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1.
Pain Res Manag ; 2021: 6655211, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33680225

RESUMO

Objectives: To provide a comprehensive review on the global scientific research status of comorbid pain and inflammation from 1981 to 2019 and capture its subsequent development trends. Data Sources. The primary database chosen to collect publications on comorbid pain and inflammation research from 1981 to 2019 was the Web of Science (WOS). Core of the search strategy was the key word "pain" and the key word "inflammation" in the medical subject headings' major field. Study Selection. All articles retrieved were included in the bibliometric analysis. Data Extraction. We used CiteSpace to analyze publication outputs, subject categories, distribution by country/institution/journal, and other types of information. Then, knowledge base, hot issues, and future development directions were explained. Data Synthesis. A total of 2887 papers met the inclusion criteria in our research. Linear regression analysis results showed that the publications of studies of comorbid pain and inflammation significantly increased (P < 0.001) and have grown about 192 times in 40 years. The countries with the most outputs were the USA (886 publications), China (375 publications), and England (236 publications). Besides, Harvard University was the most prolific institution with 730 publications and 6646 citations. In accordance with the subject categories of WOS, neurosciences (31.832%), pharmacology/pharmacy (18.427%), and clinical neurology (15.206%) were the main research areas of these 2887 papers. Conclusions: The current study reveals that research on comorbid pain and inflammation has gradually become more extensive worldwide since 1981, and neuropathic pain was the most popular study type. Most of our research output in this field came from countries in Europe and North America, although some Asian countries showed promising performance.


Assuntos
Bibliometria , Inflamação/complicações , Neuralgia/complicações , Comorbidade , Bases de Dados Factuais , Humanos , Projetos de Pesquisa
2.
Life Sci ; 273: 119308, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667520

RESUMO

AIMS: Brain-derived neurotrophic factor (BDNF) is vital in the pathogenesis of mechanical allodynia with a paucity of reports available regarding diabetic neuropathy pain (DNP). Herein we identified the involvement of BDNF in driving mechanical allodynia in DNP rats via the activation of transient receptor potential canonical 6 (TRPC6) channel. MATERIALS AND METHODS: The DNP rat model was established via streptozotocin (STZ) injection, and allodynia was assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The expression profiles of BDNF and TRPC6 in dorsal root ganglia (DRG) and spinal cord were illustrated by immunofluorescence and Western blotting. Intrathecal administration of K252a or TrkB-Fc was performed to inhibit BNDF/TrkB expression, and respective injection of GsMTX-4, BTP2 and TRPC6 antisense oligodeoxynucleotides (TRPC6-AS) was likewise conducted to inhibit TRPC6 expression in DNP rats. Calcium influx in DRG was monitored by calcium imaging. KEY FINDINGS: The time-dependent increase of BDNF and TRPC6 expression in DRG and spinal cord was observed since the 7th post-STZ day, correlated with the development of mechanical allodynia in DNP rats. Intrathecal administration of K252a, TrkB-Fc, GsMTX-4 and BTP2 prevented mechanical allodynia in DNP rats. Pre-treatment of TRPC6-AS reversed the BDNF-induced pain-like responses in DNP rats rather than the naïve rats. In addition, the TRPC6-AS reversed BDNF-induced increase of calcium influx in DRG neurons in DNP rats. SIGNIFICANCE: The intrathecal inhibition of TRPC6 alleviated the BDNF-induced mechanical allodynia in DNP rat model. This finding may validate the application of TRPC6 antagonists as interesting strategy for DNP management.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/complicações , Modelos Animais de Doenças , Hiperalgesia/etiologia , Neuralgia/complicações , Canais de Cátion TRPC/metabolismo , Animais , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC/genética
3.
BMJ Case Rep ; 14(3)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33766961

RESUMO

COVID-19 affects a wide spectrum of organ systems. We report a 52-year-old man with hypertension and newly diagnosed diabetes mellitus who presented with hypoxic respiratory failure due to COVID-19 and developed severe brachial plexopathy. He was not treated with prone positioning respiratory therapy. Associated with the flaccid, painfully numb left upper extremity was a livedoid, purpuric rash on his left hand and forearm consistent with COVID-19-induced microangiopathy. Neuroimaging and electrophysiological data were consistent with near diffuse left brachial plexitis with selective sparing of axillary, suprascapular and pectoral fascicles. Given his microangiopathic rash, elevated D-dimers and paucifascicular plexopathy, we postulate a patchy microvascular thrombotic plexopathy. Providers should be aware of this significant and potentially under-recognised neurologic complication of COVID-19.


