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1.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800907

RESUMO

BACKGROUND: In the present study, we examined superoxide-mediated excitatory nociceptive transmission on at-level neuropathic pain following spinal thoracic 10 contusion injury (SCI) in male Sprague Dawley rats. METHODS: Mechanical sensitivity at body trunk, neuronal firing activity, and expression of superoxide marker/ionotropic glutamate receptors (iGluRs)/CamKII were measured in the T7/8 dorsal horn, respectively. RESULTS: Topical treatment of superoxide donor t-BOOH (0.4 mg/kg) increased neuronal firing rates and pCamKII expression in the naïve group, whereas superoxide scavenger Tempol (1 mg/kg) and non-specific ROS scavenger PBN (3 mg/kg) decreased firing rates in the SCI group (* p < 0.05). SCI showed increases of iGluRs-mediated neuronal firing rates and pCamKII expression (* p < 0.05); however, t-BOOH treatment did not show significant changes in the naïve group. The mechanical sensitivity at the body trunk in the SCI group (6.2 ± 0.5) was attenuated by CamKII inhibitor KN-93 (50 µg, 3.9 ± 0.4) or Tempol (1 mg, 4 ± 0.4) treatment (* p < 0.05). In addition, the level of superoxide marker Dhet showed significant increase in SCI rats compared to the sham group (11.7 ± 1.7 vs. 6.6 ± 1.5, * p < 0.05). CONCLUSIONS: Superoxide and the pCamKII pathway contribute to chronic at-level neuropathic pain without involvement of iGluRs following SCI.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Hiperalgesia/tratamento farmacológico , Proteínas do Tecido Nervoso/fisiologia , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Superóxidos/metabolismo , Animais , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Contusões/fisiopatologia , Óxidos N-Cíclicos/farmacologia , Depuradores de Radicais Livres/uso terapêutico , Hiperalgesia/etiologia , Masculino , Modelos Animais , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neuralgia/etiologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Marcadores de Spin , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia , Sulfonamidas/farmacologia , Transmissão Sináptica
2.
Life Sci ; 276: 119469, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33811892

RESUMO

AIMS: Breast cancer-induced chronic pain is usually treated with opioids, but these compounds cause various adverse effects. Transient receptor potential ankyrin 1 (TRPA1) is involved in cancer pain; also, endogenous TRPA1 agonists are associated with cancer pain development. The aim of this study was to observe the antinociceptive effect of a repeated-dose TRPA1 antagonist administration and the production of endogenous TRPA1 agonists and TRPA1 expression in bone tissue in a model of breast cancer pain in mice. Second, we used a sequence reading archive (SRA) strategy to observe the presence of this channel in the mouse bone and in mouse bone cell lines. MAIN METHODS: We used BALB/c mice for experiments. The animals were subjected to the tumor cell inoculation (4 T1 strain). HC-030031 (a TRPA1 antagonist) treatment was done from day 11 to day 20 after tumor inoculation. TRPA1 expression and biochemical tests of oxidative stress were performed in the bone of mice (femur). SRA strategy was used to detect the TRPA1 presence. KEY FINDINGS: Repeated treatment with the TRPA1 antagonist produced an antinociceptive effect. There was an increase in hydrogen peroxide levels, NADPH oxidase and superoxide dismutase activities, but the expression of TRPA1 in the bone tissue was not altered. SRA did not show TRPA1 residual transcription in the osteoblast and osteoclast cell lines, as well as for mice cranial tissue and in mouse osteoclast precursors. SIGNIFICANCE: The TRPA1 receptor is a potential target for the development of new painkillers for the treatment of bone cancer pain.


Assuntos
Acetanilidas/farmacologia , Osso e Ossos/efeitos dos fármacos , Dor do Câncer/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neoplasias Mamárias Animais/complicações , Nociceptividade/efeitos dos fármacos , Purinas/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores , Acetanilidas/administração & dosagem , Animais , Osso e Ossos/metabolismo , Dor do Câncer/etiologia , Dor do Câncer/metabolismo , Dor do Câncer/patologia , Feminino , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Purinas/administração & dosagem
3.
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
4.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673008

