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1.
J Neurosci ; 39(50): 9954-9966, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676602

RESUMO

Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cationic channel activated by painful stimuli such as capsaicin and noxious heat, and enriched in sensory neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in WT controls. However, sensitization of capsaicin-mediated currents after the activation of PKC was substantially impaired in sensory neurons from KI mice. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Inflammatory thermal hyperalgesia was only marginally attenuated in KI mice. In contrast, PMA-evoked nocifensive responses and sensitization of capsaicin responses were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo Further, this suggests that interference with TRPV1 S801 phosphorylation might represent one potential way to attenuate inflammatory pain, yet spare basal sensitivity and produce fewer side effects than more general TRPV1 inhibition.SIGNIFICANCE STATEMENT Transient receptor potential vanilloid subtype 1 (TRPV1) has been considered a potential target for pain intervention. Global inhibitors of TRPV1 function, however, produce side effects which could compromise their clinical utility. By precisely removing a unique PKC phosphorylation site (TRPV1 S801) in mice through CRISPR/Cas9 editing, we provide in vivo evidence for a highly specific inhibition that leaves basal TRPV1 function intact, yet alleviates some forms of hyperalgesia. These findings support inhibition of TRPV1 S801 phosphorylation as a potential intervention for pain management.

2.
J Clin Invest ; 130: 3754-3769, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31211699

RESUMO

Although joint pain in rheumatoid arthritis (RA) is conventionally thought to result from inflammation, arthritis pain and joint inflammation are at least partially uncoupled. This suggests that additional pain mechanisms in RA remain to be explored. Here we show that FcγRI, an immune receptor for IgG immune complex (IgG-IC), is expressed in a subpopulation of joint sensory neurons and that, under naïve conditions, FcγRI crosslinking by IgG-IC directly activates the somata and peripheral terminals of these neurons to evoke acute joint hypernociception without obvious concurrent joint inflammation. These effects were diminished in both global and sensory neuron-specific Fcgr1 knockout mice. In murine models of inflammatory arthritis, FcγRI signaling was upregulated in joint sensory neurons. Acute blockade or global genetic deletion of Fcgr1 significantly attenuated arthritis pain and hyperactivity of joint sensory neurons without measurably altering joint inflammation. Conditional deletion of Fcgr1 in sensory neurons produced similar analgesic effects in these models. We therefore suggest that FcγRI expressed in sensory neurons contributes to arthritis pain independently of its functions in inflammatory cells. These findings expand our understanding of the immunosensory capabilities of sensory neurons and imply that neuronal FcγRI merits consideration as a target for treating RA pain.

3.
Medicine (Baltimore) ; 97(36): e11665, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30200061

RESUMO

INTRODUCTION: Acute intermittent porphyria (AIP) is a rare and challenging hereditary neurovisceral disease with no specific symptoms. Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome with bilateral reversible posterior gyriform lesions that can be associated with many different conditions, including AIP. Usually, peripheral neuropathy is considered the most common neurological manifestation of AIP. However, AIP should also be considered when seizures and PRES are associated with unexplained abdominal pain. CASE PRESENTATION: Both the patients were presented with seizures and PRES on brain magnetic resonance imaging (MRI). Unexplained abdominal pain occurred before the onset of seizures. The AIP diagnosis was made after repeated Watson-Schwartz tests. Hematin was not available for these 2 patients. However, supportive treatment including adequate nutrition and fluid therapy as well as specific antiepileptic drugs aided the patient's recovery and no acute attacks had occurred by the 3-year follow-up. CONCLUSION: In contrast to other causes of PRES patients, seizure is the most common symptom in AIP patients with PRES. This is a strong diagnostic clue for AIP when ambiguous abdominal pain patients presented with seizures and PRES on brain MRI. A positive prognosis can be achieved with the combination of early recognition, supportive and intravenous hematin therapy, and withdrawal of precipitating factors, including some antiepileptic drugs.


