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[PMID]:28972120
[Au] Autor:Melo-Carrillo A; Strassman AM; Nir RR; Schain AJ; Noseda R; Stratton J; Burstein R
[Ad] Endereço:Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
[Ti] Título:Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors.
[So] Source:J Neurosci;37(44):10587-10596, 2017 Nov 01.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients. Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores
Bainha de Mielina/efeitos dos fármacos
Fibras Nervosas Mielinizadas/efeitos dos fármacos
Fibras Nervosas Amielínicas/efeitos dos fármacos
Nociceptores/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Peptídeo Relacionado com Gene de Calcitonina/fisiologia
Seres Humanos
Masculino
Bainha de Mielina/fisiologia
Fibras Nervosas Mielinizadas/fisiologia
Fibras Nervosas Amielínicas/fisiologia
Nociceptores/fisiologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (TEV-48125); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171117
[Lr] Data última revisão:
171117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2211-17.2017


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[PMID]:28772166
[Au] Autor:Ye Z; Ren L; Tang Z; Deng Y; Xie X; Fu Z; Luo Z; Xu F; Zang N; Liu E
[Ad] Endereço:Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing 400014, China; Department of Respiratory Medicine, Chil
[Ti] Título:Pulmonary C-fiber degeneration downregulates IFN-γ receptor 1 via IFN-α induction to attenuate RSV-induced airway hyperresponsiveness.
[So] Source:Virology;510:262-272, 2017 Oct.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Respiratory syncytial virus (RSV) is a leading cause of respiratory infection in infants. Unfortunately, no effective vaccine or treatment against RSV is currently available. Pulmonary C-fibers (PCFs) are critical for regulating pulmonary inflammation and airway hyperresponsiveness (AHR). We previously reported that IFN-γ partially mediated RSV-induced airway disorders. In this study, we found that PCF degeneration alleviated RSV-induced airway inflammation, especially AHR by downregulating IFN-γ receptor 1 (IFNGR1), but had no effect on IFN-γ induction. In contrast, PCF degeneration actually increased IFN-α/ß levels, as were the levels of STAT1 and phosphorylated STAT1 (pSTAT1). Exogenous IFN-α treatment induced STAT1 activation and downregulated IFNGR1 expression. These results suggest that PCFs affect IFNGR1 expression by inducing IFN-α to regulate IFN-γ-mediated airway inflammation and AHR. Thus, targeting PCFs activation may help control RSV-induced airway disorders, especially AHR, even with the presence of inflammation.
[Mh] Termos MeSH primário: Regulação para Baixo
Interações Hospedeiro-Patógeno
Interferon-alfa/metabolismo
Fibras Nervosas Amielínicas/metabolismo
Receptores de Interferon/biossíntese
Hipersensibilidade Respiratória
Vírus Sinciciais Respiratórios/imunologia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Camundongos Endogâmicos BALB C
Infecções por Vírus Respiratório Sincicial/patologia
Infecções por Vírus Respiratório Sincicial/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interferon-alpha); 0 (Receptors, Interferon); 0 (interferon gamma receptor)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE


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[PMID]:28729113
[Au] Autor:Wei JY; Liu CC; Ouyang HD; Ma C; Xie MX; Liu M; Lei WL; Ding HH; Wu SL; Xin WJ
[Ad] Endereço:Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-sen University, Guangzhou 510080, China.
[Ti] Título:Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib.
[So] Source:Exp Neurol;296:74-82, 2017 Oct.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p-STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p-STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment.
[Mh] Termos MeSH primário: Bortezomib/toxicidade
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos
Dor/induzido quimicamente
Dor/tratamento farmacológico
Aldeído Pirúvico/farmacologia
Aldeído Pirúvico/uso terapêutico
Medula Espinal/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/toxicidade
Modelos Animais de Doenças
Masculino
Fibras Nervosas Amielínicas/efeitos dos fármacos
Fibras Nervosas Amielínicas/fisiologia
Dor/patologia
Medição da Dor/efeitos dos fármacos
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Ratos
Ratos Sprague-Dawley
Receptor para Produtos Finais de Glicação Avançada/genética
Receptor para Produtos Finais de Glicação Avançada/metabolismo
Fator de Transcrição STAT3/genética
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais/efeitos dos fármacos
Medula Espinal/citologia
Medula Espinal/efeitos dos fármacos
Potenciais Sinápticos/efeitos dos fármacos
Potenciais Sinápticos/genética
Transdução Genética
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ager protein, rat); 0 (Antineoplastic Agents); 0 (RNA, Small Interfering); 0 (Receptor for Advanced Glycation End Products); 0 (STAT3 Transcription Factor); 69G8BD63PP (Bortezomib); 722KLD7415 (Pyruvaldehyde)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE


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[PMID]:28637786
[Au] Autor:Kadekawa K; Majima T; Shimizu T; Wada N; de Groat WC; Kanai AJ; Goto M; Yoshiyama M; Sugaya K; Yoshimura N
[Ad] Endereço:Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
[Ti] Título:The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in spinal-intact and spinal cord-injured mice.
[So] Source:Am J Physiol Renal Physiol;313(3):F796-F804, 2017 Sep 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We examined bladder and urethral sphincter activity in mice with or without spinal cord injury (SCI) after C-fiber afferent desensitization induced by capsaicin pretreatment and changes in electrophysiological properties of mouse bladder afferent neurons 4 wk after SCI. Female C57BL/6N mice were divided into four groups: ) spinal intact (SI)-control, ) SI-capsaicin pretreatment (Cap), ) SCI-control, and ) SCI-Cap groups. Continuous cystometry and external urethral sphincter (EUS)-electromyogram (EMG) were conducted under an awake condition. In the Cap groups, capsaicin (25, 50, or 100 mg/kg) was injected subcutaneously 4 days before the experiments. In the SI-Cap group, 100 mg/kg capsaicin pretreatment significantly increased bladder capacity and decreased the silent period duration of EUS/EMG compared with the SI-control group. In the SCI-Cap group, 50 and 100 mg/kg capsaicin pretreatment decreased the number of nonvoiding contractions (NVCs) and the duration of reduced EUS activity during voiding, respectively, compared with the SCI-control group. In SCI mice, hexamethonium, a ganglionic blocker, almost completely blocked NVCs, suggesting that they are of neurogenic origin. Patch-clamp recordings in capsaicin-sensitive bladder afferent neurons from SCI mice showed hyperexcitability, which was evidenced by decreased spike thresholds and increased firing rate compared with SI mice. These results indicate that capsaicin-sensitive C-fiber afferent pathways, which become hyperexcitable after SCI, can modulate bladder and urethral sphincter activity in awake SI and SCI mice. Detrusor overactivity as shown by NVCs in SCI mice is significantly but partially dependent on capsaicin-sensitive C-fiber afferents, whereas the EUS relaxation during voiding is enhanced by capsaicin-sensitive C-fiber bladder afferents in SI and SCI mice.
[Mh] Termos MeSH primário: Capsaicina/farmacologia
Fibras Nervosas Amielínicas/efeitos dos fármacos
Neurônios Aferentes/efeitos dos fármacos
Fármacos do Sistema Sensorial/farmacologia
Traumatismos da Medula Espinal/tratamento farmacológico
Uretra/inervação
Bexiga Urinária Hiperativa/prevenção & controle
Bexiga Urinária/inervação
Micção/efeitos dos fármacos
[Mh] Termos MeSH secundário: Potenciais de Ação
Animais
Modelos Animais de Doenças
Eletromiografia
Feminino
Bloqueadores Ganglionares/farmacologia
Camundongos Endogâmicos C57BL
Fibras Nervosas Amielínicas/metabolismo
Neurônios Aferentes/metabolismo
Técnicas de Patch-Clamp
Pressão
Traumatismos da Medula Espinal/complicações
Traumatismos da Medula Espinal/fisiopatologia
Fatores de Tempo
Bexiga Urinária Hiperativa/etiologia
Bexiga Urinária Hiperativa/fisiopatologia
Urodinâmica/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ganglionic Blockers); 0 (Sensory System Agents); S07O44R1ZM (Capsaicin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00097.2017


