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2.
Eur J Med Chem ; 188: 111920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901745

RESUMO

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.


Assuntos
Analgésicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Oxaliplatina , Ligação Proteica , Estreptozocina , Relação Estrutura-Atividade
3.
Life Sci ; 240: 117085, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759042

RESUMO

AIMS: Our study was designed to explore the function and mechanism of Tanshinone IIA in alleviating pain syndrome caused by endometriosis (EMs). MAIN METHODS: Female Sprague-Dawley rats went through autotransplantation operation to establish EMs model. The rats were randomly divided into five groups: sham, model, positive, Tanshinone IIA (L) (3 mg/kg/d) and Tanshinone IIA (H) (12 mg/kg/d) group. Volume of ectopic endometrium was measured after 21 days of continuous administration. Serum estradiol (E2) was detected by enzyme linked immunosorbent assay (Elisa). The protein expression of angiotensinogen (AGT), renin (REN), angiotensin converting enzyme (ACE), angiotensin II (ANGII) and angiotensin II type 2 receptor (AT2) in the dorsal root ganglion (DRG) neurons were measured by immunohistochemistry and Western Blotting. The mRNA expression levels of AGT and ANGII were measured by Real-time polymerase chain reaction (PCR). KEY FINDINGS: Tissue measurements showed that tanshinone IIA significantly inhibited the growth of ectopic endometrium. Tanshinone IIA could improve the paw withdrawal threshold thus reducing the mechanical hyperalgesia of EMs rats. Moreover, Tanshinone IIA regulated the DRG renin angiotensin system (RAS) by reducing the protein expression of AGT, REN, ACE, ANGII and AT2 in DRG neurons. Furthermore, Real-time PCR results also showed that the mRNA expression levels of AGT and ANGII in the DRG neurons were decreased. SIGNIFICANCE: The Tanshinone IIA inhibitory effect on the EMs associated pain in EMs rats might occur through decreasing the expression of E2, ANGII and AT2, thus halting DRG sprouting and promoting hyperalgesia threshold.


Assuntos
/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Axônios/patologia , Endometriose/tratamento farmacológico , Gânglios Espinais/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Endometriose/patologia , Estradiol/metabolismo , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Ratos , Ratos Sprague-Dawley
4.
Biosci Biotechnol Biochem ; 84(1): 159-170, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31483212

RESUMO

We tested whether Sake Lees (SL) had inhibitory effects on hyperalgesia in the hindpaw under psychophysical stress conditions. Male rats were subjected to repeated forced swim stress treatments (FST) from Day -3 to Day -1. Intraperiotoneal administration of SL which contained low concentration of ethanol (SLX) was conducted after each FST. On Day 0, formalin-evoked licking behaviors and Fos responses in the lumbar spinal cord (DH) and several areas within the rostral ventromedial medulla (RVM) were quantified as nociceptive responses. FST-induced hyperalgesia in the hindpaw was prevented by repeated SL and SLX treatments. Fos expression was significantly increased in DH and some areas within the RVM under FST, which was prevented by repeated SL or SLX. These findings indicated that daily administration of SL had the potential to alleviate stress-induced hyperalgesia.


Assuntos
Fermentação , Membro Posterior/metabolismo , Hiperalgesia/tratamento farmacológico , Oryza/química , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Estresse Fisiológico/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Etanol/química , Formaldeído/administração & dosagem , Formaldeído/farmacologia , Hiperalgesia/etiologia , Imuno-Histoquímica , Masculino , Manejo da Dor , Medição da Dor , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/imunologia , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/imunologia , Serotonina/metabolismo , Natação/fisiologia , Distribuição Tecidual
5.
World J Gastroenterol ; 25(40): 6077-6093, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31686764

RESUMO

BACKGROUND: Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP. AIM: To investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis. METHODS: CP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected via pharmacological approach and chemogenetics in CP rats. RESULTS: TNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 ± 1.12 Hz in CP rats vs 2.55 ± 0.44 Hz in sham rats, P < 0.01; amplitude: 19.60 ± 1.39 pA in CP rats vs 14.71 ± 1.07 pA in sham rats; P < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission via the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 ± 1.02 g in CNQX group, 8.00 ± 0.81 g in AP-5 group and 1.10 ± 0.27 g in saline group, P < 0.001). Inhibiting the excitability of NTS neurons via chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 ± 2.55 g in Gi group, 2.00 ± 1.37 g in Gq group, and 2.36 ± 0.67 g in mCherry group, P < 0.01). CONCLUSION: Our findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP.


