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1.
Neuropharmacology ; 205: 108909, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34875284

RESUMO

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory nervous system. It is accompanied by neuronal and non-neuronal alterations, including alterations in intracellular second messenger pathways. Cellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) are regulated by phosphodiesterase (PDE) enzymes. Here, we studied the impact of PDE inhibitors (PDEi) in a mouse model of peripheral nerve injury induced by placing a cuff around the main branch of the sciatic nerve. Mechanical hypersensitivity, evaluated using von Frey filaments, was relieved by sustained treatment with the non-selective PDEi theophylline and ibudilast (AV-411), with PDE4i rolipram, etazolate and YM-976, and with PDE5i sildenafil, zaprinast and MY-5445, but not by treatments with PDE1i vinpocetine, PDE2i EHNA or PDE3i milrinone. Using pharmacological and knock-out approaches, we show a preferential implication of delta opioid receptors in the action of the PDE4i rolipram and of both mu and delta opioid receptors in the action of the PDE5i sildenafil. Calcium imaging highlighted a preferential action of rolipram on dorsal root ganglia non-neuronal cells, through PDE4B and PDE4D inhibition. Rolipram had anti-neuroimmune action, as shown by its impact on levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNFα) in the dorsal root ganglia of mice with peripheral nerve injury, as well as in human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides. This study suggests that PDEs, especially PDE4 and 5, may be targets of interest in the treatment of neuropathic pain.


Assuntos
Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/complicações , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Camundongos , Neuralgia/etiologia , Rolipram/farmacologia
2.
Mol Neurobiol ; 56(10): 7208-7221, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31001801

RESUMO

The impact of vitamin D on sensory function, including pain processing, has been receiving increasing attention. Indeed, vitamin D deficiency is associated with various chronic pain conditions, and several lines of evidence indicate that vitamin D supplementation may trigger pain relief. However, the underlying mechanisms of action remain poorly understood. We used inflammatory and non-inflammatory rat models of chronic pain to evaluate the benefits of vitamin D3 (cholecalciferol) on pain symptoms. We found that cholecalciferol supplementation improved mechanical nociceptive thresholds in monoarthritic animals and reduced mechanical hyperalgesia and cold allodynia in a model of mononeuropathy. Transcriptomic analysis of cerebrum, dorsal root ganglia, and spinal cord tissues indicate that cholecalciferol supplementation induces a massive gene dysregulation which, in the cerebrum, is associated with opioid signaling (23 genes), nociception (14), and allodynia (8), and, in the dorsal root ganglia, with axonal guidance (37 genes) and nociception (17). Among the identified cerebral dysregulated nociception-, allodynia-, and opioid-associated genes, 21 can be associated with vitamin D metabolism. However, it appears that their expression is modulated by intermediate regulators such as diverse protein kinases and not, as expected, by the vitamin D receptor. Overall, several genes-Oxt, Pdyn, Penk, Pomc, Pth, Tac1, and Tgfb1-encoding for peptides/hormones stand out as top candidates to explain the therapeutic benefit of vitamin D3 supplementation. Further studies are now warranted to detail the precise mechanisms of action but also the most favorable doses and time windows for pain relief.


Assuntos
Analgésicos Opioides/metabolismo , Colecalciferol/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Transdução de Sinais , Animais , Artrite/metabolismo , Artrite/patologia , Colecalciferol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Neuralgia/genética , Neuralgia/patologia , Nociceptividade/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
3.
J Neurosci ; 38(46): 9934-9954, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30249798

RESUMO

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and ß2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain.SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.


Assuntos
Amitriptilina/administração & dosagem , Antidepressivos/administração & dosagem , Cloridrato de Duloxetina/administração & dosagem , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Norepinefrina/metabolismo , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Manejo da Dor/métodos , Receptor A2A de Adenosina/metabolismo
4.
Pain ; 159(12): 2630-2640, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30169420

RESUMO

Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. We tested this hypothesis using a rat model of neonatal maternal separation (NMS) known to induce long-term consequences on several brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. We found that adult rats with a history of NMS were hypersensitive to noxious mechanical/thermal hot stimuli and to inflammatory pain. We failed to observe OT receptor-mediated stress-induced analgesia and OT antihyperalgesia after carrageenan inflammation. These alterations were partially rescued if NMS pups were treated by intraperitoneal daily injection during NMS with OT or its downstream second messenger allopregnanolone. The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor-mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.


