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1.
Br J Anaesth ; 123(6): 827-838, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31623841

RESUMO

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Inflamação/tratamento farmacológico , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Microglia/efeitos dos fármacos , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
2.
Adv Exp Med Biol ; 1155: 875-887, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468454

RESUMO

Diabetes mellitus (DM) is a condition characterized by chronic hyperglycemia, which leads to diabetic neuropathy and apoptosis in the spinal cord. Taurine has been found to ameliorate the diabetic neuropathy and control apoptosis in various tissues. However, there are few reports that discuss the direct relationship between spinal cord and anti-apoptotic effect of taurine. In this study, DM was induced in male SD rats with STZ @ 25 mg/Kg of body weight in combination with high fat diet. After 2 weeks, they were divided into four groups as DM: diabetic rats, T1 (0.5%), T2 (1%) and T3 (2%) taurine solution, while control group was non-diabetic rats (no treatment). The results showed that DM increased apoptosis, decreased phosphorylated Akt and Bad. DM decreased expression of Bcl-2 and increased the Bax. Moreover, the release of cytochrome c into cytosol was increased in DM and activation of caspase-3 was also increased. However, taurine reversed all these abnormal changes in a dose dependent manner. Our results suggested the involvement of Akt/Bad signaling pathway and mitochondrial apoptosis pathway in protective effect of taurine against apoptosis in the spinal cord of diabetic rats. Therefore, taurine may be a potential medicine against diabetic neuropathy by controlling apoptosis.


Assuntos
Apoptose , Neuropatias Diabéticas , Medula Espinal/efeitos dos fármacos , Taurina/farmacologia , Animais , Diabetes Mellitus Experimental , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Medula Espinal/citologia
3.
Int. j. morphol ; 37(2): 428-437, June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1002239

RESUMO

Oxidative stress and inflammation are the key players in the development of motor dysfunction post-spinal cord ischemic reperfusion injury (SC-IRI). This study investigated the protective effect of concomitant pre-administration of melatonin and alpha-tocopherol on the early complications (after 48 hours) of spinal cord IRI injury in rats. Melatonin or α-tocopherol were preadministered either individually or in combination for 2 weeks, then rats were exposed SC-IRI. Neurological examinations of the hind limbs and various biochemical markers of oxidative stress and inflammation in the SC tissue were assessed. Solely pre-administration of either melanin or α-tocopherol significantly but partially improved motor and sensory function of the hind limbs mediated by partial decreases in SC levels of MDA, AOPP and PGE2 levels and activities of SOD, partial significant decreases in plasma levels of total nitrate/nitrite and significant increases in AC activity of GSH-Px. However, combination therapy of both drugs resulted in the maximum improvements in all neurological assessments tested and biochemical endpoints. In conclusion, by their synergistic antioxidant and antiinflammatory actions, the combination therapy of melatonin and α-tocopherol alleviates SC-IRI induced paraplegia.


El estrés oxidativo y la inflamación son claves en el desarrollo de la disfunción motora posterior a lesión isquémica de la médula espinal (SC-IRI). Este estudio investigó acerca del efecto protector de la administración previa concomitante de la melatonina y alfa-tocoferol en las complicaciones tempranas (después de 48 horas) de la lesión de IRI de la médula espinal en ratas. La melatonina o el α-tocoferol se administraron individualmente o en combinación durante 2 semanas, luego las ratas fueron expuestas a SC-IRI. Se evaluaron los exámenes neurológicos de las miembros pélvicos y diversos marcadores bioquímicos de estrés oxidativo e inflamación en el tejido subcutáneo. Solo la administración previa de melatonina o α-tocoferol mejoró parcial y significativamente la función motora y sensorial de los miembros pélvicos mediadas por disminuciones parciales en los niveles de SC de los niveles de MDA, AOPP y PGE2 y las actividades de la SOD, disminuciones significativas parciales en los niveles plasmáticos del total nitrato / nitrito y aumentos significativos en la actividad de AC de GSH-Px. Sin embargo, se observaron los mejores resultados durante la combinación de ambos fármacos en todas las evaluaciones neurológicas y en los puntos finales bioquímicos. En conclusión, debido a sus acciones antioxidantes y antiinflamatorias sinérgicas, la terapia de melatonina y α-tocoferol alivia la paraplejía inducida por SC-IRI.


