Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.086
Filtrar
1.
Neurol India ; 69(4): 910-915, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34507411

RESUMO

Objective: This study aims to evaluate the effects of transforaminal epidural steroid injection (TFESI) on neuropathic pain (NP) in patients with chronic unilateral radiculopathy due to lumbar disc herniation (LDH). Patients and Methods: Between September 2018 and April 2019, a total of 61 patients who were diagnosed with unilateral/unilevel radiculopathy due to LDH and were scheduled for single-level TFESI were included in this study. The Numeric Rating Scale (NRS), modified Oswestry Disability Index (ODI), Beck Depression Inventory (BDI), and NP-Douleur Neuropathique 4 Questionnaire (DN4) were used before the procedure and at 1 hour, 3 weeks, and 3 months after the procedure. Results: There was a significant decrease in the NRS and significant improvement in the ODI, BDI, and DN4 scores in all patients at all postprocedural timepoints (P < 0.05). The number of patients with NP decreased from 35 (60.3%) at baseline to 23 (41.2%) at 3 months (P = 0.001). The NRS scores were similar at 3 weeks and 3 months between the patients with and without NP (P > 0.05). The ODI scores were significantly higher at 3 months in the patients with NP than those without NP (P = 0.013). The BDI scores at baseline, 3 weeks, and 3 months were significantly higher in the patients with NP than those without NP (P < 0.001, P = 0.016, and P = 0.016, respectively). Conclusion: Our study results suggest that TFESI is an effective and safe method to decrease not only nociceptive but also NP component in patients with chronic radiculopathy due to LDH. Clinicians should keep in mind that NP is a risk factor that adversely affects the TFESI success and patients should be evaluated before the procedure.


Assuntos
Deslocamento do Disco Intervertebral , Neuralgia , Radiculopatia , Humanos , Injeções Epidurais , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/tratamento farmacológico , Vértebras Lombares , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Estudos Prospectivos , Radiculopatia/tratamento farmacológico , Esteroides/uso terapêutico , Resultado do Tratamento
2.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4175-4186, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467730

RESUMO

Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1ß(IL-1ß), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.


Assuntos
Neuralgia , Receptores de N-Metil-D-Aspartato , Animais , Sensibilização do Sistema Nervoso Central , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo
3.
Rev Neurol (Paris) ; 177(7): 834-837, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34332778

RESUMO

Neuropathic pain remains a significant unmet need. French recommendations were updated in 2020. The goal of this minireview is to provide an update on these published guidelines. Despite newer relevant studies, our proposed algorithm remains relevant. First-line treatments include serotonin-noradrenaline reuptake inhibitors (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants, topical lidocaine and transcutaneous electrical nerve stimulation being specifically proposed for focal peripheral neuropathic pain. Second-line treatments include pregabalin (such position being confirmed by newer studies), tramadol, combinations and psychotherapy as add on, high-concentration capsaicin patches and botulinum toxin A being proposed specifically for focal peripheral neuropathic pain. Third-line treatments include high-frequency repetitive transcranial magnetic stimulation of the motor cortex, spinal cord stimulation and strong opioids (in the lack of alternative). Disseminating these recommendations and ensuring that they are well accepted by French practitioners will be necessary to optimize neuropathic pain management in real life.


Assuntos
Antidepressivos , Neuralgia , Analgésicos Opioides , Humanos , Lidocaína , Neuralgia/diagnóstico , Neuralgia/tratamento farmacológico , Inibidores de Captação de Serotonina
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(7): 673-679, 2021 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34382582

RESUMO

OBJECTIVES: To explore the effect of intrathecal administration of exogenous noggin (NOG) on the pain behavior in the neuropathic pain (NP) rats through L5 spinal nerve ligation (SNL), and to examine the regulative role of NOG in astrocyte activation, inflammatory cytokines and downstream signals. METHODS: A total of 40 adult male Sprague Dawley (SD) rats were randomly divided into 3 groups: a control group (n=10), a SNL group (SNL+intrathecal injection of artificial cerebrospinal fluid, n=15), and a SNL+NOG group (SNL+intrathecal injection of recombinant NOG protein, n=15). Von-Frey filaments were used to test the changes of paw withdrawal threshold (PWT) at Day 1 before operation, and Day 1, Day 4, Day 7 and Day 14 after operation in each group. Immunofluorescence was used to observe the activation of astrocyte located in the dorsal horn of spinal cord in the 3 groups. Western blotting was conducted to detect the expression levels of glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), signal transducer and activator of transcription (STAT3) and phosphorylation STAT3 (p-STAT3). RESULTS: Compared with the control group, the PWT in the SNL group was markedly decreased at each time point, together with the increase in GFAP, IL-6 and the ratio of p-STAT3/STAT3 (all P<0.05). Meanwhile, compared with the SNL group, the PWT in the lumbar swelling of spinal cord in the SNL+NOG group was elevated at Day 4 and lasted to Day 14 (P<0.05), accompanied by the decrease in GFAP, IL-6 and the ratio of p-STAT3/STAT3 (all P<0.05). CONCLUSIONS: The intrathecal administration of NOG may alleviate NP in the SNL rats through inhibiting astrocyte activation and down-regulating the STAT3 signal pathway.