Assuntos
Dor Crônica/fisiopatologia , Sistema Nervoso Entérico/fisiopatologia , Hiperalgesia/fisiopatologia , Pancreatite Crônica/complicações , Núcleo Solitário/fisiopatologia , Vias Aferentes/fisiopatologia , Animais , Dor Crônica/etiologia , Modelos Animais de Doenças , Humanos , Hiperalgesia/etiologia , Masculino , Neurônios/fisiologia , Pâncreas/inervação , Pancreatite Crônica/induzido quimicamente , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/citologia , Técnicas Estereotáxicas , Transmissão Sináptica/fisiologia , Ácido Trinitrobenzenossulfônico/toxicidade
6.
Endocr Regul ; 53(1): 14-25, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517620

RESUMO

OBJECTIVE: Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. METHODS: In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2-4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. RESULTS: Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrate or insulin treatment led to a significant decrease (p<0.01) in blood glucose levels, as well as a significant (p<0.05) increase in the body weight and serum NOx. Moreover, nitrate treatment significantly increased serum insulin levels (p<0.001) compared to the other groups. CONCLUSION: Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Nitratos/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/patologia , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nitratos/uso terapêutico , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina
7.
Curr Sports Med Rep ; 18(9): 325-329, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31503044

RESUMO

Complex Regional Pain Syndrome is a severe complication of extremity fracture or other injury. Patients who develop this show marked hyperalgesia and allodynia, altered vasomotor, sudomotor and trophic changes. The condition affects women more than men and is most common in those between the ages of 50 and 70 years but can be seen in younger athletes. The diagnosis is made clinically, and treatment is directed at functional recovery using medications, occupational and physical therapy, and psychological interventions. Prognosis for complete recovery is variable and unpredictable.


Assuntos
Síndromes da Dor Regional Complexa/diagnóstico , Síndromes da Dor Regional Complexa/terapia , Conservadores da Densidade Óssea/uso terapêutico , Terapia Cognitivo-Comportamental , Humanos , Hiperalgesia/etiologia , Parassimpatolíticos/uso terapêutico , Modalidades de Fisioterapia , Prognóstico
8.
Biol Pharm Bull ; 42(9): 1569-1574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474717

RESUMO

The pathophysiological mechanism of central post-stroke pain (CPSP) is complicated and not well understood. Recently, it has been reported that an increase in the levels of spinal nitric oxide synthetase (NOS) occurs in cerebral ischemia, and spinal NOS is involved in the development of neuropathic pain. The aim of this study was to elucidate the mechanism of spinal NOS signaling in the development of CPSP. Male ddY mice were subjected to 30-min long bilateral carotid artery occlusion (BCAO). The withdrawal responses to mechanical stimuli were significantly increased as determined with von Frey test on days 1 and 3 after BCAO. Protein expression of spinal N(G),N(G)-dimethylarginine dimethylaminohydralase 1 (DDAH1), a key enzyme involved in the metabolism of the endogenous NOS, increased on day 1 after BCAO, but not on day 3. Intrathecal (i.t.) injection of PD404182, a DDAH1 inhibitor, significantly suppressed mechanical allodynia on day 1, but not on day 3 after BCAO. In addition, i.t. administration of NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, significantly blocked mechanical allodynia on days 1 and 3 after BCAO. Furthermore, BCAO-induced increment of spinal NOS activity was inhibited by the pretreatment with PD404182. These results suggest that mechanical allodynia in the early stage of CPSP is caused by increment of NOS activity through upregulated DDAH1 in the spinal cord.