Assuntos
Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/diagnóstico , Síndrome da Leucoencefalopatia Posterior/complicações , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Convulsões/complicações , Convulsões/diagnóstico , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Porfiria Aguda Intermitente/fisiopatologia , Porfiria Aguda Intermitente/terapia , Síndrome da Leucoencefalopatia Posterior/fisiopatologia , Síndrome da Leucoencefalopatia Posterior/terapia , Convulsões/fisiopatologia , Convulsões/terapia
4.
J Clin Invest ; 128(8): 3246-3249, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010628

RESUMO

Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein-coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain.


Assuntos
Macrófagos , Fagocitose , Humanos , Inflamação , Mediadores da Inflamação , Dor
5.
J Dermatol Sci ; 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29903654

RESUMO

BACKGROUND: Allergic contact dermatitis (ACD) is a highly prevalent inflammatory disease of the skin. As a result of the complex etiology in ACD, therapeutic compounds targeting refractory pruritus in ACD lack efficacy and lead to numerous side effects. OBJECTIVE: In this study, we investigated the anti-pruritic effects of oxymatrine (OMT) and explored its mechanism of action in a mouse model of ACD. METHOD: 72 male SPF C57BL/6 mice were randomly divided into control group, ACD model group, dexamethasone positive control group (0.08 mg kg-1) and 3 OMT groups (80, 40, 20 mg kg-1). OMT was administrated by intraperitoneal injection 1 h before video recording on day 10, 24 h after 2nd challenge with SADBE. Cheek skin fold thickness was measured before treatment and after recording. H&E staining was used for pathological observation. RT-qPCR, Immunohistochemistry and LEGENDplexTM assay were used to detect cytokines levels. The population of Treg cells in peripheral blood were detected via flow cytometry. RESULTS: OMT treatment significantly decreases the skin inflammation and scratching bouts. It rescues defects in epidermal keratinization and inflammatory cell infiltration in ACD mice. Administration of OMT significantly reduced levels of IFN-γ, IL-13, IL-17A, TNF-α, IL-22 and mRNA expression of TNF-α and IL-1ß. Furthermore, it increased the percentage of Treg cells in peripheral blood of ACD mice. CONCLUSION: We have demonstrated that OMT exhibits anti-pruritic and anti-inflammatory effects in ACD mice by regulating inflammatory mediators. OMT might emerge as a potential drug for the treatment of pruritus and skin inflammation in the setting of ACD.

6.
Sci Rep ; 7(1): 5707, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720830

RESUMO

Neuropathic pain is a complex, chronic pain state that often accompanies tissue damage, inflammation or injury of the nervous system. However the underlying molecular mechanisms still remain unclear. Here, we showed that CXCL12 and CXCR4 were upregulated in the dorsal root ganglion (DRG) after chronic compression of DRG (CCD), and some CXCR4 immunopositive neurons were also immunopositive for the nociceptive neuronal markers IB4, TRPV1, CGRP, and substance P. The incidence and amplitude of CXCL12-induced Ca2+ response in primary sensory neurons from CCD mice was significantly increased compared to those from control animals. CXCL12 depolarized the resting membrane potential, decreased the rheobase, and increased the number of action potentials evoked by a depolarizing current at 2X rheobase in neurons from CCD mice. The mechanical and thermal hypernociception after CCD was attenuated by administration of a CXCR4 antagonist AMD3100. These findings suggest that CXCL12/CXCR4 signaling contributes to hypernociception after CCD, and targeting CXCL12/CXCR4 signaling pathway may alleviate neuropathic pain.


Assuntos
Quimiocina CXCL12/metabolismo , Gânglios Espinais/fisiopatologia , Neuralgia/fisiopatologia , Receptores CXCR4/metabolismo , Animais , Células Cultivadas , Compostos Heterocíclicos/farmacologia , Hiperalgesia/fisiopatologia , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Aferentes/fisiologia , Medição da Dor , Transdução de Sinais
7.
J Gastrointest Surg ; 21(11): 1954-1956, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28616857