Assuntos
Neuralgia , Animais , Hiperalgesia , Injeções Espinhais , Masculino , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Medula Espinal , Corno Dorsal da Medula Espinal , Nervos Espinhais
5.
Mo Med ; 118(4): 327-333, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373667

RESUMO

Chronic neuropathic pain is currently a major health issue in U.S. complicated by the lack of non-opioid analgesic alternatives. Our investigations led to the discovery of major signaling pathways involved in the transition of acute to chronic neuropathic pain and the identification of several targets for therapeutic intervention. Our translational approach has facilitated the advancement of novel medicines for chronic neuropathic pain that are in advanced clinical development and clinical trials.


Assuntos
Dor Crônica , Neuralgia , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Humanos , Neuralgia/tratamento farmacológico
6.
ACS Chem Neurosci ; 12(16): 3073-3100, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34347423

RESUMO

Neuropathic pain resistance to pharmacotherapy has encouraged researchers to develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly recognized as promising drug targets for neuropathic pain (NP) associated with imbalances in inhibitory neurotransmission. In this context, we designed and synthesized new functionalized amino acids as inhibitors of GABA uptake and assessed their activities toward all four mouse GAT subtypes (mGAT1-4). According to the obtained results, compounds 2RS,4RS-39c (pIC50 (mGAT4) = 5.36), 50a (pIC50 (mGAT2) = 5.43), and 56a (with moderate subtype selectivity that favored mGAT4, pIC50 (mGAT4) = 5.04) were of particular interest and were therefore evaluated for their cytotoxic and hepatotoxic effects. In a set of in vivo experiments, both compounds 50a and 56a showed antinociceptive properties in three rodent models of NP, namely, chemotherapy-induced neuropathic pain models (the oxaliplatin model and the paclitaxel model) and the diabetic neuropathic pain model induced by streptozotocin; however compound 56a demonstrated predominant activity. Since impaired motor coordination is also observed in neuropathic pain conditions, we have pointed out that none of the test compounds induced motor deficits in the rotarod test.


Assuntos
Aminoácidos , Neuralgia , Analgésicos/farmacologia , Animais , Proteínas da Membrana Plasmática de Transporte de GABA , Camundongos , Neuralgia/tratamento farmacológico , Ácido gama-Aminobutírico
7.
Braz J Med Biol Res ; 54(10): e11207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34378677

RESUMO

Reactive oxygen species (ROS) are involved in neuropathic pain, a complicated condition after nerve tissue lesion. Vitamin D appears to improve symptoms of pain and exhibits antioxidant properties. We investigated the effects of oral administration of vitamin D3, the active form of vitamin D, on nociception, the sciatic functional index (SFI), and spinal cord pro-oxidant and antioxidant markers in rats with chronic constriction injury (CCI) of the sciatic nerve, a model of neuropathic pain. Vitamin D3 (500 IU/kg per day) attenuated the CCI-induced decrease in mechanical withdrawal threshold and thermal withdrawal latency (indicators of antinociception) and SFI. The vitamin prevented increased lipid hydroperoxide levels in injured sciatic nerve without change to total antioxidant capacity (TAC). Vitamin D3 prevented increased lipid hydroperoxide, superoxide anion generation (SAG), and hydrogen peroxide (H2O2) levels in the spinal cord, which were found in rats without treatment at 7 and 28 days post-CCI. A significant negative correlation was found between mechanical threshold and SAG and between mechanical threshold and H2O2 at day 7. Vitamin D3 also prevented decreased spinal cord total thiols content. There was an increase in TAC in the spinal cord of vitamin-treated CCI rats, compared to CCI rats without treatment only at 28 days. No significant changes were found in body weight and blood parameters of hepatic and renal function. These findings demonstrated, for first time, that vitamin D modulated pro-oxidant and antioxidant markers in the spinal cord. Since antinociception occurred in parallel with oxidative changes in the spinal cord, the oxidative changes may have contributed to vitamin D-induced antinociception.