Assuntos
Amidoidrolases/metabolismo , Isquemia Encefálica/complicações , Hiperalgesia/etiologia , Neuralgia/etiologia , Óxido Nítrico Sintase/metabolismo , Medula Espinal/enzimologia , Animais , Isquemia Encefálica/enzimologia , Hiperalgesia/enzimologia , Masculino , Camundongos Endogâmicos , Neuralgia/enzimologia , Transdução de Sinais
9.
Niger J Clin Pract ; 22(9): 1301-1303, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31489871

RESUMO

Neuropathic pain responds poorly to common analgesics that effectively control nociceptive pain because its pathophysiology is different and it is usually associated with co-morbidities such as sleep disturbance, depression and anxiety. Patients with this chronic pain are sometimes left with neurolysis as the last resort. A 65-year-old male multiply-injured retiree presented with disabling pain following traumatic brachial plexus injury sustained from road traffic accident 5 years earlier. Other injuries resolved with therapy except the chronic severe burning and electrifying pain (VAS score 9) in the paralyzed left upper limb associated with allodynia and insomnia which was unresponsive to conventional analgesics. PainDETECT score was 29. A test supraclavicular block with 0.25% Bupivacaine was done, followed by chemical neurolysis one month later. He was placed on oral Gabapentin. The pain score a week post injection was 3 and has remained same 18 months post injection. Patient's level of satisfaction on 5 point Likert scale was 5. Chronic neuropathic pain following traumatic brachial plexus injury could be successfully managed by chemical neurolysis and oral gabapentin.


Assuntos
Analgésicos/administração & dosagem , Neuropatias do Plexo Braquial/complicações , Neuropatias do Plexo Braquial/tratamento farmacológico , Plexo Braquial/lesões , Gabapentina/administração & dosagem , Bloqueio Nervoso/métodos , Neuralgia/tratamento farmacológico , Extremidade Superior/lesões , Adulto , Idoso , Analgésicos/uso terapêutico , Neuropatias do Plexo Braquial/fisiopatologia , Bupivacaína/administração & dosagem , Gabapentina/uso terapêutico , Humanos , Hiperalgesia/etiologia , Masculino , Bloqueio Nervoso/efeitos adversos , Neuralgia/etiologia , Medição da Dor , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/etiologia , Resultado do Tratamento
10.
Molecules ; 24(16)2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430978

RESUMO

: The management of pain in patients affected by diabetic neuropathy still represents an unmet therapeutic need. Recent data highlighted the pain-relieving efficacy of glucosinolates deriving from Brassicaceae. The purpose of this study was to evaluate the anti-hyperalgesic efficacy of Eruca sativa defatted seed meal, along with its main glucosinolate, glucoerucin (GER), on diabetic neuropathic pain induced in mice by streptozotocin (STZ). The mechanism of action was also investigated. Hypersensitivity was assessed by paw pressure and cold plate tests after the acute administration of the compounds. Once bio-activated by myrosinase, both E. sativa defatted meal (1 g kg-1 p.o.) and GER (100 µmol kg-1 p.o., equimolar to meal content) showed a dose-dependent pain-relieving effect in STZ-diabetic mice, but the meal was more effective than the glucosinolate. The co-administration with H2S scavengers abolished the pain relief mediated by both E. sativa meal and GER. Their effect was also prevented by selectively blocking Kv7 potassium channels. Repeated treatments with E. sativa meal did not induce tolerance to the anti-hypersensitive effect. In conclusion, E. sativa meal can be suggested as a new nutraceutical tool for pain relief in patients with diabetic neuropathy.