Assuntos
Analgésicos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipersensibilidade/tratamento farmacológico , Privação Materna , Ocitocina/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Carragenina/toxicidade , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Hipersensibilidade/patologia , Masculino , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Células do Corno Posterior/efeitos dos fármacos , Gravidez , Pregnanolona/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Vasotocina/análogos & derivados , Vasotocina/farmacologia , Vorinostat/uso terapêutico
5.
Eur J Neurosci ; 44(3): 1952-62, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27285721

RESUMO

The nociceptive system of rodents is not fully developed and functional at birth. Specifically, C fibers transmitting peripheral nociceptive information establish synaptic connections in the spinal cord already during the embryonic period that only become fully functional after birth. Here, we studied the consequences of neonatal maternal deprivation (NMD, 3 h/day, P2-P12) on the functional establishment of C fiber-mediated neurotransmission in spinal cord and of pain-related behavior. In vivo recording revealed that C fiber-mediated excitation of spinal cord neurons could be observed at P14 only in control but not in NMD rats. NMD was associated with a strong alteration in the expression of growth factors controlling C nociceptor maturation as well as two-pore domain K+ channels known to set nociceptive thresholds. In good agreement, C-type sensory neurons from NMD animals appeared to be hypoexcitable but functionally connected to spinal neurons, especially those expressing TRPV1 receptors. In vivo and in vitro recordings of lamina II spinal neurons at P14 revealed that the NMD-related lack of C fiber-evoked responses resulted from an inhibitory barrage in the spinal cord dorsal horn. Eventually, C-type sensory-spinal processing could be recovered after a delay of about 10 days in NMD animals. However, animals remained hypersensitive to noxious stimulus up to P100 and this might be due to an excessive expression of Nav1.8 transcripts in DRG neurons. Together, our data provide evidence for a deleterious impact of perinatal stress exposure on the maturation of the sensory-spinal nociceptive system that may contribute to the nociceptive hypersensitivity in early adulthood.


Assuntos
Gânglios Espinais/fisiologia , Privação Materna , Nociceptividade , Dor Nociceptiva/fisiopatologia , Medula Espinal/fisiologia , Animais , Feminino , Gânglios Espinais/metabolismo , Masculino , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Nociceptores/metabolismo , Canais de Potássio/genética , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
6.
Brain Struct Funct ; 220(3): 1573-84, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24647754

RESUMO

The superior colliculus is a hub for multisensory integration necessary for visuo-spatial orientation, control of gaze movements and attention. The multiple functions of the superior colliculus have prompted hypotheses about its involvement in neuropsychiatric conditions, but to date, this topic has not been addressed experimentally. We describe experiments on genetically modified mice, the Isl2-EphA3 knock-in line, that show a well-characterized duplication of the retino-collicular and cortico-collicular axonal projections leading to hyperstimulation of the superior colliculus. To explore the functional impact of collicular hyperstimulation, we compared the performance of homozygous knock-in, heterozygous knock-in and wild-type mice in several behavioral tasks requiring collicular activity. The light/dark box test and Go/No-Go conditioning task revealed that homozygous mutant mice exhibit defective response inhibition, a form of impulsivity. This defect was specific to attention as other tests showed no differences in visually driven behavior, motivation, visuo-spatial learning and sensorimotor abilities among the different groups of mice. Monoamine quantification and gene expression profiling demonstrated a specific enrichment of noradrenaline only in the superficial layers of the superior colliculus of Isl2-EphA3 knock-in mice, where the retinotopy is duplicated, whereas transcript levels of receptors, transporters and metabolic enzymes of the monoaminergic pathway were not affected. We demonstrate that the defect in response inhibition is a consequence of noradrenaline imbalance in the superficial layers of the superior colliculus caused by retinotopic map duplication. Our results suggest that structural abnormalities in the superior colliculus can cause defective response inhibition, a key feature of attention-deficit disorders.