Assuntos
Antioxidantes , Neuralgia , Animais , Peróxido de Hidrogênio , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Nociceptividade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Nervo Isquiático , Medula Espinal , Vitamina D , Vitaminas
8.
ACS Chem Neurosci ; 12(15): 2917-2928, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34264648

RESUMO

Neuropathic pain is a chronic condition with little specific treatment. Insulin-like growth factor 1 (IGF1), interacting with its receptor, IGF1R, serves a vital role in neuronal and brain functions such as autophagy and neuroinflammation. Yet, the function of spinal IGF1/IGF1R in neuropathic pain is unclear. Here, we examined whether and how spinal IGF1 signaling affects pain-like behaviors in mice with chronic constriction injury (CCI) of the sciatic nerve. To corroborate the role of IGF1, we injected intrathecally IGF1R inhibitor (nvp-aew541) or anti-IGF1 neutralizing antibodies. We found that IGF1 (derived from astrocytes) in the lumbar cord increased along with the neuropathic pain induced by CCI. IGF1R was predominantly expressed on neurons. IGF1R antagonism or IGF1 neutralization attenuated pain behaviors induced by CCI, relieved mTOR-related suppression of autophagy, and mitigated neuroinflammation in the spinal cord. These findings reveal that the abnormal IGF1/IGF1R signaling contributes to neuropathic pain by exacerbating autophagy dysfunction and neuroinflammation.


Assuntos
Fator de Crescimento Insulin-Like I , Neuralgia , Animais , Autofagia , Camundongos , Neuralgia/tratamento farmacológico , Transdução de Sinais , Sirolimo/farmacologia , Medula Espinal
9.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279369

RESUMO

In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.


Assuntos
Descoberta de Drogas/métodos , Neuralgia/tratamento farmacológico , Manejo da Dor/métodos , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canabinoides/química , Canabinoides/uso terapêutico , Humanos
10.
BMJ Case Rep ; 14(7)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34301704

RESUMO

A 61-year-old man with no significant medical history developed fever, headache and mild shortness of breath. He tested positive for SARS-CoV-2 and self-isolated at home, not requiring hospital admission. One week after testing positive, he developed acute severe burning pain affecting his whole body, subsequently localised distally in the limbs. There was no ataxia or autonomic failure. Neurological examination was unremarkable. Electrophysiological tests were unremarkable. Skin biopsy, lumbar puncture, enhanced MRI of the brachial plexus and MRI of the neuroaxis were normal. His pain was inadequately controlled with pregabalin but improved while on a weaning regimen of steroids. This case highlights the variety of possible symptoms associated with SARS-CoV-2 infection.


Assuntos
COVID-19 , Neuralgia , Febre , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/diagnóstico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , SARS-CoV-2
11.
Complement Ther Clin Pract ; 44: 101430, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34217127

RESUMO

OBJECTIVE: to determine massage lavender essential oil on neuropathic pain and quality of life in diabetic patients. METHODS: A randomized three-group control trial with the pre-post design was performed from 2019 to 2020 on 75 diabetic neuropathic patients. The patients were randomly allocated into aromatherapy (n = 26), placebo (n = 26), and control (n = 26) groups. Patients in the intervention group used 2.5 cc of 3% lavender oil on their feet as a gentle massage for 10 min every night before bedtime for a month. Data collected using the Visual analog scale (VAS), Douleur Neuropathic 4 (DN4) and Quality of Life Questionnaire (SF36). RESULTS: The mean difference of pain scores in short-term and long-term in the aromatherapy group was significantly reduced compared to the placebo and control groups (P < 0.001). In addition, after four weeks, a significant increase was found in the QoL domains in the aromatherapy group (P < 0.001). CONCLUSION: Aromatherapy massage with lavender oil helped reduce neuropathic pain two to four weeks after the intervention and improved the patients' QoL without causing any side effects. Thus, nurses are recommended to use it as a complementary method to reduce neuropathic pain and improve patients' QoL.


Assuntos
Aromaterapia , Diabetes Mellitus , Neuropatias Diabéticas , Lavandula , Neuralgia , Óleos Voláteis , Humanos , Massagem , Neuralgia/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Óleos Vegetais/uso terapêutico , Qualidade de Vida
12.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202590

RESUMO

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone's antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone's action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.


Assuntos
Neuralgia , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
13.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203854

RESUMO

This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.