Assuntos
Brassicaceae/química , Neuropatias Diabéticas/complicações , Glucose/análogos & derivados , Imidoésteres/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Glucose/farmacologia , Glucosinolatos/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sementes/química , Estreptozocina/farmacologia
11.
Neuron ; 103(4): 559-562, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437452
12.
Neuropeptides ; 77: 101957, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400959

RESUMO

Irritable bowel syndrome patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting the involvement of an exaggerated signaling process in both visceral and somatic sensory pathways. Increasing evidence has shown that sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibers toward sensory neurons in dorsal root ganglia maintains and exacerbates the neuropathic and inflammatory pain, as well as colonic inflammation. The aim of the present study was to determine whether electroacupuncture could alleviate the visceral and secondary somatic hyperalgesia in colitis rats by suppressing the TH-IR expression in related dorsal root ganglia. After trinitrobenzene sulfonic acid irritation, rats developed inflammatory tissue damage in the distal colon, which was accompanied by visceral hypersensitivity and secondary hind paw hyperalgesia, as indicated by enhanced visceromotor response to colorectal distension and decreased mechanical and thermal withdrawal latency of the hind paw. Additionally, excessive TH-IR fibers sprouted toward calcitonin gene-related peptide immunoreactive sensory neurons, and TH-IR neurons also increased in the sixth lumbar dorsal root ganglia of colitis rats. Both electroacupuncture and guanethidine attenuated visceral and referred hind paw hyperalgesia by inhibiting the over-expression of TH-IR neurons and fibers in the sixth lumbar dorsal root ganglia. Moreover local inflammatory damage in the distal colon was restored after 7 days of electroacupuncture intervention. These results suggest that electroacupuncture relieved visceral and referred hind paw hypersensitivity in colitis rats by inhibiting TH expression in the sixth lumbar dorsal root ganglia.


Assuntos
Colite/complicações , Gânglios Espinais/metabolismo , Hiperalgesia/terapia , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Colite/metabolismo , Modelos Animais de Doenças , Eletroacupuntura , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Medição da Dor , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo
13.
World Neurosurg ; 132: e529-e534, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31449993

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a common type of injury, and about half of patients affected by SCI will suffer from neuropathic pain within a year after injury. However, the treatment effect of neuropathic pain is far from satisfactory. Our study attempted to reveal whether salvianolic acid B (SalB) could relieve the neuropathic pain caused by SCI in mice by inhibiting the Toll-like receptor 4 (TLR4)/Myeloid differentiation factor 88 (MyD88) pathway. METHODS: The mice were randomly divided into a sham group, model group, high-dose treatment group, and low-dose treatment group. The high- and low-dose groups received varying doses of SalB after modeling. RESULTS: The increase of pain sensitivity was evaluated by detecting paw withdrawal mechanical threshold and withdrawal thermal latency. Messenger RNA and protein expression levels of TLR4 and myD88 were detected by using quantitative reverse-transcription polymerase chain reaction and western blot, respectively. Compared with the model group, there was a significant reduction in paw withdrawal mechanical threshold and withdrawal thermal latency after SalB treatment. CONCLUSIONS: SalB reduced the release of tumor necrosis factor-α and substance P by inhibiting the TLR4/MyD88 pathway in the SCI mouse model. This not only resulted in lower pain, but also contributed to long-term relief of mechanical hyperalgesia.


Assuntos
Benzofuranos/farmacologia , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Hiperalgesia/etiologia , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/etiologia , Neuralgia/imunologia , Distribuição Aleatória , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/imunologia
14.
Int J Mol Sci ; 20(17)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461876

RESUMO

Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System.


Assuntos
Gânglios Sensitivos/metabolismo , Hiperalgesia/metabolismo , Receptores X do Fígado/metabolismo , Obesidade/complicações , Gânglios Sensitivos/fisiologia , Gânglios Sensitivos/fisiopatologia , Humanos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Receptores X do Fígado/genética , Oxisteróis/metabolismo , Células de Schwann/metabolismo , Células de Schwann/fisiologia
15.
Gene ; 719: 144080, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31454541