RESUMO

Recently, Toll-like receptors (TLRs), a family of pattern recognition receptors, are reported as potential modulators for neuropathic pain; however, the desired mechanism is still unexplained. Here, we operated on the sciatic nerve to establish a pre-clinical rodent model of chronic constriction injury (CCI) in Sprague-Dawley rats, which were assigned into CCI and Decompression groups randomly. In Decompression group, the rats were performed with nerve decompression at post-operative week 4. Mechanical hyperalgesia and mechanical allodynia were obviously attenuated after a month. Toll-like receptor 5 (TLR5)-immunoreactive (ir) expression increased in dorsal horn, particularly in the inner part of lamina II. Additionally, substance P (SP) and isolectin B4 (IB4)-ir expressions, rather than calcitonin-gene-related peptide (CGRP)-ir expression, increased in their distinct laminae. Double immunofluorescence proved that increased TLR5-ir expression was co-expressed mainly with IB4-ir expression. Through an intrathecal administration with FLA-ST Ultrapure (a TLR5 agonist, purified flagellin from Salmonella Typhimurium, only the CCI-induced mechanical hyperalgesia was attenuated dose-dependently. Moreover, we confirmed that mu-opioid receptor (MOR) and phospho-protein kinase Cα (pPKCα)-ir expressions but not phospho-protein kinase A RII (pPKA RII)-ir expression, increased in lamina II, where they mostly co-expressed with IB4-ir expression. Go 6976, a potent protein kinase C inhibitor, effectively reversed the FLA-ST Ultrapure- or DAMGO-mediated attenuated trend towards mechanical hyperalgesia by an intrathecal administration in CCI rats. In summary, our current findings suggest that nerve decompression improves CCI-induced mechanical hyperalgesia that might be through the cross-talk of TLR5 and MOR in a PKCα-dependent manner, which opens a novel opportunity for the development of analgesic therapeutics in neuropathic pain.


Assuntos
Hiperalgesia/metabolismo , Proteína Quinase C-alfa/metabolismo , Receptores Opioides mu/metabolismo , Receptor 5 Toll-Like/metabolismo , Animais , Constrição , Ativação Enzimática , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Masculino , Medição da Dor/métodos , Ratos Sprague-Dawley , Receptor Cross-Talk , Nervo Isquiático/fisiopatologia , Transdução de Sinais , Corno Dorsal da Medula Espinal/metabolismo
5.
J Oral Sci ; 63(2): 170-173, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33731507

RESUMO

PURPOSE: Infantile tissue injury induces sensory deficits in adulthood. Infantile facial incision (IFI) was reported to cause an enhancement of incision-induced mechanical hypersensitivity in adulthood due to acceleration of the trigeminal ganglion neuronal excitability. However, the effects of IFI on activation of microglia in the spinal trigeminal nucleus and its involvement in facial pain sensitivity is not well known. METHODS: A facial skin incision was made in the left whisker pad in infant (IFI) and/or adult rats (AFI). Mechanical head withdrawal threshold and microglial activation in the trigeminal spinal nucleus were analyzed. RESULTS: Mechanical pain hypersensitivity induced by AFI was significantly exacerbated and prolonged by IFI. The number of Iba1-immunoreactive cells in the trigeminal spinal nucleus following AFI was increased by IFI, suggesting that IFI facilitates microglial hyperactivation following AFI. Intraperitoneal administration of minocycline, a microglial activation inhibitor, suppressed the facial incision-induced microglial hyperactivation in the trigeminal spinal nucleus and the exacerbation of the facial mechanical pain hypersensitivity induced by IFI. CONCLUSION: These results suggest that facial trauma in infants causes hyperactivation of microglia in the trigeminal spinal nucleus following AFI, leading to the prolongation of the facial mechanical pain hypersensitivity.


Assuntos
Hiperalgesia , Microglia , Animais , Dor Facial/etiologia , Hiperalgesia/etiologia , Ratos , Ratos Sprague-Dawley , Gânglio Trigeminal
6.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540826

RESUMO

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Glicolipídeos/uso terapêutico , Hiperalgesia/prevenção & controle , Ceratite/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Glicolipídeos/farmacologia , Células HEK293 , Humanos , Hiperalgesia/etiologia , Ceratite/induzido quimicamente , Ceratite/patologia , Lipopolissacarídeos/toxicidade , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Modelos Moleculares , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Conformação Proteica , Células RAW 264.7 , Distribuição Aleatória , Nervo Isquiático/lesões , Canal de Cátion TRPA1/metabolismo
7.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498178

RESUMO

The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.


