laríngeos , Lidocaína/administração & dosagem , Cervicalgia/tratamento farmacológico , Neuralgia/diagnóstico , Neuralgia/tratamento farmacológico , Triancinolona Acetonida/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Ibuprofeno/uso terapêutico , Injeções , Masculino , Pessoa de Meia-Idade , Cervicalgia/etiologia , Neuralgia/complicações , Medição da Dor , Retratamento , Síndrome , Adulto Jovem
18.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987090

RESUMO

The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the α2-adrenergic antagonist idazoxan (10 µg, i.t.), but not the α1-adrenergic antagonist prazosin (10 µg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT3 receptor antagonist bemesetron (MDL-72222, 15 µg, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 µg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α2-adrenergic receptor, and both α2-adrenergic and 5-HT3 receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.


Assuntos
Analgésicos/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Cloridrato de Venlafaxina/uso terapêutico , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos alfa/uso terapêutico , Analgésicos/farmacologia , Animais , Temperatura Baixa , Modelos Animais de Doenças , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/complicações , Norepinefrina/metabolismo , Oxaliplatina/administração & dosagem , Receptores Adrenérgicos alfa/metabolismo , Serotonina/metabolismo , Fatores de Tempo , Cloridrato de Venlafaxina/farmacologia
19.
Biol Psychiatry ; 85(12): 1021-1035, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987747

RESUMO

BACKGROUND: Pain affects both sensory and emotional aversive responses, often provoking anxiety-related diseases when chronic. However, the neural mechanisms underlying the interactions between anxiety and chronic pain remain unclear. METHODS: We characterized the sensory, emotional, and cognitive consequences of neuropathic pain (chronic constriction injury) in a rat model. Moreover, we determined the role of the locus coeruleus (LC) neurons that project to the basolateral amygdala (BLA) using a DREADD (designer receptor exclusively activated by designer drugs). RESULTS: Chronic constriction injury led to sensorial hypersensitivity in both the short term and long term. Otherwise, long-term pain led to an anxiety-like profile (in the elevated zero maze and open field tests), as well as increased responses to learn aversive situations (in the passive avoidance and fear conditioning tests) and an impairment of nonemotional cognitive tasks (in the novel object recognition and object pattern of separation tests). Chemogenetic blockade of the LC-BLA pathway and intra-BLA or systemic antagonism of beta-adrenergic receptors abolished both long-term pain-induced anxiety and enhanced fear learning. By contrast, chemogenetic activation of this pathway induced anxiety-like behaviors and enhanced the aversive learning and memory index in sham animals, although it had little effect on short- and long-term chronic constriction injury animals. Interestingly, modulation of LC-BLA activity did not modify sensorial perception or episodic memory. CONCLUSIONS: Our results indicate that dimensions associated with pain are processed by independent pathways and that there is an overactivation of the LC-BLA pathway when anxiety and chronic pain are comorbid, which involves the activity of beta-adrenergic receptors.


Assuntos
Ansiedade/fisiopatologia , Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Locus Cerúleo/fisiopatologia , Neuralgia/fisiopatologia , Neurônios/fisiologia , Animais , Ansiedade/etiologia , Masculino , Neuralgia/complicações , Ratos Long-Evans
20.
Mol Neurobiol ; 56(11): 7338-7354, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31030416

RESUMO

Neuropathic pain is a chronic condition triggered by lesions to the somatosensory nervous system in which pain stimuli occur spontaneously or as pathologically amplified responses. In this scenario, the exchange of signaling molecules throughout cell-to-cell and cell-to-extracellular environment communications plays a key role in the transition from acute to chronic pain. As such, connexin 43 (Cx43), the core glial gap junction and hemichannel-forming protein, is considered a triggering factor for disease chronicization in the central nervous system (CNS). Drugs targeting µ opioid receptors (MOR) are currently used for moderate to severe pain conditions, but their use in chronic pain is limited by the tolerability profile. δ opioid receptors (DOR) have become attractive targets for the treatment of persistent pain and have been associated with the inhibition of pain-sustaining factors. Moreover, it has been shown that simultaneous targeting of MOR and DOR leads to an improved pharmacological fingerprint. Herein, we aimed to study the effects of the benzomorphan ligand LP2, a multitarget MOR/DOR agonist, in an experimental model of neuropathic pain induced by the unilateral sciatic nerve chronic constriction injury (CCI) on male Sprague-Dawley rats. Results showed that LP2 significantly ameliorated mechanical allodynia from the early phase of treatment up to 21 days post-ligatures. We additionally showed that LP2 prevented CCI-induced Cx43 alterations and pro-apoptotic signaling in the CNS. These findings increase the knowledge of neuropathic pain development and the role of spinal astrocytic Cx43, suggesting new approaches for the treatment of neuropathic pain.


Assuntos
Astrócitos/metabolismo , Conexina 43/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Caspase 3/metabolismo , Constrição Patológica , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Gliose/patologia , Hiperalgesia/complicações , Masculino , Neuralgia/complicações , Neuralgia/patologia , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Regulação para Cima/efeitos dos fármacos
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