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2.
Pain ; 161(2): 416-428, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31651582

RESUMO

Chronic pain and anxiety symptoms are frequently encountered clinically, but the neural circuit mechanisms underlying the comorbid anxiety symptoms in pain (CASP) in context of chronic pain remain unclear. Using viral neuronal tracing in mice, we identified a previously unknown pathway whereby glutamatergic neurons from layer 5 of the hindlimb primary somatosensory cortex (S1) (Glu), a well-known brain region involved in pain processing, project to GABAergic neurons in the caudal dorsolateral striatum (GABA). In a persistent inflammatory pain model induced by complete Freund's adjuvant injection, enhanced excitation of the Glu→GABA pathway was found in mice exhibiting CASP. Reversing this pathway using chemogenetic or optogenetic approaches alleviated CASP. In addition, the optical activation of Glu terminals in the cDLS produced anxiety-like behaviors in naive mice. Overall, the current study demonstrates the putative importance of a novel Glu→GABA pathway in controlling at least some aspects of CASP.

3.
Cell Rep ; 29(12): 3847-3858.e5, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31851918

RESUMO

While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABACeA) project to glutamatergic neurons in the parafascicular nucleus (GluPF). These GluPF neurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing. Enhanced inhibition of the GABACeA→GluPF→S2 pathway is found in mice exhibiting CP symptoms. Reversing this pathway using chemogenetic or optogenetic approaches alleviates CP symptoms. Together, the current study demonstrates the putative importance of the GABACeA→GluPF→S2 pathway in controlling at least some aspects of CP.

5.
J Neurosci ; 39(46): 9130-9144, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31604834

RESUMO

Neuropathic pain is one of the most common and notorious neurological diseases. The changes in cerebral structures after nerve injury and the corresponding contributions to neuropathic pain are not well understood. Here we found that the majority of glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) were inhibited by painful stimulation in male mice. Optogenetic manipulation revealed that these neurons were tonically involved in the inhibitory modulation of multimodal nociception. We further identified the projections to GABAergic neurons in the zona incerta (ZIGABA) mediated the pain inhibitory role. However, MCC Cg2Glu became hypoactive after nerve injury. Although a brief activation of the MCC Cg2Glu to ZIGABA circuit was able to relieve the aversiveness associated with spontaneous ongoing pain, consecutive activation of the circuit was required to alleviate neuropathic allodynia. In contrast, glutamatergic neurons in the area 1 of MCC played opposite roles in pain modulation. They became hyperactive after nerve injury and only consecutive inhibition of their activity relieved allodynia. These results demonstrate that MCC Cg2Glu constitute a component of intrinsic pain inhibitory circuitry and their hypoactivity underlies neuropathic pain. We propose that selective and persistent activation of the MCC Cg2Glu to ZIGABA circuit may serve as a potential therapeutic strategy for this disease.SIGNIFICANCE STATEMENT Glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) are tonically involved in the intrinsic pain inhibition via projecting to GABAergic neurons in the zona incerta. They are hypoactive after nerve injury. Selective activation of the circuit compensates the reduction of its analgesic strength and relieves neuropathic pain. Therefore, MCC Cg2Glu and the related analgesic circuit may serve as therapeutic targets for neuropathic pain. In contrast, MCC Cg1Glu have an opposite role in pain modulation and become hyperactive after nerve injury. The present study provides novel evidence for the concept that neuropathic pain is associated with the dysfunction of endogenous pain modulatory system and new perspective on the treatment of neuropathic pain.

6.
Nat Neurosci ; 22(10): 1649-1658, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451801

RESUMO

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.


Assuntos
Dor Crônica/patologia , Depressão/patologia , Vias Neurais/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Dor Crônica/complicações , Dor Crônica/diagnóstico por imagem , Depressão/complicações , Depressão/diagnóstico por imagem , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/patologia , Feminino , Habenula/diagnóstico por imagem , Habenula/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Optogenética , Serotonina/metabolismo , Somatostatina/metabolismo
7.
Pain Res Manag ; 2019: 6528528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467625