RESUMO

PURPOSE: The aim of this study is to explore MR features and imaging mechanism of intestinal phytobezoar and to deepen the understanding of intestinal phytobezoar. METHODS: Eighteen cases of intestinal phytobezoar (including 15 cases in small intestine and 3 cases in colon) underwent MR examinations. Summing-up and analyzing MR features combinded with intraoperative findings. RESULTS: All 18 cases of intestinal phytobezoar showed irregular shape low signal on T2-weighted image, which was named coke sign in this study. And on T1-weighted image showed as follows: (i) 12 cases of intestinal phytobezoar (11 in small intestine and 1 in ascending colon) showed internal low signal and peripheral ring-like high signal, which was named empty shell sign in this study, (ii) 4 cases of intestinal phytobezoar (3 in jejunum and 1 in ileum) showed mixed slightly higher signal, and (iii) 2 cases of intestinal phytobezoar (both in colon) showed slightly low signal. CONCLUSIONS: Intestinal phytobezoar presented coke sign on T2-weighted image and complicated signal, more often empty shell sign on T1-weighted image. Correct diagnosis of an intestinal phytobezoar has an instructive value in selection of treatment strategy.


Assuntos
Bezoares/diagnóstico por imagem , Colo/diagnóstico por imagem , Intestino Delgado/diagnóstico por imagem , Imagem por Ressonância Magnética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
J Neurophysiol ; 118(1): 619-624, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28446581

RESUMO

Persistent itch often accompanies allergic contact dermatitis (ACD), but the underlying mechanisms remain largely unexplored. We previously demonstrated that CXCL10/CXCR3 signaling activated a subpopulation of cutaneous primary sensory neurons and mediated itch response after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. The purpose of this study was to determine the ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch. In whole cell recordings, CXCL10 triggered a current in dorsal root ganglion (DRG) neurons innervating the area of CHS. This current was modulated by intracellular Cl- and blocked by the general Cl- channel inhibitors. Moreover, increasing Ca2+ buffering capacity reduced this current. In addition, blockade of Cl- channels significantly suppressed CXCL10-induced Ca2+ response. In behavioral tests, injection of CXCL10 into CHS site exacerbated itch-related scratching behaviors. Moreover, the potentiating behavioral effects of CXCL10 were attenuated by either of two Cl- channel blockers. Thus we suggest that the Cl- channel acts as a downstream target mediating the excitatory and pruritic behavioral effects of CXCL10. Cl- channels may provide a promising therapeutic target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.NEW & NOTEWORTHY The ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch are largely unexplored. This study revealed that CXCL10 evoked an ionic current mainly carried by Cl- channels. We suggest that Cl- channels are likely key molecular candidates responsible for the CXCL10-evoked neuronal activation and itch-like behaviors in a murine model of allergic contact dermatitis induced by the antigen squaric acid dibutylester. Cl- channels may emerge as a promising drug target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.


Assuntos
Quimiocina CXCL10/metabolismo , Canais de Cloreto/metabolismo , Dermatite Alérgica de Contato/metabolismo , Neurônios/metabolismo , Prurido/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Quimiocina CXCL10/administração & dosagem , Cloretos/metabolismo , Ciclobutanos , Dermatite Alérgica de Contato/patologia , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Espaço Intracelular/metabolismo , Íons/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/patologia , Prurido/patologia , Receptores CXCR3/metabolismo , Pele/inervação , Pele/metabolismo , Pele/patologia
9.
Medicine (Baltimore) ; 96(9): e6185, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28248873

RESUMO

RATIONALE: Abdominal cocoon and peritoneal loose body are both rare abdominal diseases. PATIENT CONCERNS: The patient reported in this case was a 47-year-old man who suffered from abdominal pain and distension for 3 days. DIAGNOSIS: X-ray, computed tomography, and magnetic resonance imaging revealed multiple peritoneal loose body and small bowel obstruction, characterized by a total encapsulation of the small bowel with a fibrous membrane. INTERVENTIONS: The patient underwent surgical treatment and exploratory laparotomy confirmed the diagnosis of abdominal cocoon. OUTCOMES: Histopathological examination of pelvic nodules confirmed peritoneal loose body. LESSONS: To our knowledge, the herein reported case is the first abdominal cocoon that was accompanied by multiple peritoneal loose body.