Assuntos
Neuropatias do Plexo Braquial/etiologia , COVID-19/complicações , Braço/patologia , Neuropatias do Plexo Braquial/diagnóstico , COVID-19/diagnóstico , Diabetes Mellitus , Exantema/complicações , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Hipertensão/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuralgia/complicações , Posicionamento do Paciente/efeitos adversos , Insuficiência Respiratória/etiologia , SARS-CoV-2/isolamento & purificação
4.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33404738

RESUMO

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Assuntos
Analgésicos/uso terapêutico , Curcumina/uso terapêutico , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamento farmacológico , Memória Espacial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Constrição , Curcumina/administração & dosagem , Curcumina/química , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neuralgia/complicações , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões
5.
Neurologia ; 35(9): 628-632, 2020.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32896463

RESUMO

INTRODUCTION: In recent months, doubts have arisen among patients, general practitioners, and neurologists as to whether some drugs commonly used in patients with headaches and neuralgia may favour or complicate the disease caused by SARS-CoV-2. MATERIAL AND METHODS: We collected information on the opinions of scientific societies and medicines agencies (American, European, and Spanish) to clarify doubts regarding the use of drugs such as lisinopril, candesartan, ibuprofen, corticosteroids, carbamazepine, and monoclonal antibodies targeting the calcitonin gene-related peptide in the context of the COVID-19 pandemic. RESULTS: We make recommendations about the use of standard headache treatments in the context of the COVID-19 pandemic, based on the current scientific evidence. CONCLUSIONS: At present, there is no robust scientific argument to formally contraindicate any of the standard treatments employed for headaches and neuralgias.


Assuntos
Analgésicos/efeitos adversos , Infecções por Coronavirus/complicações , Cefaleia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Pneumonia Viral/complicações , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Betacoronavirus , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Suscetibilidade a Doenças/induzido quimicamente , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Cefaleia/complicações , Cefaleia/prevenção & controle , Humanos , Ibuprofeno/efeitos adversos , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Lisinopril/efeitos adversos , Lisinopril/uso terapêutico , Neuralgia/complicações , Pandemias , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Receptores Virais/biossíntese , Receptores Virais/genética , Fatores de Risco , Tetrazóis/efeitos adversos , Tetrazóis/uso terapêutico
6.
Neurology ; 95(7): e805-e814, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32591473

RESUMO

OBJECTIVE: To determine whether cervical cord levels of metabolites are associated with pain sensation after spinal cord injury (SCI) by performing magnetic resonance spectroscopy in patients with SCI with and without neuropathic pain (NP). METHODS: Cervical cord single-voxel spectroscopic data of 24 patients with SCI (14 with NP, 10 pain-free) and 21 healthy controls were acquired at C2/3 to investigate metabolite ratios associated with neuroinflammation (choline-containing compounds to myoinositol [tCho/mI]) and neurodegeneration (total N-acetylaspartate to myo-inositol [tNAA/mI]). NP levels were measured, and Spearman correlation tests assessed associations between metabolite levels, cord atrophy, and pinprick score. RESULTS: In patients with NP, tCho/mI levels were increased (p = 0.024) compared to pain-free patients and negatively related to cord atrophy (p = 0.006, r = 0.714). Better pinprick score was associated with higher tCho/mI levels (p = 0.032, r = 0.574). In pain-free patients, tCho/mI levels were not related to cord atrophy (p = 0.881, r = 0.055) or pinprick score (p = 0.676, r = 0.152). tNAA/mI levels were similar in both patient groups (p = 0.396) and were not associated with pinprick score in patients with NP (p = 0.405, r = 0.242) and pain-free patients (p = 0.117, r = 0.527). CONCLUSIONS: Neuroinflammatory metabolite levels (i.e., tCho/mI) were elevated in patients with NP, its magnitude being associated with less cord atrophy and greater pain sensation (e.g., pinprick score). This suggests that patients with NP have more residual spinal tissue and greater metabolite turnover than pain-free patients. Neurodegenerative metabolite levels (i.e., tNAA/mI) were associated with greater cord atrophy but unrelated to NP. Identifying the metabolic NP signature provides new NP treatment targets and could improve patient stratification in interventional trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that levels of magnetic resonance spectroscopy-identified metabolites of neuroinflammation were elevated in patients with SCI with NP compared to those without NP.


