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[PMID]: 28951448 [Au] Autor: Albisetti GW; Ghanem A; Foster E; Conzelmann KK; Zeilhofer HU; Wildner H [Ad] Endereço: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zürich, Switzerland. [Ti] Título: Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus. [So] Source: J Neurosci;37(43):10358-10371, 2017 Oct 25. [Is] ISSN: 1529-2401 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Glycoprotein-deleted rabies virus-mediated monosynaptic tracing has become a standard method for neuronal circuit mapping, and is applied to virtually all parts of the rodent nervous system, including the spinal cord and primary sensory neurons. Here we identified two classes of unmyelinated sensory neurons (nonpeptidergic and C-fiber low-threshold mechanoreceptor neurons) resistant to direct and trans-synaptic infection from the spinal cord with rabies viruses that carry glycoproteins in their envelopes and that are routinely used for infection of CNS neurons (SAD-G and N2C-G). However, the same neurons were susceptible to infection with EnvA-pseudotyped rabies virus in tumor virus A receptor transgenic mice, indicating that resistance to retrograde infection was due to impaired virus adsorption rather than to deficits in subsequent steps of infection. These results demonstrate an important limitation of rabies virus-based retrograde tracing of sensory neurons in adult mice, and may help to better understand the molecular machinery required for rabies virus spread in the nervous system. In this study, mice of both sexes were used. To understand the neuronal bases of behavior, it is important to identify the underlying neural circuitry. Rabies virus-based monosynaptic tracing has been used to identify neuronal circuits in various parts of the nervous system. This has included connections between peripheral sensory neurons and their spinal targets. These connections form the first synapse in the somatosensory pathway. Here we demonstrate that two classes of unmyelinated sensory neurons, which account for >40% of dorsal root ganglia neurons, display resistance to rabies infection. Our results are therefore critical for interpreting monosynaptic rabies-based tracing in the sensory system. In addition, identification of rabies-resistant neurons might provide a means for future studies addressing rabies pathobiology. [Mh] Termos MeSH primário: Gânglios Espinais/química Rede Nervosa/química Técnicas de Rastreamento Neuroanatômico/métodos Vírus da Raiva Células Receptoras Sensoriais/química [Mh] Termos MeSH secundário: Animais Feminino Gânglios Espinais/citologia Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Transgênicos Rede Nervosa/citologia Células do Corno Posterior/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171115 [Lr] Data última revisão: 171115 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170928 [St] Status: MEDLINE [do] DOI: 10.1523/JNEUROSCI.1277-17.2017

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[PMID]: 28640016 [Au] Autor: Sugiyama D; Kang S; Arpey N; Arunakul P; Usachev YM; Brennan TJ [Ad] Endereço: From the Departments of Anesthesia (D.S., S.K., N.A., P.A., T.J.B.) and Pharmacology (Y.M.U., T.J.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa. [Ti] Título: Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors. [So] Source: Anesthesiology;127(4):695-708, 2017 Oct. [Is] ISSN: 1528-1175 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: H2O2 has a variety of actions in skin wounds but has been rarely studied in deep muscle tissue. Based on response to the transient receptor potential ankyrin 1 antagonists after plantar incision, we hypothesized that H2O2 exerts nociceptive effects via the transient receptor potential ankyrin 1 in muscle. METHODS: Nociceptive behaviors in rats (n = 269) and mice (n = 16) were evaluated after various concentrations and volumes of H2O2 were injected into the gastrocnemius muscle or subcutaneous tissue. The effects of H2O2 on in vivo spinal dorsal horn neuronal activity and lumbar dorsal root ganglia neurons in vitro were evaluated from 26 rats and 6 mice. RESULTS: Intramuscular (mean ± SD: 1,436 ± 513 s) but not subcutaneous (40 ± 58 s) injection of H2O2 (100 mM, 0.6 ml) increased nociceptive time. Conditioned place aversion was evident after intramuscular (-143 ± 81 s) but not subcutaneous (-2 ± 111 s) injection of H2O2. These H2O2-induced behaviors were blocked by transient receptor potential ankyrin 1 antagonists. Intramuscular injection of H2O2 caused sustained in vivo activity of dorsal horn neurons, and H2O2 activated a subset of dorsal root ganglia neurons in vitro. Capsaicin nerve block decreased guarding after plantar incision and reduced nociceptive time after intramuscular H2O2. Nociceptive time after intramuscular H2O2 in transient receptor potential ankyrin 1 knockout mice was shorter (173 ± 156 s) compared with wild-type mice (931 ± 629 s). CONCLUSIONS: The greater response of muscle tissue to H2O2 may help explain why incision that includes deep muscle but not skin incision alone produces spontaneous activity in nociceptive pathways. [Mh] Termos MeSH primário: Peróxido de Hidrogênio/farmacologia Músculo Esquelético/efeitos dos fármacos Nociceptividade/efeitos dos fármacos Canais de Cátion TRPC/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Anti-Infecciosos Locais/farmacologia Modelos Animais de Doenças Feminino Gânglios Espinais/efeitos dos fármacos Masculino Nociceptores/efeitos dos fármacos Células do Corno Posterior/efeitos dos fármacos Ratos Ratos Sprague-Dawley Canal de Cátion TRPA1 Canais de Cátion TRPC/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Infective Agents, Local); 0 (TRPA1 Cation Channel); 0 (TRPC Cation Channels); 0 (Trpa1 protein, rat); BBX060AN9V (Hydrogen Peroxide) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170623 [St] Status: MEDLINE [do] DOI: 10.1097/ALN.0000000000001756