Assuntos
Inibição Psicológica , Norepinefrina/análise , Desempenho Psicomotor/fisiologia , Colículos Superiores/fisiologia , Animais , Ansiedade/fisiopatologia , Ritmo Circadiano , Percepção de Profundidade/fisiologia , Dopamina/análise , Técnicas de Introdução de Genes , Proteínas com Homeodomínio LIM/genética , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora , Receptor EphA3/genética , Colículos Superiores/metabolismo , Fatores de Transcrição/genética , Acuidade Visual/fisiologia , Vias Visuais/fisiologia
7.
Pain ; 155(2): 403-412, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24239672

RESUMO

Inflammatory and degenerative diseases of the joint are major causes of chronic pain. Long-lasting pain symptoms are thought to result from a central sensitization of nociceptive circuits. These processes include activation of microglia and spinal disinhibition. Using a monoarthritic rat model of pain, we tried to potentiate neural inhibition by using etifoxine (EFX), a nonbenzodiazepine anxiolytic that acts as an allosteric-positive modulator of gamma-aminobutyric acid type A (GABAA) receptor function. Interestingly, EFX also can bind to the mitochondrial translocator protein (TSPO) complex and stimulate the synthesis of 3α-reduced neurosteroids, the most potent positive allosteric modulator of GABAA receptor function. Here we show that a curative and a preventive treatment with 50mg/kg of EFX efficiently reduced neuropathic pain symptoms. In the spinal cord, EFX analgesia was accompanied by a reduction in microglial activation and in the levels of proinflammatory mediators. Using electrophysiological tools, we found that EFX treatment not only amplified spinal GABAergic inhibition, but also prevented prostaglandin E2-induced glycinergic disinhibition and restored a "normal" spinal pain processing. Because EFX is already distributed in several countries under the trade name of Stresam for its anxiolytic actions in humans, new clinical trials are now required to further extend its therapeutic indications as pain killer.


Assuntos
Artrite Experimental/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Inibição Neural/efeitos dos fármacos , Oxazinas/uso terapêutico , Manejo da Dor/métodos , Medula Espinal/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Inibição Neural/fisiologia , Oxazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/patologia
8.
J Clin Invest ; 121(8): 3071-87, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21737879

RESUMO

Autosomal recessive primary microcephaly (MCPH) is a genetic disorder that causes a reduction of cortical outgrowth without severe interference with cortical patterning. It is associated with mutations in a number of genes encoding protein involved in mitotic spindle formation and centrosomal activities or cell cycle control. We have shown previously that blocking vasoactive intestinal peptide (VIP) during gestation in mice by using a VIP antagonist (VA) results in microcephaly. Here, we have shown that the cortical abnormalities caused by prenatal VA administration mimic the phenotype described in MCPH patients and that VIP blockade during neurogenesis specifically disrupts Mcph1 signaling. VA administration reduced neuroepithelial progenitor proliferation by increasing cell cycle length and promoting cell cycle exit and premature neuronal differentiation. Quantitative RT-PCR and Western blot showed that VA downregulated Mcph1. Inhibition of Mcph1 expression led to downregulation of Chk1 and reduction of Chk1 kinase activity. The inhibition of Mcph1 and Chk1 affected the expression of a specific subset of cell cycle­controlling genes and turned off neural stem cell proliferation in neurospheres. Furthermore, in vitro silencing of either Mcph1 or Chk1 in neurospheres mimicked VA-induced inhibition of cell proliferation. These results demonstrate that VIP blockade induces microcephaly through Mcph1 signaling and suggest that VIP/Mcph1/Chk1 signaling is key for normal cortical development.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Regulação da Expressão Gênica , Microcefalia/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais , Peptídeo Intestinal Vasoativo/fisiologia , Animais , Ciclo Celular , Proteínas de Ciclo Celular , Diferenciação Celular , Proliferação de Células , Quinase 1 do Ponto de Checagem , Proteínas do Citoesqueleto , Feminino , Camundongos , Modelos Biológicos , Neurônios/metabolismo , Células-Tronco/citologia , Peptídeo Intestinal Vasoativo/metabolismo
9.
Ann Neurol ; 70(4): 550-65, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21796662