RESUMO

Background: Surgery is a frequent cause of persistent pain. Unrelieved chronic postsurgical pain causes unnecessary patient suffering and discomfort and usually leads to psychological complications. The rat model of skin/muscle incision and retraction (SMIR) with decreased paw withdrawal thresholds developed by Flatters was usually used to investigate the underlying mechanism of chronic postsurgical pain. Objectives: The aim of our study was to develop a new mice model of SMIR for further investigation with transgenic mice and so on and to evaluate the analgesic effects of clonidine and gabapentin on pain behavior with this new mice model. Methods: Male C57BL/6 mice were anesthetized, and a 1.0-1.3 cm incision was made in the skin of the medial thigh approximately 3 mm medial to the saphenous vein to reveal the muscle of the thigh. The paw withdrawal threshold (PWT) to mechanical stimuli and the paw withdrawal latency to heat stimuli were measured before and after SMIR. Furthermore, the PWT to mechanical stimuli and conditioned place preference (CPP) was measured before and after the systemic injection of clonidine and gabapentin. Results: SMIR-evoked mechanical hypersensitivity in mice began on day 1 after the procedure, prominent between days 1 and 10 after the procedure, persisted at least until day 14, and disappeared on day 18 after the procedure. However, the mice model of SMIR did not evoke significant heat hypersensitivity. Systemic injection of clonidine and gabapentin raised the PWT in the SMIR mice dose-dependently. Compared with the mice that underwent the sham operation, mice of SMIR spent a longer time in the clonidine-paired chamber than those of NS, while the gabapentin-paired chamber has no difference with that of NS in the CPP paradigm. Conclusion: These data suggested that the mice model of SMIR demonstrated a persistent pain syndrome, including evoked pain and spontaneous pain. Clonidine and gabapentin could relieve mechanical hypersensitivity dose-dependently simultaneously. However, clonidine but not gabapentin could alleviate the spontaneous pain of SMIR in the mice model.


Assuntos
Modelos Animais de Doenças , Dor Pós-Operatória , Animais , Dor Crônica/complicações , Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/cirurgia , Pele
8.
Adv Exp Med Biol ; 1099: 115-124, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30306519

RESUMO

Spontaneous pain is the major complain for the patients to see a doctor. Human imaging studies presented that spontaneous pain is mainly associated with activity changes in medial pain pathway, while broader brain regions were activated by allodynia pain. On behavioral level, temporally disassociation between the evoked pain and spontaneous pain was observed; these data gave a hint that the spontaneous pain and evoked pain may be mediated by different neuronal mechanisms. And more attentions should be paid to the spontaneous pain to treat the chronic pain in the future.


Assuntos
Dor Crônica/fisiopatologia , Hiperalgesia/fisiopatologia , Neurônios/fisiologia , Encéfalo/diagnóstico por imagem , Humanos , Medição da Dor
9.
Front Mol Neurosci ; 11: 231, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034322

RESUMO

Leucine-rich glioma inactivated 1 (Lgi1), a putative tumor suppressor, is tightly associated with autosomal dominant lateral temporal lobe epilepsy (ADLTE). It has been shown that Lgi1 regulates the myelination of Schwann cells in the peripheral nervous system (PNS). However, the function and underlying mechanisms for Lgi1 regulation of oligodendrocyte differentiation and myelination in the central nervous system (CNS) remain elusive. In addition, whether Lgi1 is required for myelin maintenance is unknown. Here, we show that Lgi1 is necessary and sufficient for the differentiation of oligodendrocyte precursor cells and is also required for the maintenance of myelinated fibers. The hypomyelination in Lgi1-/- mice attributes to the inhibition of the biosynthesis of lipids and proteins in oligodendrocytes (OLs). Moreover, we found that Lgi1 deficiency leads to a decrease in expression of tuberous sclerosis complex 1 (TSC1) and activates mammalian target of rapamycin signaling. Together, the present work establishes that Lgi1 is a regulator of oligodendrocyte development and myelination in CNS.

10.
Nano Lett ; 18(7): 4148-4155, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29916253

RESUMO

Externally controlling the excitation of a neuronal subset through ion channels activation can modulate the firing pattern of an entire neural circuit in vivo. As nanovalves in the cell membrane, ion channels can be opened by light (optogenetics) or ultrasonic (sonogenetics) means. A thoroughly analyzed force sensor is the Escherichia coli mechano sensitive channel of large conductance (MscL). Here we expressed MscL in rat hippocampal neurons in a primary culture and showed that it could be activated by low-pressure ultrasound pulses. The gain-of-function mutation, I92L, sensitized MscL's sonic response, triggering action potentials at a peak negative pressure as low as 0.25 MPa. Further, the I92L MscL reliably elicited individual spikes by timed brief pulses, making excitation programmable. Because MscL opens to tension in the lipid bilayer, requiring no other proteins or ligands, it could be developed into a general noninvasive sonogenetic tool to manipulate the activities of neurons or other cells and potential nanodevices.