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[PMID]: 28574334 [Au] Autor: Takai K; Taniguchi M [Ad] Endereço: Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan. [Ti] Título: Modified dorsal root entry zone lesioning for intractable pain relief in patients with root avulsion injury. [So] Source: J Neurosurg Spine;27(2):178-184, 2017 Aug. [Is] ISSN: 1547-5646 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE Dorsal root entry zone (DREZ) lesioning has been the most effective surgical treatment for the relief of intractable pain due to root avulsion injury, but residual pain and a decrease in pain relief in the follow-up period have been reported in 23%-70% of patients. Based on pain topography in the most recent studies on neuropathic pain, the authors modified the conventional DREZ lesioning procedure to improve clinical outcomes. The presumed rationale for this procedure is to eliminate the spontaneous discharges of neurons in the superficial spinal dorsal horn as well as wide dynamic range neurons in the deep spinal dorsal horn. METHODS Ten patients with avulsion-related pain underwent surgery between 2011 and 2015. The surgical procedure was described and postoperative pain relief was assessed as follows: excellent (residual pain never exceeded 3 on the visual analog scale [VAS] without medication), good (residual pain never exceeded 5 on the VAS with medication), and poor (residual pain was greater than 5 with medication). Specific perioperative complications were assessed. RESULTS The aim of this surgical procedure was to destroy the deeper layers of the posterior horn of spinal gray matter, which was in contrast to the procedures of Nashold and Sindou, which were to destroy the superficial layers. All patients achieved excellent (n = 7, pain relief without medication) or good (n = 3, pain relief with medication) pain relief postoperatively, and the recurrence of pain was not reported in any patients (median 29 months after surgery, range 12-64 months). Nine patients (90%) achieved complete pain relief (a score of 0 or 1 on the VAS) with or without medication. No surgical site complications such as infection or CSF leakage were noted. No motor deficit was observed in any patient. A sensory deficit was observed in 2 patients and disappeared within 1 month in 1 patient. New pain at the adjacent level of DREZ lesioning was observed in 3 patients and disappeared within 1 month in 2 patients. In the other patient, new pain persisted and required analgesics. CONCLUSIONS These preliminary results demonstrated that total and persistent global pain relief was achieved with the modified DREZ lesioning procedure in 90% of patients without major neurological deficits. The clinical improvements achieved by this modified surgical procedure support the hypothesis that not only the superficial layers, but also deeper layers of the spinal dorsal horn are associated with intractable pain due to root avulsion injury. [Mh] Termos MeSH primário: Procedimentos Neurocirúrgicos Dor Intratável/etiologia Dor Intratável/cirurgia Raízes Nervosas Espinhais/lesões Raízes Nervosas Espinhais/cirurgia [Mh] Termos MeSH secundário: Acidentes por Quedas Acidentes de Trânsito Adulto Idoso Analgésicos/uso terapêutico Feminino Seguimentos Seres Humanos Masculino Meia-Idade Medição da Dor Dor Intratável/diagnóstico por imagem Dor Intratável/tratamento farmacológico Células do Corno Posterior Recidiva Estudos Retrospectivos Raízes Nervosas Espinhais/diagnóstico por imagem Resultado do Tratamento [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Analgesics) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170807 [Lr] Data última revisão: 170807 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170603 [St] Status: MEDLINE [do] DOI: 10.3171/2017.1.SPINE16234