RESUMO

OBJECTIVE: Perinatal inflammation is a major risk factor for neurological deficits in preterm infants. Several experimental studies have shown that systemic inflammation can alter the programming of the developing brain. However, these studies do not offer detailed pathophysiological mechanisms, and they rely on relatively severe infectious or inflammatory stimuli that most likely do not reflect the levels of systemic inflammation observed in many human preterm infants. The goal of the present study was to test the hypothesis that moderate systemic inflammation is sufficient to alter white matter development. METHODS: Newborn mice received twice-daily intraperitoneal injections of interleukin-1ß (IL-1ß) over 5 days and were studied for myelination, oligodendrogenesis, and behavior and with magnetic resonance imaging (MRI). RESULTS: Mice exposed to IL-1ß had a long-lasting myelination defect that was characterized by an increased number of nonmyelinated axons. They also displayed a reduction of the diameter of the myelinated axons. In addition, IL-1ß induced a significant reduction of the density of myelinating oligodendrocytes accompanied by an increased density of oligodendrocyte progenitors, suggesting a partial blockade in the oligodendrocyte maturation process. Accordingly, IL-1ß disrupted the coordinated expression of several transcription factors known to control oligodendrocyte maturation. These cellular and molecular abnormalities were correlated with a reduced white matter fractional anisotropy on diffusion tensor imaging and with memory deficits. INTERPRETATION: Moderate perinatal systemic inflammation alters the developmental program of the white matter. This insult induces a long-lasting myelination deficit accompanied by cognitive defects and MRI abnormalities, further supporting the clinical relevance of the present data.


Assuntos
Encéfalo/crescimento & desenvolvimento , Inflamação/patologia , Interleucina-1beta/farmacologia , Imageamento por Ressonância Magnética , Fibras Nervosas Mielinizadas/patologia , Oligodendroglia/patologia , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Injeções Intraperitoneais , Interleucina-1beta/administração & dosagem , Camundongos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos
10.
Stem Cells Dev ; 20(5): 865-79, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20964621

RESUMO

Brain damage through excitotoxic mechanisms is a major cause of cerebral palsy in infants. This phenomenon usually occurs during the fetal period in human, and often leads to lifelong neurological morbidity with cognitive and sensorimotor impairment. However, there is currently no effective therapy. Significant recovery of brain function through neural stem cell implantation has been shown in several animal models of brain damage, but remains to be investigated in detail in neonates. In the present study, we evaluated the effect of cell therapy in a well-established neonatal mouse model of cerebral palsy induced by excitotoxicity (ibotenate treatment on postnatal day 5). Neurosphere-derived precursors or control cells (fibroblasts) were implanted into injured and control brains contralateral to the site of injury, and the fate of implanted cells was monitored by immunohistochemistry. Behavioral tests were performed in animals that received early (4 h after injury) or late (72 h after injury) cell implants. We show that neurosphere-derived precursors implanted into the injured brains of 5-day-old pups migrated to the lesion site, remained undifferentiated at day 10, and differentiated into oligodendrocyte and neurons at day 42. Although grafted cells finally die there few weeks later, this procedure triggered a reduction in lesion size and an improvement in memory performance compared with untreated animals, both 2 and 5 weeks after treatment. Although further studies are warranted, cell therapy could be a future therapeutic strategy for neonates with acute excitotoxic brain injury.


Assuntos
Lesões Encefálicas/terapia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurônios/citologia , Oligodendroglia/citologia , Recuperação de Função Fisiológica/fisiologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/patologia , Transplante de Tecido Encefálico/métodos , Transplante de Tecido Encefálico/fisiologia , Diferenciação Celular , Movimento Celular , Paralisia Cerebral/patologia , Paralisia Cerebral/terapia , Feminino , Transplante de Tecido Fetal/métodos , Transplante de Tecido Fetal/fisiologia , Feto , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Ácido Ibotênico/efeitos adversos , Imuno-Histoquímica , Recém-Nascido , Memória , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Oligodendroglia/fisiologia
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