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[PMID]:28615326
[Au] Autor:Gao X; Zhao L; Zhuang J; Zang N; Xu F
[Ad] Endereço:Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
[Ti] Título:Prenatal nicotinic exposure prolongs superior laryngeal C-fiber-mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation.
[So] Source:FASEB J;31(10):4325-4334, 2017 Oct.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Maternal cigarette smoke, including prenatal nicotinic exposure (PNE), is responsible for sudden infant death syndrome (SIDS). The fatal events of SIDS are characterized by severe bradycardia and life-threatening apneas. Although activation of transient receptor potential vanilloid 1 (TRPV1) of superior laryngeal C fibers (SLCFs) could induce bradycardia and apnea and has been implicated in SIDS pathogenesis, how PNE affects the SLCF-mediated cardiorespiratory responses remains unexplored. Here, we tested the hypothesis that PNE would aggravate the SLCF-mediated apnea and bradycardia up-regulating TRPV1 expression and excitation of laryngeal C neurons in the nodose/jugular (N/J) ganglia. To this end, we compared the following outcomes between control and PNE rat pups at postnatal days 11-14: ) the cardiorespiratory responses to intralaryngeal application of capsaicin (10 µg/ml, 50 µl), a selective stimulant for TRPV1 receptors, in anesthetized preparation; ) immunoreactivity and mRNA of TRPV1 receptors of laryngeal sensory C neurons in the N/J ganglia retrogradely traced by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; and ) TRPV1 currents and electrophysiological characteristics of these neurons by using whole-cell patch-clamp technique Our results showed that PNE markedly prolonged the apneic response and exacerbated the bradycardic response to intralaryngeal perfusion of capsaicin, which was associated with up-regulation of TRPV1 expression in laryngeal C neurons. In addition, PNE increased the TRPV1 currents, depressed the slow delayed rectifier potassium currents, and increased the resting membrane potential of these neurons. Our results suggest that PNE is capable of aggravating the SLCF-mediated apnea and bradycardia through TRPV1 sensitization and neuronal excitation, which may contribute to the pathogenesis of SIDS.-Gao, X., Zhao, L., Zhuang, J., Zang, N., Xu, F. Prenatal nicotinic exposure prolongs superior laryngeal C-fiber-mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation.
[Mh] Termos MeSH primário: Apneia/metabolismo
Bradicardia/metabolismo
Fibras Nervosas Amielínicas/metabolismo
Nicotina/farmacologia
Células Receptoras Sensoriais/metabolismo
Fumaça/efeitos adversos
Canais de Cátion TRPV/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Apneia/induzido quimicamente
Bradicardia/induzido quimicamente
Capsaicina/farmacologia
Modelos Animais de Doenças
Técnicas de Patch-Clamp/métodos
Ratos Sprague-Dawley
Células Receptoras Sensoriais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Smoke); 0 (TRPV Cation Channels); 0 (Trpv1 protein, rat); 6M3C89ZY6R (Nicotine); S07O44R1ZM (Capsaicin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700163R