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[PMID]: 28559374 [Au] Autor: Sullivan SJ; Farrant M; Cull-Candy SG [Ad] Endereço: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom. [Ti] Título: TARP γ-2 Is Required for Inflammation-Associated AMPA Receptor Plasticity within Lamina II of the Spinal Cord Dorsal Horn. [So] Source: J Neurosci;37(25):6007-6020, 2017 Jun 21. [Is] ISSN: 1529-2401 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking ( ) mice. Examination of EPSCs revealed the targeting of γ-2 to be synapse-specific; the amplitude of spontaneously occurring miniature EPSCs (mEPSCs) was reduced in neurons from mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that γ-2 is associated with AMPARs at synapses in lamina II but excluded from those at C-fiber inputs, a view supported by our immunohistochemical colabeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium-permeable (CP) AMPARs. This effect was abolished in mice. Our results establish that, although γ-2 is not typically associated with calcium-impermeable AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation. In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically determine the functional properties of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. An increase in the excitability of neurons within the superficial dorsal horn (SDH) of the spinal cord is thought to underlie heighted pain sensitivity. One mechanism considered to contribute to such long-lived changes is the remodeling of the ionotropic AMPA-type glutamate receptors that underlie fast excitatory synaptic transmission in the SDH. Here we show that the TARP γ-2 (stargazin) is present in SDH neurons and is necessary in a form of inflammatory pain-induced plasticity, which involves an increase in the prevalence of synaptic calcium-permeable AMPARs. [Mh] Termos MeSH primário: Canais de Cálcio/metabolismo Inflamação/metabolismo Plasticidade Neuronal/fisiologia Células do Corno Posterior/metabolismo Receptores de AMPA/fisiologia [Mh] Termos MeSH secundário: 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia Animais Canais de Cálcio/genética Capsaicina/farmacologia Agonistas de Aminoácidos Excitatórios/farmacologia Potenciais Pós-Sinápticos Excitadores/fisiologia Feminino Masculino Camundongos Camundongos Endogâmicos C57BL Fibras Nervosas Amielínicas/efeitos dos fármacos Doenças do Sistema Nervoso Periférico/genética Doenças do Sistema Nervoso Periférico/metabolismo Receptores de AMPA/agonistas Transmissão Sináptica/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cacng2 protein, mouse); 0 (Calcium Channels); 0 (Excitatory Amino Acid Agonists); 0 (Receptors, AMPA); 6OTE87SCCW (6-Cyano-7-nitroquinoxaline-2,3-dione); S07O44R1ZM (Capsaicin) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170814 [Lr] Data última revisão: 170814 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170601 [St] Status: MEDLINE [do] DOI: 10.1523/JNEUROSCI.0772-16.2017