Assuntos
Membrana Celular/genética , Proteínas de Escherichia coli/química , Canais Iônicos/química , Neurônios/metabolismo , Sequência de Aminoácidos/genética , Animais , Fenômenos Biomecânicos , Membrana Celular/química , Escherichia coli/química , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Canais Iônicos/genética , Bicamadas Lipídicas/metabolismo , Neurônios/patologia , Cultura Primária de Células , Ratos , Ultrassom
11.
Cell Rep ; 22(7): 1734-1744, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29444427

RESUMO

Short-term memory (STM) is crucial for animals to hold information for a small period of time. Persistent or recurrent neural activity, together with neural oscillations, is known to encode the STM at the cellular level. However, the coding mechanisms at the microcircuitry level remain a mystery. Here, we performed two-photon imaging on behaving mice to monitor the activity of neuronal microcircuitry. We discovered a neuronal subpopulation in the medial prefrontal cortex (mPFC) that exhibited emergent properties in a context-dependent manner underlying a STM-like behavior paradigm. These neuronal subpopulations exclusively comprise excitatory neurons and mainly represent a group of neurons with stronger functional connections. Microcircuitry plasticity was maintained for minutes and was absent in an animal model of Alzheimer's disease (AD). Thus, these results point to a functional coding mechanism that relies on the emergent behavior of a functionally defined neuronal assembly to encode STM.


Assuntos
Memória de Curto Prazo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal , Extinção Psicológica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/fisiologia , Plasticidade Neuronal , Especificidade de Órgãos , Dor/fisiopatologia , Som
12.
Front Mol Neurosci ; 10: 289, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28955200

RESUMO

The anterior cingulate cortex (ACC) is an important brain area for the regulation of neuropathic pain. The α2A adrenoceptor is a good target for pain management. However, the role of cingulate α2A adrenoceptors in the regulation of neuropathic pain has been less studied. In this study, we investigated the involvement of cingulate α2A adrenoceptors in the regulation of neuropathic pain at different time points after peripheral nerve injury in mice. The application of clonidine, either systemically (0.5 mg/kg intraperitoneally) or specifically to the ACC, increased paw withdrawal thresholds (PWTs) and induced conditioned place preference (CPP) at day 7 after nerve injury, suggesting that cingulate α2 adrenoceptors are involved in the regulation of pain-like behaviors. Quantitative real-time PCR data showed that α2A adrenoceptors are the dominant α2 adrenoceptors in the ACC. Furthermore, the expression of cingulate α2A adrenoceptors was increased at day 3 and day 7 after nerve injury, but decreased at day 14, while no change was detected in the concentration of adrenaline or noradrenaline. BRL-44408 maleate, a selective antagonist of α2A adrenoceptors, was microinfused into the ACC. This blocking of cingulate α2A adrenoceptors activity abolished the CPP induced by clonidine (0.5 mg/kg intraperitoneally) but not the effects on PWTs at day 7. However, clonidine applied systemically or specifically to the ACC at day 14 increased the PWTs but failed to induce CPP; this negative effect was reversed by the overexpression of cingulate α2A adrenoceptors. These results suggest that cingulate α2A adrenoceptors are necessary for the analgesic effects of clonidine on spontaneous pain.

13.
Anesth Analg ; 124(4): 1330-1338, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28002166

RESUMO

BACKGROUND: Both pharmacologic and genetic approaches have been used to study the involvement of the muscarinic acetylcholine system in the regulation of chronic pain. Previous studies suggest that the M2 and M4 subtypes of muscarinic acetylcholine receptors (mAChRs) are important targets for the development of chronic pain. (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] octane (PTAC) has agonist effects on muscarinic M2 and M4 receptors and antagonist effects on muscarinic M1, M3, and M5 receptors. However, its analgesic effects have been less studied. METHODS: Male C57B L/6 mice were anesthetized, and left common peroneal nerve (CPN) ligation was performed to induce neuropathic pain. Before and after the application of PTAC systemically or specifically to the anterior cingulate cortex (ACC), the withdrawal thresholds to mechanical stimulation and static weight balance were measured, and the effects of PTAC on the conditioned place preference (CPP) were further evaluated. Western blotting was used to examine the expression of M1 and M2 in the striatum, ACC, and ventral tegmental area. RESULTS: The application of PTAC ([i.p.] intraperitoneal injection) increased the paw withdraw threshold in both the early (0.05 mg/kg, mean difference [95% confidence interval, CI]: 0.19 [0.05-0.32]; 0.10 mg/kg: mean difference [95% CI]: 0.34 [0.22-0.46]) and the late phases (0.05 mg/kg: mean difference [95% CI]: 0.45 [0.39-0.50]; 0.1 mg/kg: mean difference [95% CI]: 0.44 [0.37-0.51]) after nerve injury and rebalanced the weight distribution on the hind paws of mice (L/R ratio: before, 0.56 ± 0.03. 0.05 mg/kg, 1.00 ± 0.04, 0.10 mg/kg, 0.99 ± 0.03); however, it failed to induce place preference in the CPP (0.05 mg/kg, 2-way analysis of variance, P > .05; 0.2 mg/kg, 2-way analysis of variance, P > .05,). At the same doses, the analgesic effects at D3-5 lasted longer than the effects at D14-16. This may be due to the down-regulation of the M2 and M1 in tested brain regions. CONCLUSIONS: These observations suggested that PTAC has analgesic effects on the neuropathic pain induced by nerve injury.