Assuntos
Hiperalgesia/metabolismo , Células do Corno Posterior/metabolismo , Receptor PAR-2/metabolismo , Anilidas/farmacologia , Animais , Carragenina/farmacologia , Carragenina/toxicidade , Cinamatos/farmacologia , Potenciais Pós-Sinápticos Excitadores , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Masculino , Potenciais Pós-Sinápticos em Miniatura , Nociceptividade , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/fisiologia , Ratos , Ratos Wistar , Estaurosporina/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
8.
J Endod ; 47(5): 770-778.e1, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33516824

RESUMO

INTRODUCTION: Odontogenic pain can manifest as pulpal pain, periapical pain (mechanical allodynia), or both. This study aimed to assess the changes in the intensity of mechanical allodynia (MA) and to identify predictors of postoperative pain after root canal treatment (RCT). METHODS: In total, 579 consecutive patients who required RCT were enrolled; we included patients with asymptomatic pulpal diagnoses to avoid any effects of preoperative spontaneous pain on postoperative pain and to evaluate MA independently. Using a visual analog scale (VAS), patients separately indicated the intensity of spontaneous pain, tenderness to percussion, and pain on biting; these measurements were performed before treatment (preoperative pain), at the beginning of each visit (postpreparation pain), and daily for 1 week after RCT (postobturation pain). For analytical purposes, patients were subdivided into 2 groups based on the intensity of preoperative MA (none to mild [VAS <4] or moderate to severe [VAS ≥4]) to evaluate changes in MA and predictive factors of moderate to severe postoperative pain. A generalized estimating equation, repeated-measures analysis of variance, and logistic regression analysis were used. RESULTS: Although the intensity of MA was significantly higher in the moderate to severe group after the initiation of RCT (P < .05), 93% of them experienced alleviation in MA, and 30% of patients in the none to mild group experienced an increase in MA. After adjusting for clinical variables, moderate to severe preoperative MA and the presence of necrotic pulp were significantly correlated with moderate to severe postoperative pain with an odds ratio of 4.107 and 0.286, respectively. CONCLUSIONS: Moderate to severe preoperative MA was a predictive factor of postoperative pain in patients undergoing RCT.


Assuntos
Cavidade Pulpar , Hiperalgesia , Necrose da Polpa Dentária , Humanos , Hiperalgesia/etiologia , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Tratamento do Canal Radicular/efeitos adversos
9.
Neurol Sci ; 42(4): 1267-1276, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33502666

RESUMO

BACKGROUND: SARS-CoV-2 is a novel infectious agent causing coronavirus disease 2019, which has been declared as pandemic in March 2020. Personal protective equipment has been mandatory for healthcare workers in order to contain the outbreak of pandemic disease. Mild neurological disturbances such as headache have been related to the extensive utilization of facemask. This study aims to examine headache variations related to the intensive utilization of facemask among a cohort of healthcare professionals in a setting of low-medium risk of exposure to SARS-CoV-2. METHODS: This is a cross-sectional study among healthcare providers from different hospital and clinics in Italy. Each participant completed a specifically designed self-administered questionnaire. Headache features and outcome measures' change from baseline were evaluated over a 4-month period, in which wearing facemask has become mandatory for Italian healthcare workers. RESULTS: A total of 400 healthcare providers completed the questionnaire, 383 of them met the inclusion criteria. The majority were doctors, with a mean age of 33.4 ± 9.2 years old. Among 166/383 subjects, who were headache free at baseline, 44 (26.5%) developed de novo headache. Furthermore, 217/383 reported a previous diagnosis of primary headache disorder: 137 were affected by migraine and 80 had tension-type headache. A proportion (31.3%) of these primary headache sufferers experienced worsening of their pre-existing headache disorder, mainly for migraine frequency and attack mean duration. CONCLUSIONS: Our data showed the appearance of de novo associated facemask headache in previous headache-free subjects and an exacerbation of pre-existing primary headache disorders, mostly experienced by people with migraine disease.