Assuntos
Dor Facial/tratamento farmacológico , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Dor Facial/complicações , Dor Facial/patologia , Humanos , Neuralgia/complicações , Neuralgia/patologia , Gânglio Trigeminal/patologia
14.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208700

RESUMO

Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin's effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/77 receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system.


Assuntos
Chalconas/farmacologia , Neuralgia/tratamento farmacológico , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Chalconas/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos
15.
Ann Palliat Med ; 10(6): 6873-6882, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237985

RESUMO

BACKGROUND: microRNA-138 (miRNA-138) might have a promising therapeutic effect in the Neuropathic pain (NP). We aim to investigate the effects of miRNA-138 on NP and explore its underlying mechanism. METHODS: we performed a partial sciatic nerve ligation (pSNL) surgery in rats to induce pain and inflammation. Rats were administrated by intrathecal injection of lentiviral (LV)-mediated miRNA-138. Mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were measured to evaluate the pain degree. The expression levels of miRNA-138, toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-α), interleukin-ß (IL-ß), and IL-6 in the spinal cord were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting was performed to measure the expressions of macrophage inflammatory protein-1 alpha (MIP-1α) and C-C chemokine receptor type 1 (CCR1). Next, the mechanism of miRNA-138 on NP was investigated by intrathecal injection of CCR1 inhibitor or MIP-1α neutralizing antibody. Inflammatory factors, MWT, and PWTL were also measured on day 7. RESULTS: Intrathecal injection of miRNA138 significantly reduced MWT and PWTL. qRT-PCR showed that miRNA138 mimic group significantly reduced the level of TLR4, TNF-α, Il-ß, and IL-6 on day 7. Western blotting showed that the protein expressions of MIP-1α and CCR1 in pSNL + miRNA138 mimic group were significantly decreased on day 7. In addition, the miRNA138 inhibitor inversely increased MWT, PWTL and inflammatory cytokines. Further, the effect of miRNA138 inhibitor all were significantly reversed by CCR1 inhibitor or MIP-1α neutralizing antibody. CONCLUSIONS: Intrathecal injection of miRNA-138 can remarkably alleviate NP in rats with a pSNL, which may be achieved by suppressing the TLR4 and MIP-1α/CCR1 signaling pathways.


Assuntos
MicroRNAs , Neuralgia , Animais , Injeções Espinhais , MicroRNAs/genética , Neuralgia/tratamento farmacológico , Ratos , Nervo Isquiático , Medula Espinal
16.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199936

RESUMO

Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis of neuropathic pain. Withametelin (WMT), a potential Phytosteroid isolated from datura innoxa, exhibits remarkable neuroprotective properties. The present investigation was designed to explore the effect of withametelin on VCR-induced neuropathic pain and its underlying molecular mechanism. Initially, the neuroprotective potential of WMT was confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. To develop potential candidates for neuropathic pain treatment, a VCR-induced neuropathic pain model was established. Vincristine (75 µg/kg) was administered intraperitoneally (i.p.) for 10 consecutive days (day 1-10) for the induction of neuropathic pain. Gabapentin (GBP) (60 mg/kg, i.p.) and withametelin (0.1 and 1 mg/kg i.p.) treatments were given after the completion of VCR injection on the 11th day up to 21 days. The results revealed that WMT significantly reduced VCR-induced pain hypersensitivity, including mechanical allodynia, cold allodynia, and thermal hyperalgesia. It reversed the VCR-induced histopathological changes in the brain, spinal cord, and sciatic nerve. It inhibited VCR-induced changes in the biochemical composition of the myelin sheath of the sciatic nerve. It markedly downregulated the expression levels of TRPV1 (transient receptor potential vanilloid 1); TRPM8 (Transient receptor potential melastatin 8); and P2Y nociceptors and MAPKs signaling, including ERK (Extracellular Signal-Regulated Kinase), JNK (c-Jun N-terminal kinase), and p-38 in the spinal cord. It suppressed apoptosis by regulating Bax (Bcl2-associated X-protein), Bcl-2 (B-cell-lymphoma-2), and Caspase-3 expression. It considerably attenuated inflammatory cytokines, oxidative stress, and genotoxicity. This study suggests that WMT treatment suppressed vincristine-induced neuropathic pain by targeting the TRPV1/TRPM8/P2Y nociceptors and MAPK signaling.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Nociceptores/efeitos dos fármacos , Fitosteróis/farmacologia , Receptores Purinérgicos P2Y/química , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPV/antagonistas & inibidores , Vincristina/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Ratos
17.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208184

RESUMO

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.