RESUMO

Trigeminal neuropathic pain is seen as a huge clinical challenge. Although numerous drugs have been developed to treat the condition, some patients have shown intolerance to the drugs and thus continue to suffer. In the present study, a rat model of trigeminal neuropathic pain was established using incorrectly positioned dental implants, which had various manifestations that were similar to human trigeminal neuropathic pain. Using this model, we investigated the differential regulation of JAK2 and PTEN. Firstly, we examined the expression of JAK2 and PTEN in the medullary dorsal horn. After inhibiting JAK2/PTEN, we evaluated nociception-related behavioral alterations. The rat models were established by replacing the left lower second molar with a mini dental implant. Immunoblot assay and immunofluorescence experiments indicated high expression of JAK2 and PTEN in medullary dorsal horn after the nerve injury, which attained plateau levels on post-operative day (POD) 5-10 and 10-20. Administration of adenovirus-shRNA-JAK2 on POD 1 reduced mechanical allodynia and downstream STAT activation. Meanwhile, the administration of adenovirus-shRNA-PTEN on POD 1 attenuated mechanical allodynia while upregulating AKT. In addition to postoperative JAK2 and PTEN activation, dexmedetomidine treatment (10 mg/kg) also modulated the downstream sensors of these signaling molecules. These data suggest that JAK2 and PTEN are pivotal to the development of trigeminal neuropathic pain, and that JAK2 and PTEN suppression alleviates the neuropathic pain.


Assuntos
Técnicas de Silenciamento de Genes , Janus Quinase 2/genética , Neuralgia/diagnóstico , PTEN Fosfo-Hidrolase/genética , Neuralgia do Trigêmeo/genética , Animais , Implantes Dentários/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Janus Quinase 2/antagonistas & inibidores , Masculino , Neuralgia/genética , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Medição da Dor , Ratos , Ratos Sprague-Dawley
16.
Pain Res Manag ; 2019: 6528528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467625

RESUMO

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


Assuntos
Modelos Animais de Doenças , Dor Pós-Operatória , Animais , Dor Crônica/complicações , Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/cirurgia , Pele
17.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454988

RESUMO

Diverse transcriptional controls in the dorsal horn have been observed in pain hypersensitivity. However, the understanding of the exact causes and mechanisms of neuropathic pain development is still fragmentary. Here, the results demonstrated nerve injury decreased the expression of spinal hairy and enhancer of split 1 (Hes1), a transcriptional repressor, and enhanced metabotropic glutamate receptor subtype 5 (mGluR5) transcription/expression, which was accompanied with behavioral allodynia. Moreover, nerve injury decreased Hes1 levels and reciprocally increased cyclin dependent kinase-9 (CDK9) levels and recruited CDK9 to phosphorylate RNA polymerase II (RNAPII) in the promoter fragments of mGluR5, thereby enhancing mGluR5 transcription/expression in the dorsal horn. These effects were also induced by intrathecally administering naïve rats with Hes1 small interfering RNA (siRNA). Conversely, Hes1 overexpression using intrathecal lentiviral vectors in nerve injury rats produced reversal of pain behavior and reversed protein expressions, phosphorylation, and coupling to the promoter segments in the dorsal horn. Collectively, the results in this study indicated nerve injury diminishes spinal Hes1-dependent suppression of CDK9-dependent RNAPII phosphorylation on the mGluR5 promoter that possibly enhances mGluR5 transcription/expression for neuropathic pain development.


Assuntos
Quinase 9 Dependente de Ciclina/metabolismo , Neuralgia/etiologia , Neuralgia/metabolismo , RNA Polimerase II/metabolismo , Receptor de Glutamato Metabotrópico 5/genética , Medula Espinal/metabolismo , Fatores de Transcrição HES-1/genética , Animais , Comportamento Animal , Modelos Animais de Doenças , Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Fenótipo , Regiões Promotoras Genéticas , Ligação Proteica , Ratos , Medula Espinal/fisiopatologia , Fatores de Transcrição HES-1/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
18.
Int J Neurosci ; 129(12): 1155-1165, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31256739