Assuntos
Imagem por Ressonância Magnética , Fibrose Peritoneal/diagnóstico por imagem , Radiografia Abdominal , Dor Abdominal/diagnóstico por imagem , Dor Abdominal/etiologia , Humanos , Intestino Delgado/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Peritoneal/complicações , Fibrose Peritoneal/patologia
10.
J Ethnopharmacol ; 195: 118-126, 2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-27880884

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Angong Niuhuang Pill (ANP) is a well known Chinese traditional therapeutic for the treatment for diseases affecting the Central Nervous System (CNS). Components of the ANP formulation, including Bovis Calculus Sativus, Pulvis Bubali Comus Concentratus, Moschus, Margarita, Cinnabaris, Realgar, Coptidis Rhizoma, Scutellariae Radix, Gardeniae Fructus, Curcumae Radix, and Bomeolum Syntheticum, have been used for the treatment of stroke, encephalitis and emergency meningitis across Asia, especially in China for hundreds of years. OBJECTIVE: The goal of this study was to investigate the anti-atherosclerosis and cardio-protective effects of ANP administration using a rodent model of atherosclerosis induced by a high fat and vitamin D3. METHODS: Specific Pathogen-Free (SPF) 78 male SD rats were randomly divided into a control group and 5 atherosclerotic model groups. The atherosclerotic groups were divided to receive either Simvastatin (SVTT, 0.005g/kg), Low-dose ANP (0.125g/kg), Medium-dose ANP (0.25g/kg), and High-dose ANP (0.5g/kg). Following adaptive feeding for one week, atherosclerosis was induced and the atherosclerosis model was established. Experimental drugs (either simvastatin or ANP) or normal saline were administered intragastrically once daily for 9 weeks starting from the 8th week. A carotid artery ultrasound was performed at the 17th week to determine whether atherosclerosis had been induced. After the atherosclerosis model was successfully established, platelet aggregation rates, serum biochemical indices, apoptosis-related Bcl-2, Bax proteins levels in the heart were assayed. Pathological and histological analysis was completed using artery tissue from different experimental different groups to assess the effects of ANP. RESULTS: ANP significantly decreased aortic membrane thickness, the maximum platelet aggregation rates, and the ratio of low density lipoprotein cholesterol (LDL) to high density lipoprotein cholesterol (HDL). In addition, ANP significantly reduced serum contents of total cholesterol, low density lipoprotein, malondialdehyde, troponin I, high-sensitivity C-reactive protein, and lactate dehydrogenase. ANP markedly improved abnormal pathological conditions of the aorta and heart, and helped to prevent myocardial apoptosis. CONCLUSIONS: We have demonstrated that ANP has robust ant-atherosclerosis and cardio-protective effects on a high-fat and vitamin D3 - induced rodent model of atherosclerosis due to its antiplatelet aggregation, lipid regulatory, antioxidant, anti-inflammatory and anti-apoptotic properties.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Doenças das Artérias Carótidas/prevenção & controle , Colecalciferol , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/farmacologia , Hipolipemiantes/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/ultraestrutura , Doenças da Aorta/sangue , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/diagnóstico por imagem , Apoptose/efeitos dos fármacos , Aterosclerose/sangue , Aterosclerose/induzido quimicamente , Aterosclerose/diagnóstico por imagem , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/induzido quimicamente , Doenças das Artérias Carótidas/diagnóstico por imagem , Modelos Animais de Doenças , Enzimas/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Miocárdio/patologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Ratos Sprague-Dawley , Sinvastatina/farmacologia , Comprimidos , Fatores de Tempo
11.
Sci Rep ; 6: 28899, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27363579

RESUMO

Pain is a dominant symptom of rheumatoid arthritis (RA) and its adequate treatment represents a major unmet need. However, the cellular mechanisms that drive arthritis pain are largely unexplored. Here, we examined the changes in the activity of joint sensory neurons and the associated ionic mechanisms using an animal model of antigen-induced arthritis (AIA). Methylated-bovine serum albumin (mBSA), but not vehicle challenge, in the ankle of previously immunized mice produced time-dependent symptoms of arthritis, including joint inflammation, primary mechanical hyperalgesia in the ipsilateral ankle, and secondary mechanical and heat hyperalgesia in the ipsilateral hindpaw. In vivo electrophysiological recordings revealed that Dil-labeled joint sensory neurons in AIA mice exhibited a greater incidence of spontaneous activity, mechanically evoked after-discharges, and/or increased responses to mechanical stimulation of their receptive fields, compared to control animals. Whole-cell recordings in vitro showed that AIA enhanced the excitability of joint sensory neurons. These signs of neuronal hyperexcitability were associated with a significant reduction in the density of A-type K(+) currents. Thus, our data suggest that neuronal hyperexcitability, brought about in part by reduced A-type K(+) currents, may contribute to pain-related behaviors that accompany antigen-induced arthritis and/or other antigen-mediated diseases.