Assuntos
Medula Cervical/metabolismo , Inflamação/metabolismo , Neuralgia/metabolismo , Traumatismos da Medula Espinal/metabolismo , Adulto , Atrofia/patologia , Medula Cervical/patologia , Colina/metabolismo , Creatina/metabolismo , Feminino , Humanos , Inflamação/complicações , Inositol/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuralgia/complicações , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia
7.
Internist (Berl) ; 61(6): 617-620, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32342114

RESUMO

The case of a 72-year-old female patient with exanthem and concomitant neuropathy of the instep of the foot and progressive ipsilateral lower leg pain is reported. Sonographically, a superficial vein thrombosis with extension into the deep venous system originating from the exanthem was observed. On the basis of the clinical picture as well as the serological and electrophysiological findings, a rare diagnosis of acrodermatitis chronica atrophicans with peripheral neuropathy was made, which could significantly promote the local development of venous thrombosis.


Assuntos
Acrodermatite/diagnóstico , Exantema/complicações , Doença de Lyme/complicações , Trombose Venosa/complicações , Acrodermatite/etiologia , Idoso , Feminino , Humanos , Hiperalgesia , Doença de Lyme/diagnóstico , Neuralgia/complicações , Dor , Tromboflebite/diagnóstico
8.
Arch Biochem Biophys ; 685: 108330, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32156533

RESUMO

Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.


Assuntos
Neuropatias Diabéticas/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Animais , Linhagem Celular , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Janus Quinase 2/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/complicações , Ratos Sprague-Dawley , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/fisiologia , Estreptozocina
10.
J Steroid Biochem Mol Biol ; 196: 105488, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31589918

RESUMO

Vitamin D replacement helps in pain reduction in patients with chronic widespread pain (CWP). But the current literature lack studies that investigate its mechanism. Cutaneous silent period (CSP) is the electrophysiologic analog of the spinal inhibitory pathways and an objective method to document their involvement. This study aims to show if vitamin D replacement has an effect on the spinal inhibitory pathways through CSP parameters. Female patients who have CWP with vitamin D deficiency were included. Patients received an 8-week replacement therapy of vitamin D. Patients' pain were evaluated using the visual analog scale (VAS) and Leeds assessment of neuropathic symptoms and signs pain scale (LANSS). Quality of life with Nottingham Health Profile (NHP) and CSP parameters were also recorded before and after treatment. A total of 51 patients were included in the final analyses. The mean age of the patients was 44.3 ± 12.7 (minimum 18-maximum 65). Mean symptom duration was 13.1 ± 6.7 (minimum3-maximum 24) months. Patients' mean BMI was 21.6 ± 3.9 (minimum 18.0 maximum 29.1). Patients' median VAS and LANSS scores decreased significantly (p < 0.01) and NHP scores improved significantly in all subsets (p < 0.01). Vitamin D replacement did not significantly change CSP latency and duration (p = 0.06 and p = 0.12).Vitamin D replacement does not seem to work via modifying the spinal inhibitory pathways that are involved in the formation of the cutaneous silent period. This is the first study to objectively investigate the effect of vitamin D replacement on central sensitization mechanisms.


