Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
J Neurosci ; 41(34): 7278-7299, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34272314

RESUMO

Comorbid anxiety and depressive symptoms in chronic pain are a common health problem, but the underlying mechanisms remain unclear. Previously, we have demonstrated that sensitization of the CeA neurons via decreased GABAergic inhibition contributes to anxiety-like behaviors in neuropathic pain rats. In this study, by using male Sprague Dawley rats, we reported that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain. Bilateral electrolytic lesions of CeA, but not lateral/basolateral nucleus of the amygdala (LA/BLA), abrogated both pain hypersensitivity and aversive and depressive symptoms of neuropathic rats induced by spinal nerve ligation (SNL). Moreover, SNL rats showed structural and functional neuroplasticity manifested as reduced dendritic spines on the CeA neurons and enhanced LTD at the LA/BLA-CeA synapse. Disruption of GluA2-containing AMPAR trafficking and endocytosis from synapses using synthetic peptides, either pep2-EVKI or Tat-GluA2(3Y), restored the enhanced LTD at the LA/BLA-CeA synapse, and alleviated the mechanical allodynia and comorbid aversive and depressive symptoms in neuropathic rats, indicating that the endocytosis of GluA2-containing AMPARs from synapses is probably involved in the LTD at the LA/BLA-CeA synapse and the comorbid aversive and depressive symptoms in neuropathic pain in SNL-operated rats. These data provide a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlight that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain.SIGNIFICANCE STATEMENT Several studies have demonstrated the high comorbidity of negative affective disorders in patients with chronic pain. Understanding the affective aspects related to chronic pain may facilitate the development of novel therapies for more effective management. Here, we unravel that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain, and LTD at the amygdaloid LA/BLA-CeA synapse mediated by GluA2-containing AMPAR endocytosis underlies the comorbid aversive and depressive symptoms in neuropathic pain. This study provides a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlights that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain.


Assuntos
Ansiedade/fisiopatologia , Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Núcleo Central da Amígdala/fisiopatologia , Depressão/fisiopatologia , Hiperalgesia/fisiopatologia , Depressão Sináptica de Longo Prazo/fisiologia , Neuralgia/fisiopatologia , Receptores de AMPA/fisiologia , Animais , Ansiedade/etiologia , Comorbidade , Condicionamento Clássico , Depressão/etiologia , Emoções , Endocitose , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Comportamento Exploratório , Preferências Alimentares , Vetores Genéticos/administração & dosagem , Vetores Genéticos/farmacologia , Lentivirus/genética , Ligadura , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Neuralgia/psicologia , Técnicas de Patch-Clamp , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/genética , Teste de Desempenho do Rota-Rod , Método Simples-Cego , Nervos Espinhais/lesões , Natação
2.
Mol Pain ; 17: 17448069211023230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34102915

RESUMO

Cancer-associated pain is debilitating. However, the mechanism underlying cancer-induced spontaneous pain and evoked pain remains unclear. Here, using behavioral tests with immunofluorescent staining, overexpression, and knockdown of TRESK methods, we found an extensive distribution of TRESK potassium channel on both CGRP+ and IB4+ nerve fibers in the hindpaw skin, on CGRP+ nerve fibers in the tibial periosteum which lacks IB4+ fibers innervation, and on CGRP+ and IB4+ dorsal root ganglion (DRG) neurons in rats. Moreover, we found a decreased expression of TRESK in the corresponding nerve fibers within the hindpaw skin, the tibial periosteum and the DRG neurons in bone cancer rats. Overexpression of TRESK in DRG neurons attenuated both cancer-induced spontaneous pain (partly reflect skeletal pain) and evoked pain (reflect cutaneous pain) in tumor-bearing rats, in which the relief of evoked pain is time delayed than spontaneous pain. In contrast, knockdown of TRESK in DRG neurons produced both spontaneous pain and evoked pain in naïve rats. These results suggested that the differential distribution and decreased expression of TRESK in the periosteum and skin, which is attributed to the lack of IB4+ fibers innervation within the periosteum of the tibia, probably contribute to the behavioral divergence of cancer-induced spontaneous pain and evoked pain in bone cancer rats. Thus, the assessment of spontaneous pain and evoked pain should be accomplished simultaneously when evaluating the effect of some novel analgesics in animal models. Also, this study provides solid evidence for the role of peripheral TRESK in both cancer-induced spontaneous pain and evoked cutaneous pain.