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[PMID]: 28412220 [Au] Autor: Wigerblad G; Huie JR; Yin HZ; Leinders M; Pritchard RA; Koehrn FJ; Xiao WH; Bennett GJ; Huganir RL; Ferguson AR; Weiss JH; Svensson CI; Sorkin LS [Ad] Endereço: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. [Ti] Título: Inflammation-induced GluA1 trafficking and membrane insertion of Ca permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A. [So] Source: Exp Neurol;293:144-158, 2017 Jul. [Is] ISSN: 1090-2430 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Peripheral inflammation induces sensitization of nociceptive spinal cord neurons. Both spinal tumor necrosis factor (TNF) and neuronal membrane insertion of Ca permeable AMPA receptor (AMPAr) contribute to spinal sensitization and resultant pain behavior, molecular mechanisms connecting these two events have not been studied in detail. Intrathecal (i.t.) injection of TNF-blockers attenuated paw carrageenan-induced mechanical and thermal hypersensitivity. Levels of GluA1 and GluA4 from dorsal spinal membrane fractions increased in carrageenan-injected rats compared to controls. In the same tissue, GluA2 levels were not altered. Inflammation-induced increases in membrane GluA1 were prevented by i.t. pre-treatment with antagonists to TNF, PI3K, PKA and NMDA. Interestingly, administration of TNF or PI3K inhibitors followed by carrageenan caused a marked reduction in plasma membrane GluA2 levels, despite the fact that membrane GluA2 levels were stable following inhibitor administration in the absence of carrageenan. TNF pre-incubation induced increased numbers of Co labeled dorsal horn neurons, indicating more neurons with Ca permeable AMPAr. In parallel to Western blot results, this increase was blocked by antagonism of PI3K and PKA. In addition, spinal slices from GluA1 transgenic mice, which had a single alanine replacement at GluA1 ser 845 or ser 831 that prevented phosphorylation, were resistant to TNF-induced increases in Co labeling. However, behavioral responses following intraplantar carrageenan and formalin in the mutant mice were no different from littermate controls, suggesting a more complex regulation of nociception. Co-localization of GluA1, GluA2 and GluA4 with synaptophysin on identified spinoparabrachial neurons and their relative ratios were used to assess inflammation-induced trafficking of AMPAr to synapses. Inflammation induced an increase in synaptic GluA1, but not GluA2. Although total GluA4 also increased with inflammation, co-localization of GluA4 with synaptophysin, fell short of significance. Taken together these data suggest that peripheral inflammation induces a PI3K and PKA dependent TNFR1 activated pathway that culminates with trafficking of calcium permeable AMPAr into synapses of nociceptive dorsal horn projection neurons. [Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo Fosfatidilinositol 3-Quinases/metabolismo Células do Corno Posterior/metabolismo Radiculopatia/patologia Receptores de AMPA/metabolismo Fator de Necrose Tumoral alfa/metabolismo [Mh] Termos MeSH secundário: Animais Anti-Inflamatórios não Esteroides/uso terapêutico Cálcio/metabolismo Carragenina/toxicidade Modelos Animais de Doenças Inibidores Enzimáticos/farmacologia Inibidores Enzimáticos/uso terapêutico Etanercepte/uso terapêutico Feminino Masculino Camundongos Células do Corno Posterior/patologia Células do Corno Posterior/ultraestrutura Transporte Proteico/efeitos dos fármacos Transporte Proteico/fisiologia Radiculopatia/induzido quimicamente Radiculopatia/tratamento farmacológico Ratos Sprague-Dawley Frações Subcelulares/efeitos dos fármacos Frações Subcelulares/metabolismo Sinaptofisina/metabolismo Fator de Necrose Tumoral alfa/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Enzyme Inhibitors); 0 (Receptors, AMPA); 0 (Synaptophysin); 0 (Tumor Necrosis Factor-alpha); 0 (glutamate receptor ionotropic, AMPA 1); 9000-07-1 (Carrageenan); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); OP401G7OJC (Etanercept); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170417 [St] Status: MEDLINE

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[PMID]: 28381802 [Au] Autor: Andoh T; Uta D; Kato M; Toume K; Komatsu K; Kuraishi Y [Ad] Endereço: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama. [Ti] Título: Prophylactic Administration of Aucubin Inhibits Paclitaxel-Induced Mechanical Allodynia via the Inhibition of Endoplasmic Reticulum Stress in Peripheral Schwann Cells. [So] Source: Biol Pharm Bull;40(4):473-478, 2017. [Is] ISSN: 1347-5215 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells. [Mh] Termos MeSH primário: Estresse do Retículo Endoplasmático/efeitos dos fármacos Hiperalgesia/prevenção & controle Glucosídeos Iridoides/administração & dosagem Paclitaxel/toxicidade Profilaxia Pré-Exposição/métodos Células de Schwann/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Antineoplásicos Fitogênicos/toxicidade Linhagem Celular Estresse do Retículo Endoplasmático/fisiologia Hiperalgesia/induzido quimicamente Hiperalgesia/metabolismo Masculino Camundongos Camundongos Endogâmicos C57BL Paclitaxel/antagonistas & inibidores Células do Corno Posterior/efeitos dos fármacos Células do Corno Posterior/metabolismo Ratos Células de Schwann/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents, Phytogenic); 0 (Iridoid Glucosides); 2G52GS8UML (aucubin); P88XT4IS4D (Paclitaxel) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170724 [Lr] Data última revisão: 170724 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170407 [St] Status: MEDLINE [do] DOI: 10.1248/bpb.b16-00899