Assuntos
Dor Crônica/tratamento farmacológico , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Nervos Espinhais/efeitos dos fármacos , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Adolescente , Adulto , Idoso , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Dor Crônica/sangue , Dor Crônica/complicações , Feminino , Terapia de Reposição Hormonal , Humanos , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Manejo da Dor/métodos , Medição da Dor , Pele/efeitos dos fármacos , Pele/inervação , Pele/fisiopatologia , Nervos Espinhais/fisiopatologia , Vitamina D/farmacologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Adulto Jovem
12.
Biochem Biophys Res Commun ; 522(2): 463-470, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31780260

RESUMO

Long-term neuropathic pain can lead to anxiety, depression, and other issues, which seriously affect patients' quality of life. For this reason, it is important to find effective treatments. Studies have shown that glial cell-derived neurotrophic factor (GDNF) can relieve neuropathic pain. However, its mechanism of action is unknown. Our previous study of GDNF suggested that the N-cadherin-ß-catenin transmembrane signaling system might play a role in GDNF transmembrane signaling. Based on this, the current study aimed to produce a neuropathic pain model to confirm the activation of the N-cadherin-ß-catenin signaling system in the spinal dorsal horn under pain conditions and to study the impact of GDNF intrathecal injection on central sensitization of dorsal horn neurons. The results showed that N-cadherin expression, as well as the expression of membrane-associated ß-catenin, was reduced in the dorsal horn of the spinal cord in the chronic pain model. Intrathecal injection of GDNF could reactivate the N-cadherin-ß-catenin system, improve central sensitization, and relieve pain. Knockdown of N-cadherin or ß-catenin could significantly reduce the analgesic effect of GDNF. These results provide clear experimental evidence that the N-cadherin-ß-catenin signaling system participates in the analgesic effect of GDNF in neuropathic pain and help identify transmembrane and intracellular signal transduction mechanisms associated with GDNF's analgesic effects.


Assuntos
Analgésicos/uso terapêutico , Caderinas/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/uso terapêutico , Neuralgia/tratamento farmacológico , Transdução de Sinais , beta Catenina/metabolismo , Analgésicos/farmacologia , Animais , Constrição Patológica , Regulação para Baixo/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/complicações , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/metabolismo
13.
Malawi Med J ; 32(3): 132-138, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33488984

RESUMO

Background: Central post-stroke pain (CPSP) is a poorly diagnosed chronic pain. It is under-treated and usually mismanaged. Objective: To establish the prevalence of CPSP and its management in stroke clinics at a tertiary hospital. Methods: This was a cross-sectional design with stroke patients and health professionals from the stroke clinic at the tertiary hospital in Zimbabwe. Results: Out of 166 stroke survivors, 8% had CPSP. Younger age (<60 years) was significantly associated with CPSP (P<0.003). Pain characteristics of CPSP were hyperaesthesia (10, 71%), electric shocks (9, 64%), temperature allodynia (9, 64%) and allodynia (12, 86%). Ten health professionals participated in the study: one (10%) reported using Douleur Neuropathique 4 (to diagnose neuropathic pain) and two (20%) reported using sensory tests. Four patients (44%) were on paracetamol (acetaminophen) and on weak opiates such as codeine. None of the patients were on anticonvulsants or antidepressants. Two medical doctors (50%) used weak opiates as second-line management. Five patients (36%) reported receiving a combination of massage, stretching, general exercise and moist heat or cryotherapy. Conclusion: The prevalence of CPSP in the study group is within international range. There is a need for appropriate management and use of tests and outcome measures for diagnosis of CPSP.


Assuntos
Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/epidemiologia , Dor/etiologia , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Medição da Dor , Prevalência , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Reabilitação do Acidente Vascular Cerebral , Sobreviventes , Resultado do Tratamento , Zimbábue/epidemiologia
14.
Sci Rep ; 9(1): 19454, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857688

RESUMO

Although the tricyclic antidepressant amitriptyline (ATL) is widely used in the clinic, the mechanism underlying its high therapeutic efficacy against neuropathic pain remains unclear. NMDA receptors (NMDARs) represent a target for ATL and are involved in sensitization of neuropathic pain. Here we describe two actions of ATL on NMDARs: 1) enhancement of Ca2+-dependent desensitization and 2) trapping channel block. Inhibition of NMDARs by ATL was found to be dependent upon external Ca2+ concentration ([Ca2+]) in a voltage-independent manner, with an IC50 of 0.72 µM in 4 mM [Ca2+]. The ATL IC50 value increased exponentially with decreasing [Ca2+], with an e-fold change observed per 0.69 mM decrease in [Ca2+]. Loading neurons with BAPTA abolished Ca2+-dependent inhibition, suggesting that Ca2+ affects NMDARs from the cytosol. Since there is one known Ca2+-dependent process in gating of NMDARs, we conclude that ATL most likely promotes Ca2+-dependent desensitization. We also found ATL to be a trapping open-channel blocker of NMDARs with an IC50 of 220 µM at 0 mV. An e-fold change in ATL IC50 was observed to occur with a voltage shift of 50 mV in 0.25 mM [Ca2+]. Thus, we disclose here a robust dependence of ATL potency on extracellular [Ca2+], and demonstrate that ATL bound in the NMDAR pore can be trapped by closure of the channel.