Assuntos
Analgésicos/administração & dosagem , Compostos Bicíclicos com Pontes/administração & dosagem , Modelos Animais de Doenças , Neuralgia/tratamento farmacológico , Tiadiazóis/administração & dosagem , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Neuralgia/metabolismo , Neuralgia/patologia , Receptores Muscarínicos/biossíntese , Resultado do Tratamento
14.
Biol Psychiatry ; 81(8): 654-670, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-27916196

RESUMO

BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. METHODS: We used specific ß-adrenergic agonists, as well as ß2-adrenergic receptor (ß2AR) and arrestin knockout models, to study the effects of adaptive ß2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks. RESULTS: We observed that the duration of the adaptive ß2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged ß2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of ß2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, ß-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a ß-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1α ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of ß2ARs, which was responsible for its decreased beneficial effects. CONCLUSIONS: Our results not only revealed that ß-arrestin-1 regulated lactate metabolism to contribute to ß2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Ácido Láctico/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Estresse Psicológico/metabolismo , beta-Arrestina 1/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Animais , Astrócitos/metabolismo , Linhagem Celular , Fumarato de Formoterol/administração & dosagem , Hipocampo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoenzimas/metabolismo , L-Lactato Desidrogenase/metabolismo , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Receptores Adrenérgicos beta 2/genética , /fisiologia , Transcriptoma
16.
Neural Plast ; 2015: 453170, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26697233

RESUMO

Chronic pain is a major health issue and most patients suffer from spontaneous pain. Previous studies suggest that Huperzine A (Hup A), an alkaloid isolated from the Chinese herb Huperzia serrata, is a potent analgesic with few side effects. However, whether it alleviates spontaneous pain is unclear. We evaluated the effects of Hup A on spontaneous pain in mice using the conditioned place preference (CPP) behavioral assay and found that application of Hup A attenuated the mechanical allodynia induced by peripheral nerve injury or inflammation. This effect was blocked by atropine. However, clonidine but not Hup A induced preference for the drug-paired chamber in CPP. The same effects occurred when Hup A was infused into the anterior cingulate cortex. Furthermore, ambenonium chloride, a competitive inhibitor of acetylcholinesterase, also increased the paw-withdrawal threshold but failed to induce place preference in CPP. Therefore, our data suggest that acetylcholinesterase in both the peripheral and central nervous systems is involved in the regulation of mechanical allodynia but not the spontaneous pain.


Assuntos
Alcaloides/administração & dosagem , Analgésicos/administração & dosagem , Hiperalgesia/prevenção & controle , Neuralgia/prevenção & controle , Receptores Muscarínicos/fisiologia , Sesquiterpenos/administração & dosagem , Acetilcolinesterase/metabolismo , Cloreto de Ambenônio/administração & dosagem , Animais , Atropina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Dor Crônica/prevenção & controle , Clonidina/administração & dosagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Hiperalgesia/etiologia , Inflamação/induzido quimicamente , Inflamação/complicações , Aprendizagem/efeitos dos fármacos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/administração & dosagem , Limiar da Dor/efeitos dos fármacos , Nervo Fibular/lesões
17.
Brain Res Bull ; 119(Pt A): 73-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26321392

RESUMO

Potassium (K(+)) channels are membrane proteins that allow rapid and selective flow of K(+) ions across the cell membrane, generating electrical signals in neurons. Thus, K(+) channels play a critical role in determining the neuronal excitability. Two-pore domain (K2P) "leak" K(+) channels give rise to leak K(+) currents that are responsible for the resting membrane potential and input resistance. The wide expression of leak K(+) channels in the central and peripheral nervous system suggests that these channels are critically involved in pain signaling and behavior. Indeed, it has become apparent in the past decade that the leak K(+) channels play essential roles in the development of pain. In this review, we describe evidence for the roles of TASK1, TASK3, TREK1, TREK2, TRAAK and TRESK channels in pain signaling and behavior. Furthermore, we describe the possible involvement of TASK2 and TWIK1 channels in pain.