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[PMID]: 28326929 [Au] Autor: Cao XC; Pappalardo LW; Waxman SG; Tan AM [Ad] Endereço: 1 Department of Neurology, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA. [Ti] Título: Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury. [So] Source: Mol Pain;13:1744806916688016, 2017 Jan. [Is] ISSN: 1744-8069 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Neuropathic pain is a major complication of spinal cord injury, and despite aggressive efforts, this type of pain is refractory to available clinical treatment. Our previous work has demonstrated a structure-function link between dendritic spine dysgenesis on nociceptive sensory neurons in the intermediate zone, laminae IV/V, and chronic pain in central nervous system and peripheral nervous system injury models of neuropathic pain. To extend these findings, we performed a follow-up structural analysis to assess whether dendritic spine remodeling occurs on superficial dorsal horn neurons located in lamina II after spinal cord injury. Lamina II neurons are responsible for relaying deep, delocalized, often thermally associated pain commonly experienced in spinal cord injury pathologies. We analyzed dendritic spine morphometry and localization in tissue obtained from adult rats exhibiting neuropathic pain one-month following spinal cord injury. Although the total density of dendritic spines on lamina II neurons did not change after spinal cord injury, we observed an inverse relationship between the densities of thin- and mushroom-shaped spines: thin-spine density decreased while mushroom-spine density increased. These structural changes were specifically noted along dendritic branches within 150 µm from the soma, suggesting a possible adverse contribution to nociceptive circuit function. Intrathecal treatment with NSC23766, a Rac1-GTPase inhibitor, significantly reduced spinal cord injury-induced changes in both thin- and mushroom-shaped dendritic spines. Overall, these observations demonstrate that dendritic spine remodeling occurs in lamina II, regulated in part by the Rac1-signaling pathway, and suggests that structural abnormalities in this spinal cord region may also contribute to abnormal nociception after spinal cord injury. [Mh] Termos MeSH primário: Espinhas Dendríticas/patologia Espinhas Dendríticas/ultraestrutura Células do Corno Posterior/ultraestrutura Traumatismos da Medula Espinal/patologia [Mh] Termos MeSH secundário: Análise de Variância Animais Antineoplásicos/farmacologia Antineoplásicos/uso terapêutico Espinhas Dendríticas/efeitos dos fármacos Modelos Animais de Doenças Masculino Nocodazol/farmacologia Nocodazol/uso terapêutico Células do Corno Posterior/efeitos dos fármacos Células do Corno Posterior/patologia Ratos Ratos Sprague-Dawley Coloração pela Prata Traumatismos da Medula Espinal/tratamento farmacológico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); SH1WY3R615 (Nocodazole) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171103 [Lr] Data última revisão: 171103 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170323 [St] Status: MEDLINE [do] DOI: 10.1177/1744806916688016

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[PMID]: 28302446 [Au] Autor: Oyama M; Kuraoka S; Watanabe S; Iwai T; Tanabe M [Ad] Endereço: Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. [Ti] Título: Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice. [So] Source: J Pharmacol Sci;133(3):162-167, 2017 Mar. [Is] ISSN: 1347-8648 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs) were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS) was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors. [Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Glicina/fisiologia Células do Corno Posterior/fisiologia [Mh] Termos MeSH secundário: Animais Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos Masculino Camundongos Células do Corno Posterior/efeitos dos fármacos Sarcosina/análogos & derivados Sarcosina/farmacologia Serina/análogos & derivados Serina/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ALX 1393); 0 (Glycine Plasma Membrane Transport Proteins); 0 (N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine); 0 (Slc6a5 protein, mouse); 0 (Slc6a9 protein, mouse); 452VLY9402 (Serine); Z711V88R5F (Sarcosine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170801 [Lr] Data última revisão: 170801 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170318 [St] Status: MEDLINE