Assuntos
Amitriptilina/farmacologia , Antidepressivos Tricíclicos/farmacologia , Cálcio/metabolismo , Neurônios/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Amitriptilina/uso terapêutico , Animais , Antidepressivos Tricíclicos/uso terapêutico , Células Cultivadas , Córtex Cerebral/citologia , Dor Crônica/complicações , Dor Crônica/dietoterapia , Dor Crônica/psicologia , Citosol/efeitos dos fármacos , Citosol/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/psicologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/psicologia , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Cultura Primária de Células , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo
15.
J Pak Med Assoc ; 69(12): 1907-1909, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31853127

RESUMO

Chronic neuropathic pain is secondary to other musculoskeletal pain. The following study aimed to determine the frequency of chronic neuropathic pain and its association with depression in the elderly. A crosssectional survey was carried out on 306 participants at the National Institute of Rehabilitation Medicine (NIRM) Hospital, in Islamabad over a period of 6 months from September 2017 to February 2018. Population of ? 60 years of age with chronic pain for >6 months were included, whereas patients with malignant origin of pain, intermittent pain and psychological pain were excluded. Data was collected by using DN4 and DASS Questionnaires were analysed by SPSS. Of the 271 participants with the mean age of 66 } 5.8 years, 216 (79.9%) were male. The frequency of patients suffering from chronic neuropathic pain was 53.9%. Data showed among the elderly a strong association of chronic neuropathic pain with anxiety and stress (P<0.05), but not with depression (P>0.05).


Assuntos
Dor Crônica , Depressão , Neuralgia , Idoso , Ansiedade , Dor Crônica/complicações , Dor Crônica/epidemiologia , Estudos Transversais , Depressão/complicações , Depressão/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/complicações , Neuralgia/epidemiologia , Paquistão/epidemiologia , Estresse Psicológico
16.
BMJ Open Diabetes Res Care ; 7(1): e000752, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803481

RESUMO

Introduction: The determinants and mechanisms contributing to diabetic sensorimotor polyneuropathy (DSPN) remain unclear. Since neuroinflammation and altered nerve regeneration have been implicated in the pathogenesis of both DSPN and neuropathic pain, we hypothesized that the corresponding biomarkers could be associated with DSPN in general and could have the potential to discriminate between the painful and painless DSPN entities. Methods: In a cross-sectional study using multimarker proximity extension assay technology we assessed 71 serum biomarkers including cytokines, chemokines, growth factors, receptors, and others in patients with type 2 diabetes with DSPN (DSPN+) (n=304) or without DSPN (DSPN-) (n=158) and persons with normal glucose tolerance (NGT) without polyneuropathy (n=354). Results: After adjustment for multiple testing and sex, age, body mass index, HbA1c, and smoking, the serum levels of 17 biomarkers (four cytokines, five chemokines, four growth factors, two receptors, two miscellaneous) were lower in DSPN+ than in DSPN- and NGT. In DSPN+, six of these biomarkers were associated with peripheral nerve function. The concentrations of 15 other biomarkers differed between NGT and both DSPN+ and DSPN-, but not between DSPN+ and DSPN-. No differences in biomarker levels were found between patients with painful (n=164) and painless DSPN (n=140). Conclusions: Deficits in systemic cytokines, chemokines, and growth factors promoting nerve regeneration in patients with type 2 diabetes are linked to polyneuropathy in general but not specifically to the painful or painless entity. Trial registration number: NCT02243475.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Regeneração Nervosa , Inflamação Neurogênica/sangue , Polineuropatias/sangue , Idoso , Estudos de Casos e Controles , Quimiocinas/sangue , Estudos Transversais , Citocinas/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Pessoa de Meia-Idade , Regeneração Nervosa/efeitos dos fármacos , Neuralgia/sangue , Neuralgia/complicações , Polineuropatias/complicações
17.
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
18.
Biomed Res Int ; 2019: 3467121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737660