Assuntos
Neoplasias Ósseas , Canais de Potássio , Animais , Neoplasias Ósseas/complicações , Gânglios Espinais , Dor/complicações , Ratos , Ratos Sprague-Dawley
3.
Transl Cancer Res ; 9(5): 3274-3281, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-35117694

RESUMO

BACKGROUND: This study explores the effect of different registration methods on the placement accuracy and dosimetric analysis of adaptive radiation therapy (ART) after breast conserving surgery for breast cancer, based on cone-beam computed tomography (CBCT). METHODS: Thirty breast cancer patients, who underwent breast conserving surgery, were divided into three groups, with 10 patients in each group: automatic grayscale registration (group A), automatic bony marker registration (group B), and automatic grayscale registration combined with manual bony marker registration (group C). Three registration methods were conducted before the first radiotherapy, and once a week under the guidance of CBCT. The dosimetric comparison was made with the original plan. RESULTS: The X direction was significantly different between groups A and B (P=0.036). The X and Y direction were significantly different between groups A and C (P=0.001, P=0.019). The placement errors were significantly different between groups B and C in the X and Y directions (P<0.001, P=0.003). The ART plan was significantly better than the original plan, in terms of the Dmax, Dmean, D90, V90, V100, V95, HI and CI of planning target volume (PTV) (P<0.05). Furthermore, the ART plan was significantly better, in terms of the Dmean, V5, V10, V20 and V30 of the affected lung, the Dmean, V5, V10, V20 and V30 of the double lung, and the Dmean, V5, V10, V20 and V30 of the heart. Moreover, the Dmax, V5 and V10 of the contralateral breast were significantly lower than those in the original CT plan (P<0.05). CONCLUSIONS: For the CBCT placement verification after breast conserving surgery, the accuracy and stability of automatic gray-scale registration combined with manual bone markers are better than those of the automatic gray-scale registration and automatic bone marker registration.

4.
Neuropharmacology ; 137: 104-113, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29758384

RESUMO

Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) is one of the non-receptor-like phosphatases that are highly enriched in hematopoietic cells. Although accumulating evidence has implicated the protein tyrosine phosphatases in the regulation of nociceptive transmission and plasticity, it is largely unknown whether SHP1 was expressed in pain-related spinal cord dorsal horn and engaged in the synaptic modification of nociceptive signals. Here we found that SHP1 was present in spinal neurons of rats and functionally coupled to GluN2A subunit-containing N-methyl-d-aspartate subtype of glutamate receptors, one of the key players in central sensitization of nociceptive behaviors. SHP1 interacted with a membrane-proximal region within the cytoplasmic tail of GluN2A. This interaction was necessary to stimulate SHP1 activity and more importantly, restrict SHP1 signaling to specifically enhance the tyrosine phosphorylation of GluN2A during inflammatory pain. Electrophysiological and behavioral studies showed that SHP1 binding potentiated GluN2A currents and evoked GluN2A-dependent pain hypersensitivity. The siRNA-mediated knockdown of SHP1 or interference with SHP1/GluN2A interaction by a synthetic peptide alleviated inflammatory pain induced by either Complete Freund's Adjuvant or formalin. Our data implicated that SHP1 was a specific enhancer of GluN2A-mediated nociceptive synaptic transmission in spinal cord dorsal horn, and manipulation of SHP1 activity may serve as an effective strategy for the treatment of inflammatory pain.


Assuntos
Inflamação/metabolismo , Dor/metabolismo , Células do Corno Posterior/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Analgésicos não Narcóticos/farmacologia , Animais , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Inflamação/tratamento farmacológico , Masculino , Dor/tratamento farmacológico , Células do Corno Posterior/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Quinases da Família src/metabolismo
5.
Neuropharmacology ; 126: 158-167, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28882563

RESUMO

Adenosine is present at the extracellular space within spinal cord dorsal horn and engaged in the processing of nociceptive sensory signals. Systemic or spinal administration of exogenous adenosine produces a potent analgesia against pathological pain. Here we found that inhibitory glycinergic neurotransmission was an important target for adenosine regulation. In spinal cord slices from intact rats, adenosine increased the inhibitory postsynaptic currents mediated by glycine receptors (GlyRs). In spinal slices from Complete Freund's Adjuvant-injected rats, adenosine potentiated glycinergic transmission to a more degree than in control rats. This synaptic potentiation was dependent on the activation of adenosine A1 receptor (A1R), and attributed to the modification of postsynaptic GlyRs function. The Gi protein-coupled A1R typically signals through Gαi/cAMP-dependent protein kinase (PKA) and Gßγ pathways. We found that blockade of either Gαi/PKA or Gßγ signaling attenuated the ability of adenosine to increase glycinergic synaptic responses in inflamed rats. To identify which GlyRs subunit was subjected to A1R regulation, we recorded glycine-evoked whole-cell currents in HEK293T cells co-transfected with A1R and distinct GlyRs subunit. We found that α1, the most abundant functional GlyRs subunit in adult spinal cord, was insensitive to A1R activation. However, when GlyRs α3 subunit or α1ins subunit, a longer α1 isoform, was co-expressed with A1R, adenosine caused a significant increase of glycinergic currents. Inhibition of PKA and Gßγ abolished the stimulatory effects of A1R on α3 and α1ins, respectively. These data suggested that A1R might potentiate glycinergic transmission through Gαi/PKA/α3 and Gßγ/α1ins pathways in inflamed rat.