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[PMID]:28576935
[Au] Autor:Dickie AC; McCormick B; Lukito V; Wilson KL; Torsney C
[Ad] Endereço:Centre for Integrative Physiology, Edinburgh Medical School: Biomedical Sciences, The University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
[Ti] Título:Inflammatory Pain Reduces C Fiber Activity-Dependent Slowing in a Sex-Dependent Manner, Amplifying Nociceptive Input to the Spinal Cord.
[So] Source:J Neurosci;37(27):6488-6502, 2017 Jul 05.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:C fibers display activity-dependent slowing (ADS), whereby repetitive stimulation (≥1 Hz) results in a progressive slowing of action potential conduction velocity, which manifests as a progressive increase in response latency. However, the impact of ADS on spinal pain processing has not been explored, nor whether ADS is altered in inflammatory pain conditions. To investigate, compound action potentials were made, from dorsal roots isolated from rats with or without complete Freund's adjuvant (CFA) hindpaw inflammation, in response to electrical stimulus trains. CFA inflammation significantly reduced C fiber ADS at 1 and 2 Hz stimulation rates. Whole-cell patch-clamp recordings in the spinal cord slice preparation with attached dorsal roots also demonstrated that CFA inflammation reduced ADS in the monosynaptic C fiber input to lamina I neurokinin 1 receptor-expressing neurons (1-10 Hz stimulus trains) without altering the incidence of synaptic response failures. When analyzed by sex, it was revealed that females display a more pronounced ADS that is reduced by CFA inflammation to a level comparable with males. Cumulative ventral root potentials evoked by long and short dorsal root stimulation lengths, to maximize and minimize the impact of ADS, respectively, demonstrated that reducing ADS facilitates spinal summation, and this was also sex dependent. This finding correlated with the behavioral observation of increased noxious thermal thresholds and enhanced inflammatory thermal hypersensitivity in females. We propose that sex/inflammation-dependent regulation of C fiber ADS can, by controlling the temporal relay of nociceptive inputs, influence the spinal summation of nociceptive signals contributing to sex/inflammation-dependent differences in pain sensitivity. The intensity of a noxious stimulus is encoded by the frequency of action potentials relayed by nociceptive C fibers to the spinal cord. C fibers conduct successive action potentials at progressively slower speeds, but the impact of this activity-dependent slowing (ADS) is unknown. Here we demonstrate that ADS is more prevalent in females than males and is reduced in an inflammatory pain model in females only. We also demonstrate a progressive delay of C fiber monosynaptic transmission to the spinal cord that is similarly sex and inflammation dependent. Experimentally manipulating ADS strongly influences spinal summation consistent with sex differences in behavioral pain thresholds. This suggests that ADS provides a peripheral mechanism that can regulate spinal nociceptive processing and pain sensation.
[Mh] Termos MeSH primário: Fibras Nervosas Amielínicas
Condução Nervosa
Neuralgia/fisiopatologia
Nociceptividade
Medula Espinal/fisiopatologia
Raízes Nervosas Espinhais/fisiopatologia
[Mh] Termos MeSH secundário: Vias Aferentes/fisiopatologia
Animais
Feminino
Masculino
Ratos
Ratos Sprague-Dawley
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3816-16.2017


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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


  8 / 1655 MEDLINE  
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[PMID]:28542001
[Au] Autor:Ohashi N; Uta D; Sasaki M; Ohashi M; Kamiya Y; Kohno T
[Ad] Endereço:Division of Anesthesiology (N.O., T.K.) and Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine (M.O.), Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan; Department of Applied Pharmacology, Toyama University Graduate School of Medicine and Pharmaceutical Sciences, Toyama City, Japan (D.U.); and Division of Anesthesiology, Niigata University Medical and Dental Hospital, Uonuma Institute of Community Medicine, Minami-Uonuma City, Japan (M.S., Y.K.).
[Ti] Título:Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn.
[So] Source:Anesthesiology;127(2):355-371, 2017 Aug.
[Is] ISSN:1528-1175
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. METHODS: We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. RESULTS: Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. CONCLUSIONS: Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.
[Mh] Termos MeSH primário: Acetaminofen/farmacologia
Analgesia/métodos
Neurônios Aferentes/efeitos dos fármacos
Dor/prevenção & controle
Corno Dorsal da Medula Espinal/efeitos dos fármacos
Canais de Cátion TRPV/efeitos dos fármacos
[Mh] Termos MeSH secundário: Analgésicos não Entorpecentes/farmacologia
Animais
Modelos Animais de Doenças
Masculino
Fibras Nervosas Amielínicas/efeitos dos fármacos
Ratos
Ratos Wistar
Canais de Cátion TRPV/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Non-Narcotic); 0 (TRPV Cation Channels); 0 (Trpv1 protein, rat); 362O9ITL9D (Acetaminophen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1097/ALN.0000000000001700