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[PMID]: 28251660 [Au] Autor: Tsuda M; Koga K; Chen T; Zhuo M [Ad] Endereço: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [Ti] Título: Neuronal and microglial mechanisms for neuropathic pain in the spinal dorsal horn and anterior cingulate cortex. [So] Source: J Neurochem;141(4):486-498, 2017 May. [Is] ISSN: 1471-4159 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Neuropathic pain is a debilitating chronic pain condition occurring after damage in the nervous system and is refractory to the currently available treatments. Major challenges include elucidating its mechanisms and developing new medications to treat it. Nerve injury-induced pain hypersensitivity involves aberrant excitability in spinal dorsal horn (SDH) neurons as a consequence of dysfunction of inhibitory interneurons and of hyperactivity of glial cells, especially microglia, the immune cells of the central nervous system. Evidence of this is found using animal models to investigate the molecular and cellular mechanisms of neuropathic pain. The pathologically altered somatosensory signals in the SDH then convey to the brain regions, including the anterior cingulate cortex (ACC). In these regions, nerve injury produces pre- and postsynaptic long-term plasticity, which contributes to negative emotions and anxiety associated with chronic pain conditions. Furthermore, recent evidence also indicates that the descending projection pathways from the ACC directly and indirectly to the SDH (the top-down corticospinal network) regulate nociceptive sensory transmission in the SDH. Thus, understanding a possible connection between the SDH and ACC, including a neuron-microglia interaction, may provide us with insights into the mechanisms used to amplify pain signals related to neuropathic pain and clues to aid the development of new therapeutic agents for the management of chronic pain. This article is part of the special article series "Pain". [Mh] Termos MeSH primário: Giro do Cíngulo/fisiopatologia Microglia Neuralgia/fisiopatologia Células do Corno Posterior Medula Espinal/fisiopatologia [Mh] Termos MeSH secundário: Animais Seres Humanos Corno Dorsal da Medula Espinal [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170807 [Lr] Data última revisão: 170807 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170303 [St] Status: MEDLINE [do] DOI: 10.1111/jnc.14001

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MEDLINE

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[PMID]: 28134928 [Au] Autor: Burma NE; Bonin RP; Leduc-Pessah H; Baimel C; Cairncross ZF; Mousseau M; Shankara JV; Stemkowski PL; Baimoukhametova D; Bains JS; Antle MC; Zamponi GW; Cahill CM; Borgland SL; De Koninck Y; Trang T [Ad] Endereço: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada. [Ti] Título: Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. [So] Source: Nat Med;23(3):355-360, 2017 Mar. [Is] ISSN: 1546-170X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide ( panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia. [Mh] Termos MeSH primário: Comportamento Animal/efeitos dos fármacos Conexinas/genética Microglia/efeitos dos fármacos Morfina/efeitos adversos Entorpecentes/efeitos adversos Proteínas do Tecido Nervoso/genética Células do Corno Posterior/efeitos dos fármacos Síndrome de Abstinência a Substâncias/genética [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Animais Apirase/farmacologia Western Blotting Técnicas de Cultura de Células Técnicas de Cocultura Conexinas/antagonistas & inibidores Conexinas/metabolismo Mefloquina/farmacologia Camundongos Microglia/metabolismo Naloxona/farmacologia Antagonistas de Entorpecentes/efeitos adversos Proteínas do Tecido Nervoso/antagonistas & inibidores Proteínas do Tecido Nervoso/metabolismo Neurônios/efeitos dos fármacos Neurônios/metabolismo Nociceptividade/efeitos dos fármacos Células do Corno Posterior/metabolismo Probenecid/farmacologia Ratos Síndrome de Abstinência a Substâncias/etiologia Síndrome de Abstinência a Substâncias/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Connexins); 0 (Narcotic Antagonists); 0 (Narcotics); 0 (Nerve Tissue Proteins); 0 (Panx1 protein, mouse); 0 (pannexin 1, rat); 36B82AMQ7N (Naloxone); 76I7G6D29C (Morphine); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.1.5 (Apyrase); PO572Z7917 (Probenecid); TML814419R (Mefloquine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170807 [Lr] Data última revisão: 170807 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170131 [St] Status: MEDLINE [do] DOI: 10.1038/nm.4281

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