RESUMO

Spinal cord injury (SCI) is a highly debilitating disease and is increasingly being recognized as an important global health priority. However, the mechanisms underlying SCI have not yet been fully elucidated, and effective therapies for SCI are lacking. Long noncoding RNAs (lncRNAs), which form a major class of noncoding RNAs, have emerged as novel targets for regulating several physiological functions and mediating numerous neurological diseases. Notably, gene expression profile analyses have demonstrated aberrant changes in lncRNA expression in rats or mice after traumatic or nontraumatic SCI. LncRNAs have been shown to be associated with multiple pathophysiological processes following SCI including inflammation, neural apoptosis, and oxidative stress. They also play a crucial role in the complications associated with SCI, such as neuropathic pain. At the same time, some lncRNAs have been found to be therapeutic targets for neural stem cell transplantation and hydrogen sulfide treatment aimed at alleviating SCI. Therefore, lncRNAs could be promising biomarkers for the diagnosis, treatment, and prognosis of SCI. However, further researches are required to clarify the therapeutic effects of lncRNAs on SCI and the mechanisms underlying these effects. In this study, we reviewed the current progress of the studies on the involvement of lncRNAs in SCI, with the aim of drawing attention towards their roles in this debilitating condition.


Assuntos
Inflamação/genética , Neuralgia/genética , RNA Longo não Codificante/genética , Traumatismos da Medula Espinal/genética , Apoptose/genética , Regulação da Expressão Gênica , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Neuralgia/complicações , Neuralgia/fisiopatologia , Estresse Oxidativo/genética , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Transcriptoma
19.
Rev Med Suisse ; 15(670): 2039-2043, 2019 Nov 06.
Artigo em Francês | MEDLINE | ID: mdl-31696679

RESUMO

Polyneuropathies occur frequently (> 30 %) among elderly people and can result in increased morbidity and impaired quality of life. Diabetes, chronic kidney disease, water-soluble vitamins deficiencies, drugs and alcohol side effects are the major etiologies after a systematic assessment. Neurologist referral is indicated when the diagnosis remains unclear and therapeutic options exist. Treatment strategies focus on reversal of underlying conditions, prevention, stabilization and alleviation of symptoms, especially neuropathic pain and maintain the best autonomy.


Assuntos
Polineuropatias/terapia , Idoso , Humanos , Neuralgia/complicações , Polineuropatias/complicações , Qualidade de Vida , Insuficiência Renal Crônica/complicações
20.
Sci Rep ; 9(1): 15656, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666661

RESUMO

Neuropathic pain (NeP) is commonly encountered in patients with diseases associated with spinal cord damage (e.g., spinal cord injury (SCI) and compressive myelopathy). Recent studies described persistent glial activation and neuronal hyperactivity in SCI, but the pathomechanisms of NeP in chronic compression of the spinal cord remains elusive. The purpose of the present study was to determine the roles of microglia and infiltrating macrophages in NeP. The study was conducted in chimeric spinal hyperostotic mice (ttw/ttw), characterized by chronic progressive compression of the spinal cord as a suitable model of human compressive myelopathy. The severity of spinal cord compression correlated with proportion of activated microglia and hematogenous macrophages. Spinal cord compression was associated with overexpression of mitogen-activated protein kinases (MAPKs) in infiltrating macrophages and reversible blood-spinal cord barrier (BSCB) disruption in the dorsal horns. Our results suggested that chronic neuropathic pain in long-term spinal cord compression correlates with infiltrating macrophages, activated microglial cells and the associated damage of BSCB, together with overexpression of p-38 MAPK and p-ERK1/2 in these cells. Our findings are potentially useful for the design of new therapies to alleviate chronic neuropathic pain associated with compressive myelopathy.


Assuntos
Progressão da Doença , Macrófagos/citologia , Microglia/patologia , Neuralgia/complicações , Neuralgia/patologia , Compressão da Medula Espinal/complicações , Animais , Hiperalgesia/complicações , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo
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