  9 / 1655 MEDLINE  
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[PMID]:28522561
[Au] Autor:Hsu CC; Lin YS; Lin RL; Lee LY
[Ad] Endereço:Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky.
[Ti] Título:Immediate and delayed potentiating effects of tumor necrosis factor-α on TRPV1 sensitivity of rat vagal pulmonary sensory neurons.
[So] Source:Am J Physiol Lung Cell Mol Physiol;313(2):L293-L304, 2017 Aug 01.
[Is] ISSN:1522-1504
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We studied acute effects of tumor necrosis factor-α (TNFα) on the sensitivity of isolated rat vagal pulmonary sensory neurons. Our results showed the following. First, a brief pretreatment with a low dose of TNFα (1.44 nM, 9 min) enhanced the sensitivity of transient receptor potential vanilloid type 1 (TRPV1) receptors in these neurons in two distinct phases: the inward current evoked by capsaicin was amplified (Δ = 247%) immediately following the TNFα pretreatment, which gradually declined toward control and then increased again reaching another peak (Δ = 384%) after 60-90 min. Second, the immediate phase of this potentiating effect of TNFα was completely abolished by a pretreatment with a selective cyclooxygenase-2 (COX-2) inhibitor, NS-398, whereas the delayed potentiation was only partially attenuated. Third, in sharp contrast, TNFα did not generate any potentiating effect on the responses to non-TRPV1 chemical activators of these neurons. Fourth, the selectivity of the TNFα action on TRPV1 was further illustrated by the responses to acid (pH 6.0); TNFα did not affect the rapid transient current mediated by acid-sensing ion channels but significantly augmented the slow sustained current mediated by TRPV1 in the same neurons. Fifth, in anesthetized rats, a similar pattern of acute sensitizing effects of TNFα on pulmonary C-fiber afferents and the involvement of COX-2 were also clearly shown. In conclusion, a brief pretreatment with TNFα induced both immediate and delayed potentiating effects on the TRPV1 sensitivity in pulmonary sensory neurons, and the production of COX-2 arachidonic acid metabolites plays a major role in the immediate sensitizing effect of TNFα.
[Mh] Termos MeSH primário: Pulmão/metabolismo
Células Receptoras Sensoriais/metabolismo
Canais de Cátion TRPV/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
[Mh] Termos MeSH secundário: Canais Iônicos Sensíveis a Ácido/metabolismo
Animais
Capsaicina/farmacologia
Ciclo-Oxigenase 2/metabolismo
Pulmão/efeitos dos fármacos
Masculino
Fibras Nervosas Amielínicas/metabolismo
Nitrobenzenos/farmacologia
Ratos
Ratos Sprague-Dawley
Células Receptoras Sensoriais/efeitos dos fármacos
Sulfonamidas/farmacologia
Nervo Vago/efeitos dos fármacos
Nervo Vago/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channels); 0 (Nitrobenzenes); 0 (Sulfonamides); 0 (TRPV Cation Channels); 0 (Trpv1 protein, rat); 0 (Tumor Necrosis Factor-alpha); 123653-11-2 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide); EC 1.14.99.1 (Cyclooxygenase 2); S07O44R1ZM (Capsaicin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1152/ajplung.00235.2016


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[PMID]:28476920
[Au] Autor:Beaumont E; Campbell RP; Andresen MC; Scofield S; Singh K; Libbus I; KenKnight BH; Snyder L; Cantrell N
[Ad] Endereço:Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee; beaumont@etsu.edu.
[Ti] Título:Cervical vagus nerve stimulation augments spontaneous discharge in second- and higher-order sensory neurons in the rat nucleus of the solitary tract.
[So] Source:Am J Physiol Heart Circ Physiol;313(2):H354-H367, 2017 Aug 01.
[Is] ISSN:1522-1539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insensitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts. Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents but indirectly activated a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for vagus nerve stimulation efficacy.
[Mh] Termos MeSH primário: Potenciais de Ação
Potenciais Evocados
Fibras Nervosas Mielinizadas/fisiologia
Fibras Nervosas Amielínicas/fisiologia
Células Receptoras Sensoriais/fisiologia
Núcleo Solitário/fisiologia
Estimulação do Nervo Vago/métodos
Nervo Vago/fisiologia
[Mh] Termos MeSH secundário: Animais
Barorreflexo
Pressão Sanguínea
Bradicardia/etiologia
Bradicardia/fisiopatologia
Frequência Cardíaca
Masculino
Modelos Animais
Vias Neurais/fisiologia
Ratos Sprague-Dawley
Estimulação do Nervo Vago/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE
[do] DOI:10.1152/ajpheart.00070.2017



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