Assuntos
Animais , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Isquemia do Cordão Espinal/tratamento farmacológico , Melatonina/administração & dosagem , Antioxidantes/administração & dosagem , Paraplegia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Dinoprostona/sangue , Ratos Sprague-Dawley , Estresse Oxidativo/efeitos dos fármacos , Tocoferóis/farmacologia , Melatonina/farmacologia , Nitritos/sangue , Antioxidantes/farmacologia
5.
Cell Biol Int ; 43(6): 706-714, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977573

RESUMO

Early exposure to lead (Pb) has been associated with an elevated risk of developing neurodegenerative diseases. There is evidence that neuronal damage in chronic Pb exposure can be caused by the convergence of glial damage. Apoptosis may be a possible mechanism of Pb-induced cell death in the central nervous system. We tested cellular damage and apoptosis in the spinal cord of Wistar rats treated with Pb. Twelve rats were divided into two groups (n = 6): the control group was treated with only drinking water and the other group received 500 ppm of Pb acetate. After 3 months of Pb treatment, all animals were euthanized and spinal cords were extracted. Morphology was evaluated by Nissl and Kluver-Barrera stainings. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Specific antibodies were used to evaluate Pb damage in oligodendrocytes, astrocytes, and microglia. A large number of apoptotic bodies was observed in the white matter of the Pb-treated group. The Pb-treated group also showed a reduced number of neurons and oligodendrocytes but had an increased number of astrocytes compared with the nontreated group. Our results demonstrate that chronic Pb treatment induces neurodegeneration, demyelination, and astrogliosis in the rat spinal cord.


Assuntos
Intoxicação por Chumbo/metabolismo , Chumbo/efeitos adversos , Medula Espinal/efeitos dos fármacos , Animais , Apoptose/fisiologia , Astrocitoma/metabolismo , Astrocitoma/fisiopatologia , Morte Celular/fisiologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
6.
Dokl Biol Sci ; 484(1): 5-9, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31016495

RESUMO

When studying a preparation of the isolated spinal cord segment of an adult frog, damaged and intact lumbar motoneurons were found to differ significantly in the membrane potential, input resistance and the action potential properties (amplitude, duration, fast and medium phases of the afterhyperpolarization, and the frequency of spikes). Serotonin (5-HT) reduced the amplitude of afterpolarization and increased the frequency of the spikes of the intact neurons, while in the damaged motoneurons, 5-HT increased the amplitude of afterpolarization and had no effect on the frequency of discharges.


Assuntos
Neurônios Motores/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/efeitos dos fármacos , Potenciais de Ação , Animais , Neurônios Motores/fisiologia , Ranidae , Medula Espinal/fisiopatologia
7.
Pain ; 160(5): 1059-1069, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31008815

RESUMO

The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.


Assuntos
Hiperalgesia/terapia , Limiar da Dor/efeitos dos fármacos , Medula Espinal/fisiologia , Sacarose/uso terapêutico , Edulcorantes/uso terapêutico , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Temperatura Alta/efeitos adversos , Hiperalgesia/induzido quimicamente , Injeções Espinhais/métodos , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Rimonabanto/farmacologia , Medula Espinal/efeitos dos fármacos , Privação de Água/fisiologia
8.
J Colloid Interface Sci ; 549: 50-62, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31015056

RESUMO

Spinal cord injury (SCI) can cause locomotor dysfunctions and sensory deficits. Evidence shows that functional nanodrugs can regulate macrophage polarization and promote anti-inflammatory cytokine expression, which is feasible in SCI immunotherapeutic treatments. Molybdenum disulfide (MoS2) nanomaterials have garnered great attention as potential carriers for therapeutic payload. Herein, we synthesize MoS2@PEG (MoS2 = molybdenum disulfide, PEG = poly (ethylene glycol)) nanoflowers as an effective carrier for loading etanercept (ET) to treat SCI. We characterize drug loading and release properties of MoS2@PEG in vitro and demonstrate that ET-loading MoS2@PEG obviously inhibits the expression of M1-related pro-inflammatory markers (TNF-α, CD86 and iNOS), while promoting M2-related anti-inflammatory markers (Agr1, CD206 and IL-10) levels. In vivo, the mouse model of SCI shows that long-circulating ET-MoS2@PEG nanodrugs can effectively extravasate into the injured spinal cord up to 96 h after SCI, and promote macrophages towards M2 type polarization. As a result, the ET-loading MoS2@PEG administration in mice can protect survival motor neurons, thus, reducing injured areas at central lesion sites, and significantly improving locomotor recovery. This study demonstrates the anti-inflammatory and neuroprotective activities of ET-MoS2@PEG and promising utility of MoS2 nanomaterial-mediated drug delivery.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dissulfetos/química , Etanercepte/farmacologia , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Molibdênio/química , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Portadores de Fármacos , Liberação Controlada de Fármacos , Etanercepte/uso terapêutico , Feminino , Humanos , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho da Partícula , Permeabilidade , Polietilenoglicóis , Células RAW 264.7 , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Propriedades de Superfície
9.
Recent Pat Biotechnol ; 13(2): 137-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973107

RESUMO

BACKGROUND: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods. OBJECTIVE: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance. METHOD: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test. RESULTS: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord. CONCLUSION: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.


Assuntos
Analgésicos Opioides/farmacologia , Antioxidantes/farmacologia , Tolerância a Medicamentos/genética , Genes fos , Morfina/farmacologia , Dor/tratamento farmacológico , alfa-Tocoferol/farmacologia , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Dor/genética , Dor/metabolismo , Dor/fisiopatologia , Patentes como Assunto , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
10.
J Neuroinflammation ; 16(1): 57, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30851734

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorder (herein called NMO) is an inflammatory demyelinating disease that can be initiated by binding of immunoglobulin G autoantibodies (AQP4-IgG) to aquaporin-4 on astrocytes, causing complement-dependent cytotoxicity (CDC) and downstream inflammation. The increased NMO pathology in rodents deficient in complement regulator protein CD59 following passive transfer of AQP4-IgG has suggested the potential therapeutic utility of increasing the expression of complement regulator proteins. METHODS: A cell-based ELISA was developed to screen for pharmacological upregulators of endogenous CD55 and CD59 in a human astrocyte cell line. A statin identified from the screen was characterized in cell culture models and rodents for its action on complement regulator protein expression and its efficacy in models of seropositive NMO. RESULTS: Screening of ~ 11,500 approved and investigational drugs and nutraceuticals identified transcriptional upregulators of CD55 but not of CD59. Several statins, including atorvastatin, simvastatin, lovastatin, and fluvastatin, increased CD55 protein expression in astrocytes, including primary cultures, by three- to four-fold at 24 h, conferring significant protection against AQP4-IgG-induced CDC. Mechanistic studies revealed that CD55 upregulation involves inhibition of the geranylgeranyl transferase pathway rather than inhibition of cholesterol biosynthesis. Oral atorvastatin at 10-20 mg/kg/day for 3 days strongly increased CD55 immunofluorescence in mouse brain and spinal cord and reduced NMO pathology following intracerebral AQP4-IgG injection. CONCLUSION: Atorvastatin or other statins may thus have therapeutic benefit in AQP4-IgG seropositive NMO by increasing CD55 expression, in addition to their previously described anti-inflammatory and immunomodulatory actions.


Assuntos
Aquaporina 4/imunologia , Astrócitos/metabolismo , Antígenos CD55/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Imunoglobulina G/administração & dosagem , Neuromielite Óptica/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Transformada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Camundongos , Neuromielite Óptica/metabolismo , Neuromielite Óptica/patologia , RNA Mensageiro/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Ativação Transcricional/efeitos dos fármacos , Receptor fas/metabolismo
11.
Biomed Pharmacother ; 114: 108777, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30925455

RESUMO

Burn pain is one of the worst imaginable pain, associated with considerable morbidity and mortality worldwide. The management of pain made significant progress; however, more research is needed for burn pain. In the present study, the antinociceptive effect of honokiol extracted from Magnolia officinalis was assessed for 3 consecutive days. The third-degree burns were induced by the hot water method. The honokiol both by intraperitoneal (i.p) and intra plantar (i.pl) route and in combination with tramadol (i.p) was found to be effective in significantly reducing the mechanical allodynia, hyperalgesia, thermal hyperalgesia and paw edema. Honokiol also succeeded in reducing weight loss and spontaneous pain behavior in mice. Honokiol treatment both i.p and ipl decrease significantly the loss of total protein (3.3 and 3.4 g/dl of total protein) and albumin (2.2 and 2.6 g/dl of total albumin) respectively. It also significantly recovers the normal balance of blood electrolytes and normalizes blood profile. Effect of honokiol on cytokines and mRNA expression levels of TRPV1 and P2Y were also assessed. Honokiol significantly decreases the expression of TNF-α, IL-1ß and IL-6 and decreases expression level of TRPV1 and P2Y. Additionally, TRPV1 and P2Y proteins expression levels were also assessed by Western blot in paw skin tissue, sciatic nerve and spinal cord which were remarkably down-regulated by honokiol. Histological analysis of vehicle control and drug-treated paws were also performed through hematoxylin and eosin (H&E) staining which exhibited that honokiol significantly reduced the dermal layers distortion and inflammation associated with the burn. The antioxidant enzymes and nitric oxide (NO) were also determined through ELISA. Honokiol treatment also potentiates the expression of reduced glutathione and glutathione S-transferase, and catalase levels and reduced significantly the nitric oxide (NO) as compared to the burn-induced group. It can be concluded on the base of the results that honokiol has a significant analgesic activity through its action on cytokines and by downregulating TRPV1 and P2Y receptors. It also has a protective role against burn damage by upregulation of antioxidants.


Assuntos
Compostos de Bifenilo/farmacologia , Queimaduras/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Magnolia/química , Receptores Purinérgicos P2Y/metabolismo , Canais de Cátion TRPV/metabolismo , Analgésicos/farmacologia , Animais , Queimaduras/metabolismo , Citocinas/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dor/tratamento farmacológico , Dor/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Eur J Pharmacol ; 853: 56-64, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876975

RESUMO

Opioids are potent analgesic drugs, but their use has been limited due to their side effects. Antinociceptive effects of D2-like receptor agonists such as quinpirole have been shown at the spinal cord level; however, their efficacy is not as high as that of opioids. Dopaminergic agonists are long-prescribed and well-tolerated drugs that have been useful to treat clinically and experimentally painful conditions. Because current pain treatments are not completely effective, the aim of this work was to determine if a D2-like receptor agonist improves the antinociceptive effects of a µ-opioid receptor agonist. Drugs were intrathecally administered in adult rats; mechanonociceptive and thermonociceptive tests were carried out. Intraplantar injection of complete Freund's adjuvant (CFA) and sciatic loose ligation (SLL) were used for inflammatory and neuropathic models of pain, respectively. In intact animals, D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO; a µ-opioid receptor agonist) increased the paw withdrawal latencies (PWL) in thermal and mechanical nociceptive tests in a dose-dependent manner. Quinpirole (D2-like receptor agonist) increased PWL only in mechanonociception. In the presence of quinpirole (1 nmol), the ED50 of the mechanical antinociceptive effect of DAMGO was significantly decreased (8-fold). Coadministration of 1 nmol quinpirole and 30 pmol DAMGO completely reversed hyperalgesia in the CFA model, whereas 100 pmol DAMGO plus 1 nmol quinpirole reversed the allodynia in the SLL model. This work offers evidence about a synergistic antinociceptive effect between opioidergic and dopaminergic drugs. This combination may relieve painful conditions resistant to conventional treatments, and it may reduce the adverse effects of chronic opioid administration.


Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Receptores Opioides mu/agonistas , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Inflamação/tratamento farmacológico , Masculino , Neuralgia/fisiopatologia , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos
13.
J Neuroinflammation ; 16(1): 65, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898121

RESUMO

BACKGROUND: Neurokine signaling via the release of neurally active cytokines arises from glial reactivity and is mechanistically implicated in central nervous system (CNS) pathologies such as chronic pain, trauma, neurodegenerative diseases, and complex psychiatric illnesses. Despite significant advancements in the methodologies used to conjugate, incorporate, and visualize fluorescent molecules, imaging of rare yet high potency events within the CNS is restricted by the low signal to noise ratio experienced within the CNS. The brain and spinal cord have high cellular autofluorescence, making the imaging of critical neurokine signaling and permissive transcriptional cellular events unreliable and difficult in many cases. METHODS: In this manuscript, we developed a method for background-free imaging of the transcriptional events that precede neurokine signaling using targeted mRNA transcripts labeled with luminescent lanthanide chelates and imaged via time-gated microscopy. To provide examples of the usefulness this method can offer to the field, the mRNA expression of toll-like receptor 4 (TLR4) was visualized with traditional fluorescent in situ hybridization (FISH) or luminescent lanthanide chelate-based in situ hybridization (LISH) in mouse BV2 microglia or J774 macrophage phenotype cells following lipopolysaccharide stimulation. TLR4 mRNA staining using LISH- and FISH-based methods was also visualized in fixed spinal cord tissues from BALB/c mice with a chronic constriction model of neuropathic pain or a surgical sham model in order to demonstrate the application of this new methodology in CNS tissue samples. RESULTS: Significant increases in TLR4 mRNA expression and autofluorescence were visualized over time in mouse BV2 microglia or mouse J774 macrophage phenotype cells following lipopolysaccharide (LPS) stimulation. When imaged in a background-free environment with LISH-based detection and time-gated microscopy, increased TLR4 mRNA was observed in BV2 microglia cells 4 h following LPS stimulation, which returned to near baseline levels by 24 h. Background-free imaging of mouse spinal cord tissues with LISH-based detection and time-gated microscopy demonstrated a high degree of regional TLR4 mRNA expression in BALB/c mice with a chronic constriction model of neuropathic pain compared to the surgical sham model. CONCLUSIONS: Advantages offered by adopting this novel methodology for visualizing neurokine signaling with time-gated microscopy compared to traditional fluorescent microscopy are provided.


Assuntos
Dor Crônica/diagnóstico , Regulação da Expressão Gênica/fisiologia , Hibridização In Situ/métodos , Elementos da Série dos Lantanídeos/metabolismo , RNA Mensageiro/metabolismo , Receptor 4 Toll-Like/genética , Animais , Linhagem Celular Transformada , Dor Crônica/etiologia , Modelos Animais de Doenças , Fluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Luminescência , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Medição da Dor , Neuropatia Ciática/complicações , Neuropatia Ciática/diagnóstico , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Receptor 4 Toll-Like/metabolismo
14.
Pain ; 160(5): 1166-1174, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30913166

RESUMO

Recent studies have made significant progress in identifying distinct populations of peripheral neurons involved in itch transmission, whereas the cellular identity of spinal interneurons that contribute to itch processing is still a debate. Combining genetic and pharmacological ablation of spinal excitatory neuronal subtypes and behavioral assays, we demonstrate that spinal somatostatin-positive (SOM) excitatory interneurons transmit pruritic sensation. We found that the ablation of spinal SOM/Lbx1 (SOM) neurons caused significant attenuation of scratching responses evoked by various chemical pruritogens (chemical itch). In an attempt to identify substrates of spinal itch neural circuit, we observed that spinal SOM neurons partially overlapped with neurons expressing natriuretic peptide receptor A (Npra), the receptor of peripheral itch transmitter B-type natriuretic peptide. Spinal SOM neurons, however, did not show any overlap with itch transmission neurons expressing gastrin-releasing peptide receptor in the dorsal spinal cord, and the gastrin-releasing peptide-triggered scratching responses were intact after ablating spinal SOM neurons. Dual ablation of SOM and Npra neurons in the spinal cord reduced chemical itch responses to a greater extent than ablation of SOM or Npra neurons alone, suggesting the existence of parallel spinal pathways transmitting chemical itch. Furthermore, we showed that SOM peptide modulated itch processing through disinhibition of somatostatin receptor 2A-positive inhibitory interneuron. Together, our findings reveal a novel spinal mechanism for sensory encoding of itch perception.


Assuntos
Interneurônios/metabolismo , Prurido/induzido quimicamente , Prurido/patologia , Somatostatina/metabolismo , Medula Espinal/patologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Inibidores da Angiogênese/farmacologia , Animais , Cloroquina/toxicidade , Modelos Animais de Doenças , Técnicas In Vitro , Interneurônios/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Nitrobenzoatos/farmacologia , Técnicas de Patch-Clamp , Proteínas Proto-Oncogênicas c-fos/metabolismo , Somatostatina/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , p-Metoxi-N-metilfenetilamina/toxicidade , Proteínas tau/genética , Proteínas tau/metabolismo
15.
Tissue Cell ; 56: 31-40, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30736902

RESUMO

After injury of the nervous system glial cells react according to the stimuli by modifying their morphology and function. Glia activation was reported in different kainic acid (KA)-induced neurodegeneration models. Here, we describe glial morphometric changes occurring in an excitotoxic KA-induced cervical spinal cord injury model. Concomitant degenerative and apoptotic processes are also reported. Male rats injected at the spinal cord C5 segment either with KA or saline were euthanized at post-injection (PI) days 1, 2, 3 or 7. Anti-IBA-1 and anti-GFAP antibodies were used to identify microglia and activated astrocytes, respectively, and to morphometrically characterized them. Fluoro-Jade B staining and TUNEL reaction were used to determine neuronal and glial degeneration and apoptosis. KA-injected group showed a significant increase in microglia number at the ipsilateral side by PI day 3. Different microglia reactive phenotypes were observed. Reactive microglia was still present by PI day 7. Astrocytes in KA-injected group showed a biphasic increase in number at PI days 1 and 3. Degenerative and apoptotic events were only observed in KA-injected animals, increasing mainly by PI day 1. Understanding the compromise of glia in different neurodegenerative processes may help to define possible common or specific therapeutic approaches directed towards neurorestorative strategies.


Assuntos
Anticorpos Anti-Idiotípicos/administração & dosagem , Proteína Glial Fibrilar Ácida/imunologia , Degeneração Neural/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anticorpos Anti-Idiotípicos/imunologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Proteína Glial Fibrilar Ácida/antagonistas & inibidores , Ácido Caínico/toxicidade , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/imunologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/induzido quimicamente , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
16.
Tissue Cell ; 56: 90-97, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30736910

RESUMO

Nowadays there are various models of spinal cord injury (SCI) that recreate mechanisms of human SCI. The ex vivo modeling of injury is a robust approach, confronts with less experimental and ethical challenges. Currently almost all ex vivo models are obtained either from embryonic or postnatal animals, which can hardly mimic features of human SCI. This study was designed to develop SCI in slice culture of adult rats. Here, the lumbar enlargement of an adult rat was sliced and cultured. After seven days in vitro, a weight was dropped to simulate the injury. The result showed that although the rate of cell death in first days of in vitro was high, it reduced after 7 days and dropping a weight at the time caused significant rate of cell death in slices. It was shown that injury can disturb histological features and neuronal integrity in the slices. Treating the injured slices with valproic acid resulted in a significant decrease of TNF-α and increase of BDNF expression. Collected data revealed obtained slices from adult rat were able to adjust to the culture environment after 7 days and dropping a weight at the time point could simulate the injury. Besides mimicking the disturbing features of human SCI, this model can response to VPA pharmacological treatment.


Assuntos
Técnicas de Cultura de Órgãos , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/crescimento & desenvolvimento , Ácido Valproico/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neurônios/patologia , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia , Fator de Necrose Tumoral alfa/genética
17.
Nutrients ; 11(2)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791474

RESUMO

A chemotherapy drug, oxaliplatin, induces cold and mechanical hypersensitivity, but effective treatments for this neuropathic pain without side effects are still lacking. We previously showed that Cinnamomi Cortex suppresses oxaliplatin-induced pain behaviors in rats. However, it remains unknown which phytochemical of Cinnamomi Cortex plays a key role in that analgesic action. Thus, here we investigated whether and how cinnamic acid or cinnamaldehyde, major components of Cinnamomi Cortex, alleviates cold and mechanical allodynia induced by a single oxaliplatin injection (6 mg/kg, i.p.) in rats. Using an acetone test and the von Frey test for measuring cold and mechanical allodynia, respectively, we found that administration of cinnamic acid, but not cinnamaldehyde, at doses of 10, 20 and 40 mg/kg (i.p.) significantly attenuates the allodynic behaviors in oxaliplatin-injected rats with the strongest effect being observed at 20 mg/kg. Our in vivo extracellular recordings also showed that cinnamic acid (20 mg/kg, i.p.) inhibits the increased activities of spinal wide dynamic range neurons in response to cutaneous mechanical and cold stimuli following the oxaliplatin injection. These results indicate that cinnamic acid has an effective analgesic action against oxaliplatin-induced neuropathic pain through inhibiting spinal pain transmission, suggesting its crucial role in mediating the effect of Cinnamomi Cortex.


Assuntos
Acroleína/análogos & derivados , Cinamatos/uso terapêutico , Cinnamomum aromaticum/química , Medicamentos de Ervas Chinesas/uso terapêutico , Neuralgia/prevenção & controle , Oxaliplatina/efeitos adversos , Medula Espinal/efeitos dos fármacos , Acroleína/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Cinamatos/farmacologia , Temperatura Baixa , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Masculino , Neuralgia/induzido quimicamente , Compostos Organoplatínicos/efeitos adversos , Ratos Sprague-Dawley
18.
Life Sci ; 220: 147-155, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30731141

RESUMO

AIMS: Neuroinflammatory changes in the central nervous system are widely involved in the initiation and maintenance of neuropathic pain after peripheral nerve injury. The present study investigated how losartan treatment may affect the development of neuropathic pain and neuroinflammation. MAIN METHODS: The effect of losartan treatment on the development of peripheral neuropathy was studied in L5 spinal nerve ligation (SNL) model in rats with systemic (100 mg/kg) or intrathecal (10 µl/ 20 µM solution) application of losartan. Electronic von Frey filament and plantar test were used to determine pain thresholds to mechanical and thermal stimulations. At the 7th post-operative day, CD68-positive cells in DRG and dorsal roots were quantified by immunohistochemistry and western blot analyses were used to compare the expression levels of neuroinflammatory markers in lumbar spinal cord (SC). KEY FINDINGS: Our data confirmed the presence of SNL-evoked heat hyperalgesia and mechanical allodynia. Losartan application blocked the SNL-induced hypersensitivity to thermal stimuli but failed to prevent mechanical allodynia. No significant difference between systemic and i.t. administration of losartan was observed. Immunohistochemistry confirmed the presence of infiltrated macrophages in the ipsilateral DRG that was significantly attenuated with the losartan treatment. Western blot SC tissue analysis revealed that systemic treatment with losartan prevented SNL-induced upregulation of CCR2, TNFα, TNFR1, and OX42 while its effect on CCL2 and AT1R expression was not significant. SIGNIFICANCE: Our results show that losartan treatment attenuates neuroinflammation and neuropathic pain after SNL. These effects of losartan represent an interesting direction for the development of novel treatments of peripheral neuropathy.


Assuntos
Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Losartan/farmacologia , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Losartan/metabolismo , Masculino , Neuralgia/metabolismo , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Nervos Espinhais/efeitos dos fármacos
19.
Int J Mol Sci ; 20(4)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769838

RESUMO

Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in the analgesic mechanisms of these drugs. Gabapentinoids activate the LC by inhibiting the release of γ-aminobutyric acid (GABA) and inducing the release of glutamate, thereby increasing noradrenaline levels in the spinal cord. Antidepressants increase noradrenaline levels in the spinal cord by inhibiting reuptake, and accumulating noradrenaline inhibits chronic pain through α2-adrenergic receptors in the spinal cord. Recent animal studies, however, revealed that the function of the descending noradrenergic inhibitory system is impaired in chronic pain states. Other recent studies found that histone deacetylase inhibitors and antidepressants restore the impaired noradrenergic descending inhibitory system acting on noradrenergic neurons in the LC.


Assuntos
Dor Crônica/tratamento farmacológico , Norepinefrina/antagonistas & inibidores , Receptores Adrenérgicos alfa 2/genética , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Antidepressivos Tricíclicos/administração & dosagem , Dor Crônica/genética , Dor Crônica/fisiopatologia , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/metabolismo , Gabapentina/administração & dosagem , Humanos , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiopatologia , Norepinefrina/genética , Norepinefrina/metabolismo , Pregabalina/administração & dosagem , Inibidores de Captação de Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/fisiopatologia
20.
Neurol Res ; 41(6): 519-527, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30759061

RESUMO

Background and Objectives: Studying the underlying mechanisms of opiate-induced hyperalgesia is fundamental to understanding and treating pain. Our previous study has proved that ephrinB/EphB signaling contributes to opiate-induced hyperagesia, but the manner in which ephrinB/EphB signaling acts on spinal nociceptive information networks to produce hyperalgesia remains unclear. Other studies have suggested that ephrinB/EphB signaling, NMDA receptor and COX-2 act together to participate in the modulation of nociceptive information processes at the spinal level. The objective of this research was to investigate the role of COX-2 in remifentanil-induced hyperalgesia and its relationship with ephrinB/EphB signaling. Methods: We characterized the remifentanil-induced pain behaviours by evaluating thermal hyperalgesia and mechanical allodynia in a mouse hind paw incisional model. Protein expression of COX-2 in spinal cord was assayed by western blotting and mRNA level of COX-2 was assayed by Real-time PCR (RT-PCR). Results: Continuing infusion of remifentanil produced thermal hyperalgesia and mechanical allodynia, which was accompanied by increased expression of spinal COX-2 protein and mRNA. This response was inhibited by pre-treatment with EphB2-Fc, an antagonist of ephrinB/EphB. SC58125 and NS398, inhibitors of COX-2, suppressed pain behaviours induced by remifentanil infusion and reversed the increased pain behaviours induced by intrathecal injection of ephrinB2-Fc, an agonist of ephrinB/EphB. Conclusions: Our findings confirmed that COX-2 is involved in remifentanil-induced hyperalgesia related to ephrinB/EphB signaling. EphrinB/EphB signaling might be the upstream of COX-2.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Efrinas/metabolismo , Hiperalgesia/metabolismo , Remifentanil/farmacologia , Animais , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Injeções Espinhais , Camundongos , Pirazóis/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
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