Assuntos
Cefaleia/etiologia , Pessoal de Saúde , Máscaras/efeitos adversos , Pandemias , Equipamento de Proteção Individual/efeitos adversos , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Cefaleia/epidemiologia , Transtornos da Cefaleia/epidemiologia , Transtornos da Cefaleia/etiologia , Humanos , Hiperalgesia/epidemiologia , Hiperalgesia/etiologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/etiologia , Médicos , Inquéritos e Questionários
11.
Medicine (Baltimore) ; 99(38): e22198, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957350

RESUMO

Consistency between back pain intensity and degenerative changes on magnetic resonance imaging (MRI) of the lumbar spine is poor. This study aimed to show whether tender point (TP) examination, used as a test for diffuse central sensitization, may add valuable information to clinical assessment of patients with low back pain (LBP).This was a cross-sectional study including 141 patients with LBP on sick leave. Baseline measures comprised back pain, leg pain intensity, and LBP examination including TP examination. Degenerative MRI findings were assessed in a standardized manner and blinded for clinical data. The number of TPs was analyzed in relation to sex, widespread pain, radiculopathy, pain duration, and degenerative changes on MRI.The number of TPs was positively associated with the female sex, widespread pain, and pain duration. It was negatively associated with degenerative manifestations and radiculopathy, the latter displaying a low level similar to that of the general population. A positive association between back pain intensity and TPs was present in patients with and without radiculopathy and in patients with substantial degenerative changes. Men with >7-8 TPs and women with >10-11 TPs had more back pain and similar or fewer degenerative changes than patients with few TPs (<3 and <6 TPs, respectively), thereby identifying 34% to 44% of patients with nonspecific LBP and 5% to 8% of patients with radiculopathy, respectively, with disproportionate back pain in relation to degenerative changes.Supplemental TP examination improved clinical and MRI evaluation of patients with LBP. By using gender-specific cut points, patients with disproportionate back pain were identified, presumably indicating diffuse central sensitization.


Assuntos
Sensibilização do Sistema Nervoso Central , Dor Crônica/complicações , Hiperalgesia/diagnóstico , Dor Lombar/complicações , Adulto , Estudos Transversais , Feminino , Humanos , Hiperalgesia/etiologia , Dor Lombar/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tato
12.
J Stroke Cerebrovasc Dis ; 29(9): 105030, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807443

RESUMO

PURPOSE: Spinal epidural hematoma is a rare but important disease as it can be a stroke mimic. Our aim was to investigate the clinical characteristics of patients with an activated stroke code and spinal epidural hematoma. METHODS: Patients with an activated stroke code were examined retrospectively. Patients with spinal epidural hematoma were evaluated with further neurological examinations and neuroimaging. RESULTS: Of 2866 patients with an activated stroke code, spinal epidural hematoma was detected in 5 (0.2%, 63-79 years, 2 men). In all 5 cases, hematoma was located in the unilateral dorsal region of the spinal canal and spread to 5-9 vertebral segments at the C1-T3 level. None of the patients had a medical history of head or neck injury, coagulopathy, or use of anti-thrombotic agents. All of the patients had occipital, neck, and/or back pain, and their hemiparesis occurred simultaneously or within 1 h after the onset of pain. Hyperalgesia ipsilateral to the hematoma was observed in 1 patient, hypoalgesia contralateral to the hematoma was observed in 1, and quadriparesis and bilateral hypoalgesia were observed in 1. The hematomas spontaneously decreased in size in 4 patients, and cervical laminectomy was performed in the other patient. In the 1860 patients with an activated stroke code and spontaneous eye opening, the sensitivity of pain as a predictor of spinal epidural hematoma was 100%, with a specificity of 88.7%, and positive predictive value of 2.3%. CONCLUSION: Patients with spinal epidural hematoma could present with clinical characteristics mimicking ischemic stroke. Spinal epidural hematoma should be differentiated in patients treated under stroke code activation.


Assuntos
Avaliação da Deficiência , Hematoma Epidural Espinal/diagnóstico , Imagem por Ressonância Magnética , Medição da Dor , Acidente Vascular Cerebral/diagnóstico , Idoso , Diagnóstico Diferencial , Feminino , Hematoma Epidural Espinal/complicações , Hematoma Epidural Espinal/fisiopatologia , Hematoma Epidural Espinal/cirurgia , Humanos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Laminectomia , Masculino , Pessoa de Meia-Idade , Limiar da Dor , Paresia/etiologia , Paresia/fisiopatologia , Valor Preditivo dos Testes , Quadriplegia/etiologia , Quadriplegia/fisiopatologia , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia
13.
Health Psychol ; 39(10): 927-933, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32658497