Assuntos
Potenciais de Ação/fisiologia , Artrite Experimental/fisiopatologia , Modelos Animais de Doenças , Ativação do Canal Iônico/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Células Receptoras Sensoriais/fisiologia , Animais , Articulação do Tornozelo/inervação , Antígenos/imunologia , Artrite Experimental/imunologia , Células Cultivadas , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/fisiopatologia , Camundongos , Dor/fisiopatologia , Técnicas de Patch-Clamp , Células Receptoras Sensoriais/metabolismo
12.
PLoS One ; 10(9): e0137512, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26356638

RESUMO

Radicular pain in humans is usually caused by intraforaminal stenosis and other diseases affecting the spinal nerve, root, or dorsal root ganglion (DRG). Previous studies discovered that a chronic compression of the DRG (CCD) induced mechanical allodynia in rats and mice, with enhanced excitability of DRG neurons. We investigated whether CCD altered the pain-like behavior and also the responses of cutaneous nociceptors with unmyelinated axons (C-fibers) to a normally aversive punctate mechanical stimulus delivered to the hairy skin of the hind limb of the mouse. The incidence of a foot shaking evoked by indentation of the dorsum of foot with an aversive von Frey filament (tip diameter 200 µm, bending force 20 mN) was significantly higher in the foot ipsilateral to the CCD surgery as compared to the contralateral side on post-operative days 2 to 8. Mechanically-evoked action potentials were electrophysiologically recorded from the L3 DRG, in vivo, from cell bodies visually identified as expressing a transgenically labeled fluorescent marker (neurons expressing either the receptor MrgprA3 or MrgprD). After CCD, 26.7% of MrgprA3+ and 32.1% MrgprD+ neurons exhibited spontaneous activity (SA), while none of the unoperated control neurons had SA. MrgprA3+ and MrgprD+ neurons in the compressed DRG exhibited, in comparison with neurons from unoperated control mice, an increased response to the punctate mechanical stimuli for each force applied (6, 20, 40, and 80 mN). We conclude that CCD produced both a behavioral hyperalgesia and an enhanced response of cutaneous C-nociceptors to aversive punctate mechanical stimuli.


Assuntos
Gânglios Espinais/fisiopatologia , Síndromes de Compressão Nervosa/fisiopatologia , Nociceptores/metabolismo , Dor/fisiopatologia , Potenciais de Ação , Animais , Doença Crônica , Hiperalgesia/complicações , Hiperalgesia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Dor/complicações
13.
Pain ; 156(9): 1737-46, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25932692

RESUMO

Persistent itch is a common symptom of allergic contact dermatitis (ACD) and represents a significant health burden. The chemokine CXCL10 is predominantly produced by epithelial cells during ACD. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of ACD, it is largely unexplored for itch and pain accompanying this disorder. Here, we showed that CXCL10 and CXCR3 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. CXCL10 directly activated a subset of cutaneous dorsal root ganglion neurons innervating the area of CHS through neuronal CXCR3. In behavioral tests, a CXCR3 antagonist attenuated spontaneous itch- but not pain-like behaviors directed to the site of CHS. Injection of CXCL10 into the site of CHS elicited site-directed itch- but not pain-like behaviors, but neither type of CXCL10-evoked behaviors was observed in control mice. These results suggest that CXCL10/CXCR3 signaling mediates allergic itch but not inflammatory pain in the context of skin inflammation. Thus, upregulation of CXCL10/CXCR3 signaling in sensory neurons may contribute to itch associated with ACD. Targeting the CXCL10/CXCR3 signaling might be beneficial for the treatment of allergic itch.