Assuntos
Inflamação/fisiopatologia , Potenciais Pós-Sinápticos Inibidores , Receptor A1 de Adenosina/fisiologia , Receptores de Glicina/fisiologia , Corno Dorsal da Medula Espinal/fisiologia , Adenosina/administração & dosagem , Adenosina/fisiologia , Animais , Células HEK293 , Humanos , Inflamação/metabolismo , Masculino , Ratos Sprague-Dawley , Receptor A1 de Adenosina/metabolismo , Transdução de Sinais
6.
Neuroscience ; 352: 97-105, 2017 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-28389375

RESUMO

Striatal-enriched phosphatase 61 (STEP61) is a member of intracellular protein tyrosine phosphatases, which is involved in the regulation of synaptic plasticity and a line of neuropsychiatric disorders. This protein tyrosine phosphatase is also abundant in pain-related spinal cord dorsal horn neurons. However, whether and how this tyrosine phosphatase modulates the nociceptive plasticity and behavioral hypersensitivity remain largely unknown. The present study recorded the long-term potentiation (LTP) of primary afferent C fiber-evoked field potentials in vivo in superficial dorsal horn of rats, and tested the possible role of STEP61 in spinal LTP. We found that LTP induction significantly increased STEP61 phosphorylation at Ser221 residue, a key molecular event that has been shown to impair the phosphatase activity. The STEP61 hypoactivity allowed for the activation of three substrates, GluN2B subunit-containing N-methyl-d-aspartate-subtype glutamate receptors, Src-family protein tyrosine kinase member Fyn and extracellular signal-regulated kinase 1/2, through which the thresholds for LTP induction were noticeably decreased. To reinstate STEP61 activity, we overexpressed wild-type STEP61 [STEP61(WT)] in spinal dorsal horn, finding that STEP61(WT) completely blunted LTP induction. Behavioral tests showed that LTP blockade by STEP61(WT) correlated with a long-lasting alleviation of thermal hypersensitivity and mechanical allodynia induced by chronic constriction injury of sciatic nerves. These data implicated that STEP61 exerted a negative control over spinal nociceptive plasticity, which might have therapeutic benefit in pathological pain.


Assuntos
Potenciação de Longa Duração/fisiologia , Neuralgia/patologia , Proteínas Tirosina Fosfatases/metabolismo , Células Receptoras Sensoriais/enzimologia , Corno Dorsal da Medula Espinal/patologia , Vias Aferentes/fisiopatologia , Animais , Butadienos/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hiperalgesia/patologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Fibras Nervosas/fisiologia , Nitrilas/farmacologia , Medição da Dor , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução Genética
7.
J Inorg Biochem ; 121: 108-13, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23376332

RESUMO

A dinuclear ruthenium(II) complex linked via a reducible azo group [Ru(bpy)2(azobpy)Ru(bpy)2]Cl4 (Ru2azo, bpy=2,2'-bipyridine, azobpy=4,4″-azobis (2,2'-bipyridine)) was adopted as a probe for thiols. Results showed that Ru2azo could selectively and effectively react with biological thiols (such as cysteine, homocysteine and glutathione) with a 10(-7)M detection limit. After it reacted with thiols, the original gray color of Ru2azo solution immediately turned yellow and the luminescence significantly enhanced, showing "naked-eye" colorimetric and "off-on" luminescent dual-signaling response for thiols. Mechanism studies demonstrated that Ru2azo reacted with thiols undergoing a two-electron transfer process, forming the azo(2-) anion product.


Assuntos
Complexos de Coordenação/química , Cisteína/análise , Glutationa/análise , Homocisteína/análise , Sondas Moleculares/química , Rutênio/química , Complexos de Coordenação/síntese química , Transporte de Elétrons , Limite de Detecção , Medições Luminescentes , Sondas Moleculares/síntese química , Soluções
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA