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1.
J Neuroimmunol ; 345: 577261, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32570135

RESUMO

The development and maintenance of neuropathic pain is now given far more attention in the clinic work. Increasing evidence has shown that colony-stimulating factor 1 (CSF1) is involved in microglial activation and may further induce pain. Here, we observed the signaling events that link the CSF1-induced microglial activated and consequences for pain processing. For the in vitro study, flow cytometry showed the microglial activity was markedly increased after CSF1 stimulation. Western blot showed the increased expression of p-PRKAA1/PRKAA1, p-AMPK/AMPK, p-ULK1/ULK1, p-S6k/S6k and LC3-II/LC3-I. QRT-PCR showed the IL-1, TNF-α and BDNF were simultaneously upregulated in the activated microglia cells, whereas the specific AMPK inhibitor compound C exhibited reverse effects in microglia. Using immunofluorescence staining and electron microscopy, we found CSF1 decreased microglial p62 expression and induced the number of autophagosomes, whereas compound C significantly exhibited the reverse effects. For the in vivo study, compared with the control and AMPK-siRNA transfection, the mice under CSF1 intrathecal injection increased CSF1 receptor and LC3 expressed in the activated spinal microglia. More importantly, qRT-PCR showed CSF1 intrathecal injection substantially upregulated BDNF and c-Fos mRNA expression as well as the ensuing neuropathic pain. Our findings demonstrated that CSF1 induced a significant upregulation of microglial activation via the AMPK signaling pathway and resulted in an increasing microglial autophagic level. An increasing CSF1 level in the central nervous system can mimic and cause pain syndromes by up-regulation of AMPK-depended autophagy, thus offering a new target for the therapy of neuropathic pain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Microglia/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Injeções Espinhais , Fator Estimulador de Colônias de Macrófagos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Neuralgia/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
2.
J Cancer Res Ther ; 16(1): 34-39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362607

RESUMO

Background and Objective: Metformin (MET) has been used as an antidiabetic agent for type II diabetes. At the same time, recent researches have shown that the clinical improvement of MET is useful for nerve damage. In this study, we investigated the analgesic effect of MET in paclitaxel (PAC)-induced neuropathic pain. Materials and Methods: Forty-two adult, female rats, Wistar strain weighing 220 ± 10 g were randomly divided into 5 experimental groups. PAC was intraperitoneally (IP) administered (2.0 mg/kg) for 4 groups every other day (0, 2, 4, and 6 days). By the 30th day, MET (100, 200, and 400 mg/kg) was administered to 4 groups. Before and after treatment, basal pain threshold values were measured with Randall-Selitto analgesiometer test. At the end of experiment, pathological values were measured in selected regions including brain (motor cortex, M1), spinal cord (L4-L5), sciatic nerve, and muscle. Results: According to our results, PAC-induced neuropathic pain reached to highest level at 14th day. Four hundred milligram/kilogram concentration of MET remarkably decreased PAC-induced neuropathic pain. On the other hand, pathologic features have shown that PAC had significant pathological change in the brain and spinal cord while in the peripheral nerves and muscles had not shown any pathological change. Conclusion: The pathological results of the current study for the first time demonstrated that MET beside of its antidiabetic effects reversed neuropathic pain induced by PAC. Consequently, this research can be promising for cancer patients that suffering from neuropathic pain induced by anticancer drugs.


Assuntos
Analgésicos/farmacologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Neoplasias/complicações , Neuralgia/prevenção & controle , Paclitaxel/efeitos adversos , Limiar da Dor/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Modelos Animais de Doenças , Feminino , Neoplasias/patologia , Neuralgia/induzido quimicamente , Neuralgia/patologia , Ratos , Ratos Wistar
3.
J Med Chem ; 63(11): 6107-6133, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32368909

RESUMO

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.


Assuntos
Cromanos/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Cromanos/farmacocinética , Cromanos/uso terapêutico , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
4.
PLoS One ; 15(4): e0231597, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287325

RESUMO

Resident microglia of the central nervous system are being increasingly recognized as key players in diseases such as neuropathic pain. Biochemical and behavioral studies in neuropathic pain rodent models have documented compelling evidence of the critical role of ATP mediated-P2X4R-brain-derived neurotrophic factor (BDNF) signaling pathway in the initiation and maintenance of pain hypersensitivity, a feature driving neuropathic pain-related behavior. The goal of this study was to develop and characterize an in vitro cell line model of activated microglia that can be subsequently utilized for screening neuropathic pain therapeutics. In the present study, we characterized the SIM-A9 microglia cell line for key molecules in the P2X4R-BDNF signaling axis using a combination of biochemical techniques and developed an ATP-activated SIM-A9 microglia model. We present three novel findings: first, SIM-A9 cells expressed P2X4R and BDNF proteins, second, ATP, but not LPS, was cytocompatible with SIM-A9 cells and third, exposure of cells to optimized ATP concentrations for defined periods increased intracellular expression of Iba1 and BDNF proteins. Increased Iba1 levels confirmed microglia activation and increased BDNF expression confirmed ATP-mediated stimulation of the P2X4R signaling pathway. We propose that this ATP-activated SIM-A9 cell line model system can be utilized for screening both small- as well as macro-molecular neuropathic pain therapeutics targeting BDNF and/or P2X4R knockdown.


Assuntos
Microglia/metabolismo , Neuralgia/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Técnicas de Cultura de Células/métodos , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Neuralgia/patologia , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X4/metabolismo
6.
Sci Rep ; 10(1): 3371, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32099076

RESUMO

Neuropathic pain is believed to arise from damage to nociceptive C fibres in diabetic neuropathy (DN). We have utilised corneal confocal microscopy (CCM) to quantify the severity of small nerve fibre damage in relation to the severity of neuropathic pain and quality of life (QoL) in patients with and without painful DN. 30 controls and patients with painful (n = 78) and painless (n = 62) DN underwent assessment of large and small nerve fibre function, CCM, neuropathic symptoms (small fibre neuropathy symptom inventory questionnaire, neuropathic pain scale) and QoL (SF-36, pre-R-ODS and hospital anxiety and depression scale). Patients with painful compared to painless DN, had comparable neurophysiology and vibration perception, but lower corneal nerve fibre density (20.1 ± 0.87 vs. 24.13 ± 0.91, P = 0.005), branch density (44.4 ± 3.31 vs. 57.74 ± 3.98, P = 0.03), length (19.61 ± 0.81 vs. 22.77 ± 0.83, P = 0.01), inferior whorl length (18.03 ± 1.46 vs. 25.1 ± 1.95, P = 0.005) and cold sensation threshold (21.35 ± 0.99 vs. 26.08 ± 0.5, P < 0.0001) and higher warm sensation threshold (43.7 ± 0.49 vs. 41.37 ± 0.51, P = 0.004) indicative of small fibre damage. There was a significant association between all CCM parameters and the severity of painful neuropathic symptoms, depression score and QoL. CCM identifies small nerve fibre loss, which correlates with the severity of neuropathic symptoms and reduced QoL in patients with painful diabetic neuropathy.


Assuntos
Córnea/patologia , Neuropatias Diabéticas/fisiopatologia , Fibras Nervosas/fisiologia , Idoso , Estudos de Casos e Controles , Depressão/patologia , Neuropatias Diabéticas/complicações , Feminino , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Neuralgia/etiologia , Neuralgia/patologia , Qualidade de Vida , Limiar Sensorial , Índice de Gravidade de Doença
7.
Int J Mol Sci ; 21(3)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028715

RESUMO

Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.


Assuntos
Gangliosídeos/metabolismo , Neuralgia/patologia , Doenças do Sistema Nervoso Periférico/complicações , Animais , Humanos , Neuralgia/etiologia , Neuralgia/metabolismo , Transdução de Sinais
8.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070010

RESUMO

: The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury.


Assuntos
Proteína Glial Fibrilar Ácida/genética , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico/genética , Células Satélites de Músculo Esquelético/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Modelos Animais de Doenças , Humanos , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Nervo Mandibular/metabolismo , Nervo Mandibular/patologia , Traumatismos do Nervo Mandibular/tratamento farmacológico , Traumatismos do Nervo Mandibular/metabolismo , Traumatismos do Nervo Mandibular/patologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , Neuroglia/metabolismo , Ratos , Ratos Sprague-Dawley , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais/genética , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/patologia , Traumatismos do Nervo Trigêmeo/genética , Traumatismos do Nervo Trigêmeo/metabolismo , Traumatismos do Nervo Trigêmeo/patologia
9.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093166

RESUMO

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.


Assuntos
Sistemas de Liberação de Medicamentos , Endocanabinoides/metabolismo , Inibidores Enzimáticos/uso terapêutico , Dor Facial , Neuralgia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Animais , Dor Facial/tratamento farmacológico , Dor Facial/metabolismo , Dor Facial/patologia , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia
10.
Eur J Med Chem ; 191: 112144, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087465

RESUMO

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (µ) opioid receptor agonists, and measured their affinity for σ1 and µ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and µ receptor (Ki µ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/µ receptor profiles, may be a potential candidate for treating neuropathic pain.


Assuntos
Amidas/farmacologia , Neuralgia/tratamento farmacológico , Piperidinas/farmacologia , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inibidores , Amidas/administração & dosagem , Amidas/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído , Cobaias , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/patologia , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Relação Estrutura-Atividade
11.
Phytomedicine ; 67: 153166, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31955133

RESUMO

BACKGROUND: Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. PURPOSE: This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. RESULTS: Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1ß), inflammatory proteins (TNF-α, IL-1ß, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. CONCLUSION: Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1ß-dependent NF-κB activation.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Iridoides/farmacologia , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Células de Schwann/efeitos dos fármacos , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Dor Crônica/patologia , Constrição , Citocinas/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Interleucina-1beta/metabolismo , Masculino , Neuralgia/metabolismo , Neuralgia/patologia , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Biochem Pharmacol ; 174: 113825, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987854

RESUMO

We have previously reported that the spinal angiotensin (Ang) system is involved in the modulation of streptozotocin (STZ)-induced diabetic neuropathic pain in mice. An important drawback of this model however is the fact that the neuropathic pain is independent of hyperglycemia and produced by the direct stimulation of peripheral nerves. Here, using the leptin deficient ob/ob mouse as a type 2 diabetic model, we examined whether the spinal Ang system was involved in naturally occuring diabetic neuropathic pain. Blood glucose levels were increased in ob/ob mice at 5-15 weeks of age. Following the hyperglycemia, persistent tactile and thermal hyperalgesia were observed at 11-14 and 9-15 weeks of age, respectively, which was ameliorated by insulin treatment. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the spinal plasma membrane fraction was decreased in ob/ob mice. Spinal ACE2 was expressed in neurons and microglia but the number of NeuN-positive neurons was decreased in ob/ob mice. In addition, the intrathecal administration of Ang (1-7) and SB203580, a p38 MAPK inhibitor, attenuated hyperalgesia in ob/ob mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in ob/ob mice. These inhibitory effects of Ang (1-7) were prevented by A779, a Mas receptor antagonist. In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in ob/ob mice and is accompanied by a loss of ACE2-positive neurons. Furthermore, Ang (1-7) decreased the diabetic neuropathic pain through inhibition of p38 MAPK phosphorylation via spinal Mas receptors.


Assuntos
Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Regulação para Baixo/fisiologia , Neuralgia/enzimologia , Peptidil Dipeptidase A/deficiência , Medula Espinal/enzimologia , Angiotensina I/metabolismo , Angiotensina I/farmacologia , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Camundongos Transgênicos , Neuralgia/genética , Neuralgia/patologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Exp Neurol ; 327: 113208, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31962127

RESUMO

Spinal cord injury (SCI) produces both locomotor deficits and sensory dysfunction that greatly reduce the overall quality of life. Mechanisms underlying chronic pain include increased neuro-inflammation and changes in spinal processing of sensory signals, with reduced inhibitory GABAergic signaling a likely key player. Our previous research demonstrated that spinal transplantation of GABAergic neural progenitor cells (NPCs) reduced neuropathic pain while intensive locomotor training (ILT) could reduce development of pain and partially reverse already established pain behaviors. Therefore, we evaluate the potential mutually beneficial anti-hypersensitivity effects of NPC transplants cells in combination with early or delayed ILT. NPC transplants were done at 4 weeks post-SCI. ILT, using a progressive ramping treadmill protocol, was initiated either 5 days post-SCI (early: pain prevention group) or at 5 weeks post-SCI (delayed: to reverse established pain) in male Sprague Dawley rats. Results showed that either ILT alone or NPCs alone could partially attenuate SCI neuropathic pain behaviors in both prevention and reversal paradigms. However, the combination of ILT with NPC transplants significantly enhanced neuropathic pain reduction on most of the outcome measures including tests for allodynia, hyperalgesia, and ongoing pain. Immunocytochemical and neurochemical analyses showed decreased pro-inflammatory markers and spinal pathology with individual treatments; these measures were further improved by the combination of either early or delayed ILT and GABAergic cellular transplantation. Lumbar dorsal horn GABAergic neuronal and process density were nearly restored to normal levels by the combination treatment. Together, these interventions may provide a less hostile and more supportive environment for promoting functional restoration in the spinal dorsal horn and attenuation of neuropathic pain following SCI. These findings suggest mutually beneficial effects of ILT and NPC transplants for reducing SCI neuropathic pain.


Assuntos
Neurônios GABAérgicos/transplante , Atividade Motora/fisiologia , Células-Tronco Neurais/transplante , Neuralgia/terapia , Condicionamento Físico Animal/fisiologia , Traumatismos da Medula Espinal/terapia , Medula Espinal/patologia , Animais , Transplante de Células , Modelos Animais de Doenças , Masculino , Neuralgia/etiologia , Neuralgia/patologia , Limiar da Dor/fisiologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/patologia , Resultado do Tratamento
14.
Biomed Pharmacother ; 123: 109812, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31945696

RESUMO

Wu-tou decoction (WTD), a classic Traditional Chinese medicine formula, has been extensively used in the treatment of neuropathic pain (NP) such as chronic inflammatory pain, trigeminal neuralgia, and cancer-induced pain. Our previous studies have shown that the severity of mechanical allodynia and thermo hypersensitivity in NP rats are reduced by WTD, of which analgesic candidates are paeoniflorin (Pae) and liquiritin (Liq). The aim of this study was to clarify the molecular mechanisms of WTD, Pae and Liq against NP based on the primary rat glial cells in vitro. The gene expression levels of neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Artemin and C-C chemokine receptor type 5 (CCR5) were augmented by inflammatory cytokines, while chemokines increased only CCR5 gene expression. The constitutive and cytokine-augmented neurotrophic factor gene expression was enhanced by WTD, Pae, and Liq through PI3K- and PKA-dependent pathways in rat glial cells, leading to the increase of NGF and BDNF production. Furthermore, the CCR5 gene expression under basal and chemokine-treated conditions was suppressed by these reagents, in which signal pathway(s) was independent on the activation of PI3K and PKA. Moreover, there was no cytotoxicity in the WTD, Pae, and Liq treatments in glial cells. Thus, these results provide a novel evidence that WTD may exert the anti-NP actions by predominantly increasing the production of neurotrophic factors through PI3K- and PKA-signaling pathways in rat glial cells. Furthermore, Pae and Liq may play as analgesic candidates in WTD-mediated NP management.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Fatores de Crescimento Neural/metabolismo , Neuralgia/tratamento farmacológico , Neuroglia/metabolismo , Neuroglia/patologia , Receptores CCR5/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/farmacologia , Mediadores da Inflamação/metabolismo , Monoterpenos/farmacologia , Fatores de Crescimento Neural/genética , Neuralgia/genética , Neuralgia/patologia , Neuroglia/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores CCR5/genética , Transdução de Sinais/efeitos dos fármacos
15.
Eur J Pharmacol ; 868: 172859, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31843515

RESUMO

The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α2-adrenoceptors. Histaminergic innervation from the tuberomammillary nucleus of the LC increases firing of noradrenergic neurons and might contribute to pain control. Here we evaluated the contribution of LC histaminergic innervation in descending modulation of neuropathic hypersensitivity, by investigating the role of the histamine H4 receptor subtype in a mouse model of neuropathic pain. Intra LC administration of the H4 agonist VUF 8430 attenuated mechanical and thermal allodynia of mice that underwent spared nerve injury (SNI). Similarly, histamine in the LC showed mechanical and thermal anti-hypersensitivity. Pretreatment of LC with JNJ 10191584 (H4 antagonist) prevented the beneficial effect of VUF 8430 and histamine on nociceptive behaviour. Comparable results were obtained after intrathecal administration of drugs. The intrathecal administration of the α2-adrenoceptor agonist clonidine ameliorated mechanical and thermal allodynia in SNI mice. The clonidine-induced anti-hypersensitivity effect was prevented by intra LC pretreatment with JNJ 10191584. In addition, clonidine failed to suppress neuropathic pain in H4 deficient mice. LC H4 receptors showed a ubiquitous distribution within LC, a neuronal localization and H4 immunostaining was detected on noradrenergic neurons expressing phosphorylated cAMP response element-binding protein (CREB), a marker of neuronal activation. Under pain pathological conditions H4 stimulation might promote the activation of the coeruleospinal noradrenergic neurons that exert an inhibitory control over spinal dorsal horn neuronal excitability. Thus, histamine H4 receptor stimulation may represent a perspective for neuropathic pain management.


Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Guanidinas/administração & dosagem , Locus Cerúleo/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Receptores Histamínicos H4/agonistas , Tioureia/análogos & derivados , Neurônios Adrenérgicos/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Benzimidazóis/administração & dosagem , Clonidina/administração & dosagem , Modelos Animais de Doenças , Histamina/metabolismo , Humanos , Injeções Espinhais , Locus Cerúleo/patologia , Masculino , Camundongos , Camundongos Knockout , Microinjeções , Neuralgia/patologia , Norepinefrina/metabolismo , Manejo da Dor/métodos , Receptores Histamínicos H4/genética , Receptores Histamínicos H4/metabolismo , Tioureia/administração & dosagem
16.
Eur J Pharmacol ; 868: 172880, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31863767

RESUMO

Neuropathic pain is a severe disease caused by lesions or diseases in the somatosensory system. Long non-coding RNAs (lncRNAs) are important in the development and maintenance of neuropathic pain. However, the precise role of lncRNAs in regulating neuropathic pain remains largely unknown. In this study, a rat model of bilateral chronic constriction injury (bCCI) was established, and microarray was applied to analyze differentially expressed lncRNAs among sham group, bCCI group and the experimental group (bCCI rats administrated with a specific STAT3 inhibitor WP1066). Linc00311 and lncRNA-AK141205 were uncharacterized lncRNAs both upregulated by > 2 folds in bCCI model compared with Sham group, and they were downregulated by > 2 folds following WP1066 administration compared with bCCI group. Downregulation of linc00311 and lncRNA-AK141205 by specific siRNAs significantly attenuated mechanical allodynia, thermal and cold hyperalgesia in bCCI rats. In addition, inhibition of linc00311 and lncRNA-AK141205 inactivated the signal transducer and activator of transcription 3 (STAT3) signaling in spinal microglia in vivo and in vitro. Inhibition of linc00311 and lncRNA-AK141205 could reduce activation of STAT3 and production of proinflammatory cytokines. Moreover, activating STAT3 with SD19 could antagonize the effect of the suppressive effect of siRNAs on production of proinflammatory cytokines. Hence, it is likely that silencing linc00311 and lncRNA-AK141205 may be a promising and novel treatment for neuropathic pain.


Assuntos
Neuralgia/imunologia , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/patologia , Neuralgia/tratamento farmacológico , Neuralgia/genética , Neuralgia/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Piridinas/administração & dosagem , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Ratos , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Medula Espinal/imunologia , Medula Espinal/patologia , Tirfostinas/administração & dosagem
17.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801267

RESUMO

The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be multimodal (pharmacological and non-pharmacological), including causal anticancer and symptomatic analgesic treatment to improve quality of life (QoL). The aim of this paper is to discuss the mechanisms involved in the occurrence and persistence of cancer-associated bone pain and to review the treatment methods recommended by experts in clinical practice. The final part of the paper reviews experimental therapeutic methods that are currently being studied and that may improve the efficacy of bone pain treatment in cancer patients in the future.


Assuntos
Analgésicos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/terapia , Dor do Câncer/terapia , Dor Musculoesquelética/terapia , Neuralgia/terapia , Neoplasias Ósseas/fisiopatologia , Neoplasias Ósseas/psicologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Dor do Câncer/patologia , Dor do Câncer/fisiopatologia , Dor do Câncer/psicologia , Difosfonatos/uso terapêutico , Feminino , Raios gama/uso terapêutico , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Neoplasias Renais/psicologia , Neoplasias Renais/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/psicologia , Neoplasias Pulmonares/terapia , Masculino , Dor Musculoesquelética/patologia , Dor Musculoesquelética/fisiopatologia , Dor Musculoesquelética/psicologia , Neuralgia/patologia , Neuralgia/fisiopatologia , Neuralgia/psicologia , Manejo da Dor/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Neoplasias da Próstata/psicologia , Neoplasias da Próstata/terapia , Qualidade de Vida/psicologia
18.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835716

RESUMO

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.


Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Somatostatina/agonistas , Administração Oral , Analgésicos/química , Animais , Células CHO , Doença Crônica , Cricetinae , Cricetulus , Diterpenos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Inflamação/patologia , Ligantes , Masculino , Camundongos , Simulação de Dinâmica Molecular , Neuralgia/complicações , Neuralgia/patologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/química , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores de Somatostatina/metabolismo
19.
PLoS One ; 14(11): e0225586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31765435

RESUMO

Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 µg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gânglios Espinais/metabolismo , Neuralgia/patologia , Oxaliplatina/toxicidade , Regulação para Cima/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Hiperalgesia/prevenção & controle , Masculino , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775332

RESUMO

Paclitaxel-induced peripheral neuropathy is a common adverse effect during paclitaxel treatment resulting in sensory abnormalities and neuropathic pain during chemotherapy and in cancer survivors. Conventional therapies are usually ineffective and possess adverse effects. Here, we examined the effects of electroacupuncture (EA) on a rat model of paclitaxel-induced neuropathic pain and related mechanisms. EA robustly and persistently alleviated paclitaxel-induced pain hypersensitivities. Mechanistically, TLR4 (Toll-Like Receptor 4) and downstream signaling MyD88 (Myeloid Differentiation Primary Response 88) and TRPV1 (Transient Receptor Potential Vallinoid 1) were upregulated in dorsal root ganglion (DRGs) of paclitaxel-treated rats, whereas EA reduced their overexpression. Ca2+ imaging further indicated that TRPV1 channel activity was enhanced in DRG neurons of paclitaxel-treated rats whereas EA suppressed the enhanced TRPV1 channel activity. Pharmacological blocking of TRPV1 mimics the analgesic effects of EA on the pain hypersensitivities, whereas capsaicin reversed EA's effect. Spinal astrocytes and microglia were activated in paclitaxel-treated rats, whereas EA reduced the activation. These results demonstrated that EA alleviates paclitaxel-induced peripheral neuropathic pain via mechanisms possibly involving suppressing TLR4 signaling and TRPV1 upregulation in DRG neurons, which further result in reduced spinal glia activation. Our work supports EA as a potential alternative therapy for paclitaxel-induced neuropathic pain.


Assuntos
Eletroacupuntura/métodos , Neuralgia/prevenção & controle , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/prevenção & controle , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/toxicidade , Regulação da Expressão Gênica , Masculino , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
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