Assuntos
Dor/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Animais , Humanos , Dor/tratamento farmacológico , Percepção da Dor/efeitos dos fármacos , Percepção da Dor/fisiologia
18.
J Neurosci ; 34(32): 10675-87, 2014 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-25100600

RESUMO

Temporal properties of spike firing in the central nervous system (CNS) are critical for neuronal coding and the precision of information storage. Chronic pain has been reported to affect cognitive and emotional functions, in addition to trigger long-term plasticity in sensory synapses and behavioral sensitization. Less is known about the possible changes in temporal precision of cortical neurons in chronic pain conditions. In the present study, we investigated the temporal precision of action potential firing in the anterior cingulate cortex (ACC) by using both in vivo and in vitro electrophysiological approaches. We found that peripheral inflammation caused by complete Freund's adjuvant (CFA) increased the standard deviation (SD) of spikes latency (also called jitter) of ∼51% of recorded neurons in the ACC of adult rats in vivo. Similar increases in jitter were found in ACC neurons using in vitro brain slices from adult mice with peripheral inflammation or nerve injury. Bath application of glutamate receptor antagonists CNQX and AP5 abolished the enhancement of jitter induced by CFA injection or nerve injury, suggesting that the increased jitter depends on the glutamatergic synaptic transmission. Activation of adenylyl cyclases (ACs) by bath application of forskolin increased jitter, whereas genetic deletion of AC1 abolished the change of jitter caused by CFA inflammation. Our study provides strong evidence for long-term changes of temporal precision of information coding in cortical neurons after peripheral injuries and explains neuronal mechanism for chronic pain caused cognitive and emotional impairment.


Assuntos
Cognição/fisiologia , Giro do Cíngulo/patologia , Giro do Cíngulo/fisiopatologia , Neurônios/fisiologia , Doenças do Sistema Nervoso Periférico/patologia , Transmissão Sináptica/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Valina/análogos & derivados , Valina/farmacologia
19.
J Neurochem ; 126(5): 636-50, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23786569

RESUMO

Recent investigations into the mechanisms mediating itch transmission have focused on spinal mechanisms, whereas few studies have investigated the role of the cerebral cortex in itch-related behaviors. Human imaging studies show that several cortical regions are active in correspondence with itch, including the anterior cingulate cortex (ACC). We present here evidence of cortical modulation of pruritogen-induced scratching behavior. We combine pharmacological, genetic, and electrophysiological approaches to show that cortical GluK1-containing kainate (KA) receptors are involved in scratching induced by histamine and non-histamine-dependent itching stimuli. We further show that scratching corresponds with enhanced excitatory transmission in the ACC through KA receptor modulation of inhibitory circuitry. In addition, we found that inhibiting GluK1-containing KA receptors in the ACC also reduced behavioral nociceptive responses induced by formalin. Our results reveal a new role of the cortex in pruritogen-induced scratching.


Assuntos
Córtex Cerebral/fisiologia , Prurido/fisiopatologia , Receptores de Ácido Caínico/fisiologia , Animais , Antipruriginosos/farmacologia , Fenômenos Eletrofisiológicos , Genes fos/genética , Genes fos/fisiologia , Histamina/farmacologia , Histamina/fisiologia , Imuno-Histoquímica , Inflamação/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microinjeções , Medição da Dor/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Prurido/induzido quimicamente , Prurido/psicologia , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de Ácido Caínico/genética , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia
20.
Mol Pain ; 8: 53, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22818293

RESUMO

The neurons in neocortex layer I (LI) provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies were reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC), a key cortical area for sensory and cognitive functions, by using whole-cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all of the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay-sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP, named ADP1 and ADP2, respectively. Using pharmacological approaches, we found that LI neurons received both excitatory (mediated by AMPA, kainate and NMDA receptors), and inhibitory inputs (which were mediated by GABA(A) receptors). Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice.


Assuntos
Envelhecimento/fisiologia , Giro do Cíngulo/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Potenciais de Ação/fisiologia , Animais , Análise por Conglomerados , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Técnicas de Patch-Clamp , Receptores de AMPA/metabolismo , Receptores de GABA-A , Receptores de Ácido Caínico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
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