Assuntos
Cloridrato de Duloxetina/farmacologia , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Neuralgia/tratamento farmacológico , Oxaliplatina/toxicidade , Limiar da Dor/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Antibacterianos/farmacologia , Antineoplásicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Combinação de Medicamentos , Masculino , Camundongos , Microglia/fisiologia , Neuralgia/induzido quimicamente , Neuralgia/patologia
18.
BMJ Open ; 11(6): e047785, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193496

RESUMO

INTRODUCTION: Gabapentin (Neurontin) is prescribed widely for conditions for which it has not been approved by regulators, including certain neuropathic pain conditions. There is limited evidence that gabapentin is safe and effective for the treatment of neuropathic pain. Published trial reports, and systematic reviews based on published trial reports, mislead patients and providers because information about gabapentin's harms has been published only partly. We confirmed that trials conducted by the drug developer have been abandoned, and we plan to conduct a restoration with support from the Restoring Invisible and Abandoned Trials Support Centre (https://restoringtrials.org/). METHODS AND ANALYSIS: In this study, we will analyse and report the harms that were observed in six trials of gabapentin, which have not been reported publicly (eg, in journal articles). We will use clinical study reports and individual participant data to identify and report the harms observed in each individual trial and to summarise the harms observed across all six trials. We will report all adverse events observed in the included trials by sharing deidentified data and summary tables on the Open Science Framework (https://osf.io/w8puv/). Additionally, we will produce a summary report that describes differences between the randomised groups in each trial and across trials for prespecified harms outcomes. ETHICS AND DISSEMINATION: We will use secondary data. This study was determined to be exempt from Institutional Review Board (IRB) review (protocol #1910607198).


Assuntos
Ácidos Cicloexanocarboxílicos , Neuralgia , Aminas/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Gabapentina/uso terapêutico , Humanos , Neuralgia/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico
19.
Eur J Med Chem ; 222: 113581, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102377

RESUMO

A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC50 as low as 37 nM) and B. anthracis edema factor (IC50 as low as 235 nM) in enzymatic assays. Furthermore, several ANPs were found to be selective mammalian AC1 inhibitors in HEK293 cell-based assays (although with some associated cytotoxicity) and one compound exhibited selective inhibition of mammalian AC2 (only 12% of remaining adenylate cyclase activity) but no observed cytotoxicity. The mammalian AC1 inhibitors may represent potential leads in development of agents for treatment of human inflammatory and neuropathic pain.


Assuntos
Toxina Adenilato Ciclase/antagonistas & inibidores , Inibidores de Adenilil Ciclases/farmacologia , Antibacterianos/farmacologia , Organofosfonatos/farmacologia , Tiazóis/farmacologia , Toxina Adenilato Ciclase/metabolismo , Inibidores de Adenilil Ciclases/síntese química , Inibidores de Adenilil Ciclases/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Bacillus anthracis/efeitos dos fármacos , Bordetella pertussis/efeitos dos fármacos , Bordetella pertussis/enzimologia , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuralgia/tratamento farmacológico , Organofosfonatos/química , Relação Estrutura-Atividade , Tiazóis/química
20.
J Med Chem ; 64(13): 9271-9278, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142837

RESUMO

Venom-derived compounds are of broad interest in neuropharmacology and drug development. α-Conotoxins are small disulfide-containing peptides from Conus snails that target nicotinic acetylcholine receptors (nAChRs) and are in clinical development for non-opioid-based treatment of intractable pain. Although refined by evolution for interaction with target prey receptors, enhancements of pharmacological properties are needed for use in mammalian systems. Therefore, we synthesized analogues of α-conotoxin RgIA using a combination of selective penicillamine substitutions together with natural and non-natural amino acid replacements. This approach resulted in a peptide with 9000-fold increased potency on the human α9α10 nAChR and improved resistance to disulfide shuffling compared to the native peptide. The lead analogue, RgIA-5474, potently blocked α9α10 nAChRs, but not opioid- or other pain-related targets. In addition, RgIA-5474 effectively reversed chemotherapy-induced neuropathic pain.


Assuntos
Analgésicos/farmacologia , Conotoxinas/farmacologia , Desenvolvimento de Medicamentos , Neuralgia/tratamento farmacológico , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Analgésicos/síntese química , Analgésicos/química , Conotoxinas/síntese química , Conotoxinas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Neuralgia/metabolismo , Antagonistas Nicotínicos/síntese química , Antagonistas Nicotínicos/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...