RESUMO

Aim of the study: The current study was aimed to investigate the neuropathic pain attenuating mechanism of pregabalin using chronic constriction injury (CCI) model in rats. Material and Methods: The sciatic nerve was ligated by placing four loose ligatures around it to induce neuropathic pain. The pain development in terms of cold allodynia, mechanical hyperalgesia, and heat hyperalgesia was assessed on the 7th and 14th day after surgery, using acetone drop, pinprick, and hot plate tests. On the 14th day after the injury, pain parameters were assessed 30 minutes after administration of pregabalin (30 mg/kg) and sodium nitroprusside (5 mg/kg) in CCI-subjected rats. Results: CCI led to induction of neuropathic pain, which was more prominent on 14th day in comparison to 7th day. A single administration of pregabalin and sodium nitroprusside on 14th day, markedly reduced pain parameters and increased serum nitrite levels. Pretreatment with L-NAME abolished neuropathic pain attenuating effects of pregabalin suggesting that pregabalin may increase the levels of nitric oxide to mitigate neuropathic pain. Pretreatment with naloxone significantly abrogated pain attenuating effects of pregabalin and sodium nitroprusside in CCI-subjected rats suggesting that pregabalin and nitric oxide-mediated analgesic action are mediated through release of endogenous opioids. Moreover, naloxone failed to modulate pregabalin-induced increase in nitric oxide levels suggesting that the opioid system does not control the nitric oxide levels, and opioids may be downstream modulators of nitric oxide. Conclusion: Pregabalin may increase the release of nitric oxide, which may increase the release of endogenous opioids to attenuate neuropathic pain in CCI subjected rats.


Assuntos
Analgésicos/administração & dosagem , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Pregabalina/administração & dosagem , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Neuralgia/etiologia , Nitroprussiato/administração & dosagem , Medição da Dor , Ratos Wistar
19.
Phytomedicine ; 60: 152987, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31257118

RESUMO

BACKGROUND: Urinary tract infections are among the most common types of infections and give rise to inflammation with pain as one of the main symptoms. The herbal medicinal product Canephron® N contains BNO 2103, a defined mixture of pulverized rosemary leaves, centaury herb, and lovage root, and has been used in the treatment of urinary tract infections for more than 25 years. PURPOSE: To test the hypothesis that BNO 2103 reduces pain in cystitis and prostatitis by virtue of anti-inflammatory properties, and to reveal potential mechanisms underlying the anti-inflammatory features. STUDY DESIGN: BNO 2103 was studied for anti-inflammatory and analgesic properties in three animal models in vivo, and the mode of action underlying the anti-inflammatory features was investigated in human leukocytes and cell-free assays in vitro. METHODS: To assess the anti-inflammatory and analgesic efficacy of BNO 2103 we employed cyclophosphamide-induced cystitis and carrageenan-induced prostatitis in rats, and zymosan-induced peritonitis in mice. Human neutrophils and monocytes as well as isolated human 5-lipoxygenase and microsomal prostaglandin E2 synthase-1-containing microsomes were utilized to assess inhibition of leukotriene and/or prostaglandin E2 production by HPLC and/or ELISA. RESULTS: When given orally, BNO 2103 reduced inflammation and hyperalgesia in experimental cystitis in rats, while individual components of BNO 2103 also reduced hyperalgesia. Furthermore, BNO 2103 reduced hyperalgesia in rats with carrageenan-induced prostatitis. Cell-based and cell-free studies implicate inhibition of prostaglandin E2 and leukotriene B4 biosynthesis as potential mechanisms underlying the analgesic and anti-inflammatory effects. CONCLUSION: Our data support the hypothesis that BNO 2103 reduces pain by virtue of its anti-inflammatory properties, possibly related to suppression of prostaglandin E2 and leukotriene B4 formation, and suggest that this combination has the potential to treat clinical symptoms such as inflammatory pain. Thus BNO 2103 may represent an alternative to reduce the use of antibiotics in urinary tract infections.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Cistite/complicações , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Prostatite/complicações , Analgésicos/química , Animais , Anti-Inflamatórios/química , Carragenina/efeitos adversos , Ciclofosfamida/efeitos adversos , Cistite/induzido quimicamente , Medicamentos de Ervas Chinesas , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Dor/etiologia , Extratos Vegetais/química , Prostatite/induzido quimicamente , Ratos , Ratos Sprague-Dawley
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