Assuntos
Dermatite Alérgica de Contato/complicações , Prurido/etiologia , Receptores CXCR3/metabolismo , Transdução de Sinais/fisiologia , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Animais , Antialérgicos/farmacologia , Antialérgicos/uso terapêutico , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/citologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Prurido/tratamento farmacológico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Receptores CXCR3/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/inervação , Regulação para Cima/efeitos dos fármacos
14.
J Clin Invest ; 124(8): 3540-50, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24983315

RESUMO

The cellular response to stress involves the recruitment and coordination of molecular signaling pathways that prevent cell death. D-dopachrome tautomerase (DDT) is an enzyme that lacks physiologic substrates in mammalian cells, but shares partial sequence and structural homology with macrophage migration inhibitory factor (MIF). Here, we observed that DDT is highly expressed in murine cardiomyocytes and secreted by the heart after ischemic stress. Antibody-dependent neutralization of secreted DDT exacerbated both ischemia-induced cardiac contractile dysfunction and necrosis. We generated cardiomyocyte-specific DDT knockout mice (Myh6-Cre Ddtfl/fl), which demonstrated normal baseline cardiac size and function, but had an impaired physiologic response to ischemia-reperfusion. Hearts from Myh6-Cre Ddtfl/fl mice exhibited more necrosis and LV contractile dysfunction than control hearts after coronary artery ligation and reperfusion. Furthermore, treatment with DDT protected isolated hearts against injury and contractile dysfunction after ischemia-reperfusion. The protective effect of DDT required activation of the metabolic stress enzyme AMP-activated protein kinase (AMPK), which was mediated by a CD74/CaMKK2-dependent mechanism. Together, our data indicate that cardiomyocyte secretion of DDT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Hipóxia Celular/fisiologia , Feminino , Oxirredutases Intramoleculares/deficiência , Oxirredutases Intramoleculares/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miócitos Cardíacos/enzimologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
15.
Neurosci Lett ; 579: 190-4, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-24704378

RESUMO

Chemical pruritogens and algogens evoke primarily itch and pain, respectively, when administered to the skin of healthy human subjects. However, the dominant sensory quality elicited by an algesic chemical stimulus may change in patients with chronic itch where bradykinin, elicits itch in addition to pain. Here we tested whether normally pruritic and algesic chemicals evoked abnormal itch- or pain-like behaviors in the mouse after the development of contact hypersensitivity (CHS), an animal model of allergic contact dermatitis. Mice previously sensitized to a hapten (squaric acid dibutylester) applied to the abdomen, exhibited spontaneous itch-like scratching and pain-like wiping directed to the site on the cheek of the CHS elicited by a subsequent challenge with the same hapten. In comparison with responses of control mice, CHS mice exhibited a significant increase in the scratching evoked by bovine adrenal medulla 8-22, a peptide that elicits a histamine-independent itch, but did not alter the scratching to histamine. Bradykinin, an algogen that elicited only wiping in control mice, additionally evoked significant scratching in CHS mice. Thus, within an area of CHS, histamine-independent itch is enhanced and chemically evoked pain is accompanied by itch.


Assuntos
Alérgenos , Dermatite Alérgica de Contato/psicologia , Prurido/induzido quimicamente , Prurido/psicologia , Animais , Comportamento Animal , Ciclobutanos , Dermatite Alérgica de Contato/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos
16.
Brain ; 137(Pt 4): 1039-50, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24549959

RESUMO

Itch is a common symptom of diseases of the skin but can also accompany diseases of other tissues including the nervous system. Acute itch from chemicals experimentally applied to the skin is initiated and maintained by action potential activity in a subset of nociceptive neurons. But whether these pruriceptive neurons are active or might become intrinsically more excitable under the pathological conditions that produce persistent itch and nociceptive sensations in humans is largely unexplored. Recently, two distinct types of cutaneous nociceptive dorsal root ganglion neurons were identified as responding to pruritic chemicals and playing a role in itch sensation. One expressed the mas-related G-coupled protein receptor MRGPRA3 and the other MRGPRD (MRGPRA3+ and MRGPRD+ neurons, respectively). Here we tested whether these two distinct pruriceptive nociceptors exhibited an enhanced excitability after the development of contact hypersensitivity, an animal model of allergic contact dermatitis, a common pruritic disorder in humans. The characteristics of increased excitability of pruriceptive neurons during this disorder may also pertain to the same types of neurons active in other pruritic diseases or pathologies that affect the nervous system and other tissues or organs. We found that challenging the skin of the calf of the hind paw or the cheek of previously sensitized mice with the hapten, squaric acid dibutyl ester, produced symptoms of contact hypersensitivity including an increase in skin thickness and site-directed spontaneous pain-like (licking or wiping) and itch-like (biting or scratching) behaviours. Ablation of MRGPRA3+ neurons led to a significant reduction in spontaneous scratching of the hapten-challenged nape of the neck of previously sensitized mice. In vivo, electrophysiological recordings revealed that MRGPRA3+ and MRGPRD+ neurons innervating the hapten-challenged skin exhibited a greater incidence of spontaneous activity and/or abnormal after-discharges in response to mechanical and heat stimuli applied to their receptive fields compared with neurons from the vehicle-treated control animals. Whole-cell recordings in vitro showed that both MRGPRA3+ and MRGPRD+ neurons from hapten-challenged mice displayed a significantly more depolarized resting membrane potential, decreased rheobase, and greater number of action potentials at twice rheobase compared with neurons from vehicle controls. These signs of neuronal hyperexcitability were associated with a significant increase in the peak amplitude of tetrodotoxin-sensitive and resistant sodium currents. Thus, the hyperexcitability of MRGPRA3+ and MRGPRD+ neurons, brought about in part by enhanced sodium currents, may contribute to the spontaneous itch- and pain-related behaviours accompanying contact hypersensitivity and/or other inflammatory diseases in humans.


Assuntos
Dermatite de Contato/metabolismo , Neurônios/metabolismo , Nociceptores/fisiologia , Prurido/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Dermatite de Contato/fisiopatologia , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dor/metabolismo , Técnicas de Patch-Clamp , Prurido/etiologia , Pele/inervação
17.
Nat Neurosci ; 16(2): 174-82, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23263443

RESUMO

Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3(+) neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3(+) neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3(+) neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3(+) neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.


Assuntos
Nociceptores/classificação , Nociceptores/fisiologia , Prurido/patologia , Células Receptoras Sensoriais/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Antirreumáticos/farmacologia , Cálcio/metabolismo , Capsaicina/farmacologia , Células Cultivadas , Cloroquina/farmacologia , Epiderme/inervação , Gânglios Espinais/citologia , Regulação da Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Histamina/efeitos adversos , Temperatura Alta/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Fibras Nervosas/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Medição da Dor , Limiar da Dor/fisiologia , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/efeitos adversos , Lectinas de Plantas/metabolismo , Proteínas/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Prurido/induzido quimicamente , Prurido/genética , RNA não Traduzido , Receptores da Bombesina/metabolismo , Receptores Acoplados a Proteínas-G/genética , Teste de Desempenho do Rota-Rod , Células Receptoras Sensoriais/efeitos dos fármacos , Fármacos do Sistema Sensorial/farmacologia , Medula Espinal/citologia , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/metabolismo
18.
J Neurosci ; 32(28): 9554-62, 2012 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-22787041

RESUMO

Chronic pain may accompany immune-related disorders with an elevated level of serum IgG immune complex (IgG-IC), but the underlying mechanisms are obscure. We previously demonstrated that IgG-IC directly excited a subpopulation of dorsal root ganglion (DRG) neurons through the neuronal Fc-gamma receptor I (FcγRI). This might be a mechanism linking IgG-IC to pain and hyperalgesia. The purpose of this study was to investigate the signaling pathways and transduction channels activated downstream of IgG-IC and FcγRI. In whole-cell recordings, IgG-IC induced a nonselective cation current (I(IC)) in the rat DRG neurons, carried by Ca(2+) and Na(+). The I(IC) was potentiated or attenuated by, respectively, lowering or increasing the intracellular Ca(2+) buffering capacity, suggesting that this current was regulated by intracellular calcium. Single-cell RT-PCR revealed that transient receptor potential canonical 3 (TRPC3) mRNA was always coexpressed with FcγRI mRNA in the same DRG neuron. Moreover, ruthenium red (a general TRP channel blocker), BTP2 (a general TRPC channel inhibitor), and pyrazole-3 (a selective TRPC3 blocker) each potently inhibited the I(IC). Specific knockdown of TRPC3 using small interfering RNA attenuated the IgG-IC-induced Ca(2+) response and the I(IC). Additionally, the I(IC) was blocked by the tyrosine kinase Syk inhibitor OXSI-2, the phospholipase C (PLC) inhibitor neomycin, and either the inositol triphosphate (IP(3)) receptor antagonist 2-aminoethyldiphenylborinate or heparin. These results indicated that the activation of neuronal FcγRI triggers TRPC channels through the Syk-PLC-IP(3) pathway and that TRPC3 is a key molecular target for the excitatory effect of IgG-IC on DRG neurons.


Assuntos
Gânglios Espinais/citologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Canais de Cátion TRPC/metabolismo , Acetanilidas/farmacologia , Anilidas/farmacologia , Animais , Biofísica , Cálcio/metabolismo , Cátions/metabolismo , Células Cultivadas , Quelantes/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Feminino , Potenciais da Membrana/genética , Neurônios/fisiologia , Técnicas de Patch-Clamp , Purinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de IgG/metabolismo , Rutênio Vermelho/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estatísticas não Paramétricas , Canais de Cátion TRPC/agonistas , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Tiadiazóis/farmacologia , Transfecção
19.
Neural Regen Res ; 7(26): 2075-9, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25624839

RESUMO

Chronic pain often accompanies immune-related diseases with an elevated level of IgG immune complex (IgG-IC) in the serum and/or the affected tissues though the underlying mechanisms are largely unknown. Fc gamma receptors (FcγRs), known as the receptors for the Fc domain of immunoglobulin G (IgG), are typically expressed on immune cells. A general consensus is that the activation of FcγRs by IgG-IC in such immune cells induces the release of proinflammatory cytokines from the immune cells, which may contribute to the IgG-IC-mediated peripheral sensitization. In addition to the immune cells, recent studies have revealed that FcγRI, but not FcγRII and FcγRIII, is also expressed in a subpopulation of primary sensory neurons. Moreover, IgG-IC directly excites the primary sensory neurons through neuronal FcγRI. These findings indicate that neuronal FcγRI provides a novel direct linkage between immunoglobulin and primary sensory neurons, which may be a novel target for the treatment of pain in the immune-related disorders. In this review, we summarize the expression pattern, functions, and the associated cellular signaling of FcγRs in the primary sensory neurons.

20.
Brain Behav Immun ; 25(7): 1399-407, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21521651

RESUMO

Pain often accompanies antigen-specific immune-related disorders though little is known of the underlying neural mechanisms. A common feature among these disorders is the elevated level of antigen-specific immunoglobulin (Ig) G in the serum and the presence of IgG immune complex (IC) in the affected tissue. We hypothesize that IC may directly activate the Fc-gamma receptor type I (FcγRI) expressed in nociceptive dorsal root ganglion (DRG) neurons and increase neuronal excitability thus potentially contributing to pain. Immunofluorescent labeling indicated that FcγRI, but not FcγRIIB or FcγRIII, was expressed in a subpopulation of rat DRG neurons including those expressing nociceptive markers. Calcium imaging revealed that the IC, but neither of the antibody (IgG) or antigen alone, produced an increase in intracellular calcium. This effect was abolished by the removal of the IgG Fc portion in the IC or the application of an anti-FcγRI antibody, suggesting a key role of the FcγRI receptor. Removal of extracellular calcium or depletion of intracellular calcium stores prevented the IC-induced calcium response. In whole-cell current-clamp recordings, IC depolarized the resting membrane potential, decreased the rheobase, and increased the number of action potentials evoked by a depolarizing current at 2× rheobase. In about half of the responsive neurons, IC evoked action potential discharges. These results suggest that a subpopulation of nociceptive neurons expresses functional FcγRI and that the activation of this receptor by IC increases neuronal excitability.


Assuntos
Complexo Antígeno-Anticorpo/farmacologia , Gânglios Espinais/fisiologia , Imunoglobulina G/farmacologia , Neurônios/fisiologia , Receptores de IgG/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Células Cultivadas , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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