RESUMO

OBJECTIVE: Pain catastrophizing and cutaneous allodynia represent two risk factors for greater headache-related disability. Yet, there is limited knowledge of the extent to which these risk factors are modifiable and whether nonpharmacological treatment-related changes are associated with migraine improvements. Using data from the Women's Health and Migraine (WHAM) study, a randomized controlled trial that compared effects of behavioral weight loss (BWL) and migraine education (ME) in women with migraine and overweight/obesity, we tested whether: (a) BWL versus ME produced greater changes in pain catastrophizing and allodynia from baseline across posttreatment and follow-up time points, and (b) whether these improvements were associated with improvements in headache disability. METHOD: Women (N = 110) were randomly assigned to 16 weeks of either BWL or ME and assessed at baseline, posttreatment, and follow up (32 weeks). Multilevel mixed effects modeling tested: (a) for between-groups differences in pain catastrophizing and allodynia changes over time, and (b) associations of changes in pain catastrophizing and allodynia with changes in headache disability, adjusting for migraine severity and weight loss. RESULTS: Both BWL and ME had significant reductions in pain catastrophizing and allodynia from baseline to posttreatment and follow up, and the improvements were comparable across conditions. Reductions in pain catastrophizing and cutaneous allodynia were associated with significant reductions in headache disability, even when controlling for intervention-related improvements in migraine and weight loss. CONCLUSION: Pain catastrophizing and allodynia are not only reduced after nonpharmacologic treatments for migraine, but greater improvements are associated with greater reductions in headache-related disability, independent of migraine severity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Hiperalgesia/terapia , Transtornos de Enxaqueca/terapia , Obesidade/complicações , Sobrepeso/complicações , Dor/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Hiperalgesia/etiologia , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etiologia , Adulto Jovem
14.
Pain Res Manag ; 2020: 4807674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190166

RESUMO

Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in modulating release of glutamate, acted a key player in the formation of heat hyperalgesia of inflammatory pain. However, it remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in inflammatory pain mediated by Cdk5 in the inflammatory pain model induced by complete Freund's adjuvant (CFA). Our results showed that the coexpression of Cdk5/VGLUT2 in small- and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA was significantly increased. Moreover, our study revealed that the expression of VGLUT2 protein in the DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection and was significantly reduced by roscovitine, a selective antagonist of Cdk5. Additionally, p25 but not p35, an activator of Cdk5, protein was significantly increased by CFA and reduced by roscovitine. Our findings suggested that VGLUT2/Cdk5 signaling pathway contributes to inflammatory pain mediated by Cdk5/p25.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Animais , Adjuvante de Freund/farmacologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Neurônios/metabolismo , Dor/etiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Medula Espinal/metabolismo
15.
Pain Physician ; 23(2): 219-227, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214304

RESUMO

BACKGROUND: A method for assessing dynamic muscle hyperalgesia (dynamic pressure algometry) has been developed and applied in tension-type and migraine headaches. OBJECTIVES: To investigate differences in dynamic pressure pain assessment over the trigeminal area between men with cluster headache (CH) and headache-free controls, and the association between dynamic and static pressure pain sensitivity. STUDY DESIGN: A case-control study. SETTING: Tertiary urban hospital. METHODS: Forty men with episodic CH and 40 matched controls participated. Dynamic pressure pain sensitivity was assessed with a dynamic pressure algometry set consisting of 8 rollers with different fixed levels (500, 700, 850, 1,350, 1,550, 2,200, 3,850, and 5,300 g). Each roller was moved at a speed of 0.5 cm/sec over a diagonal line covering the temporalis muscle from an anterior to posterior direction. The dynamic pressure threshold (DPT; load level of the first painful roller) and the pain intensity perceived at the DPT level (roller-evoked pain) were assessed. Static pressure pain thresholds (PPT) were also assessed with a digital pressure algometer applied statically over the mid-muscle belly of the temporalis. Patients were assessed in a remission phase, at least 3 months from the last cluster attack, and without preventive medication. RESULTS: Side-to-side consistency between DPTs (r = 0.781, P < 0.001), roller-evoked pain on DPT (r = 0.586; P < 0.001), and PPTs (r = 0.874; P < 0.001) were found in men with CH. DPT was moderately, bilaterally, and side-to-side associated with PPTs (0.663 > r > 0.793, all P < 0.001). Men with CH had bilateral lower DPT and PPT and reported higher levels of roller-evoked pain (all P < 0.001) than headache-free controls. LIMITATIONS: Only men with episodic CH were included. CONCLUSIONS: This study supports that a dynamic pressure algometry is as valid as a static pressure algometry for assessing pressure pain sensitivity in patients with CH. Assessing both dynamic and static pain sensitivity may provide new opportunities for differentiated diagnostics. KEY WORDS: Cluster headache, dynamic pressure pain, pressure pain threshold.


Assuntos
Cefaleia Histamínica/diagnóstico , Hiperalgesia/diagnóstico , Medição da Dor/métodos , Dor/diagnóstico , Pressão/efeitos adversos , Músculo Temporal/patologia , Adulto , Estudos de Casos e Controles , Cefaleia Histamínica/complicações , Humanos , Hiperalgesia/etiologia , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Limiar da Dor/fisiologia
16.
BMC Neurol ; 20(1): 61, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070321

RESUMO

BACKGROUND: We report a patient with unusual occipital neuropathic pain (at-level neuropathic pain) due to a small central cervical spinal cord injury (SCI). CASE PRESENTATION: A 50-year-old man presented with severe bilateral occipital pain after falling from a height of 2 m, 2 weeks ago. The degree of pain was evaluated to be 9 out of 10 using the numeric rating scale (NRS). The nature of the pain was tingling, burning, and piercing, and hyperalgesia was present over the bilateral posterior head regions. Greater occipital nerve block with bupivacaine and dexamethasone was not effective. On axial T2-cervical magnetic resonance imaging (MRI), a focal high signal change was observed in the central portion of the spinal cord at the C2 level. We deliberated that the patient's pain was due to the SCI observed on MRI, and after administration of oral medications, the NRS pain score reduced from 9 to 2. CONCLUSIONS: Neuropathic pain caused by SCI varies according to the location and degree of injury of the pain-related neural tracts; therefore, clinicians should closely observe the pain patterns and findings on imaging in patients with SCI to determine the cause of pain accurately.


Assuntos
Medula Cervical/lesões , Neuralgia/etiologia , Traumatismos da Medula Espinal/complicações , Medula Cervical/patologia , Humanos , Hiperalgesia/etiologia , Masculino , Pessoa de Meia-Idade
18.
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
19.
J Neuroinflammation ; 17(1): 19, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931832

RESUMO

BACKGROUND: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. METHODS: Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. RESULTS: BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1ß in the SDH of our CYP-induced cystitis model. CONCLUSIONS: In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1ß, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cistite/complicações , Hiperalgesia/etiologia , Microglia/metabolismo , Animais , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/metabolismo , Feminino , Hiperalgesia/metabolismo , Imunossupressores/toxicidade , Inflamação/etiologia , Inflamação/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Corno Dorsal da Medula Espinal/metabolismo
20.
Pain Pract ; 20(4): 371-386, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31782603

RESUMO

BACKGROUND: There is a wide range of animal models available today for studying chronic pain associated with a variety of etiologies and an extensive list of clinical manifestations of peripheral neuropathies. Photobiomodulation is a new tool for the treatment of pain in a convenient, noninvasive way. OBJECTIVE: The aim of this work is to elucidate the effects of infrared light-emitting diodes (LEDs) on behavioral responses to nociceptive stimuli in chronic pain models. METHODS: Forty-eight Swiss male mice weighing 25 to 35 g were used. Two chronic pain models, ischemia-reperfusion (IR) and spared spinal nerve injury, were performed and then treated with infrared LED irradiation (390 mW, 890 nm, 17.3 mW/cm2 , 20.8 J/cm2 , for 20 minutes). The behavioral tests used were a mechanical hypersensitivity test von Frey test) and a cold allodynia test (acetone test). RESULTS: The results showed that, in the IR model, the infrared LED had a significant effect on mechanical stimulation and cold allodynia on every day of treatment. In the spared nerve injury model, an analgesic effect was observed on every treatment day (when started on the 3rd and 7th days after the surgery). In both models, the effect was abolished when the treatment was interrupted. CONCLUSIONS: These findings suggest that photobiomodulation therapy may be a useful adjunct treatment for chronic pain.


Assuntos
Hiperalgesia , Raios Infravermelhos , Neuralgia , Nervos Periféricos/efeitos da radiação , Animais , Dor Crônica/etiologia , Modelos Animais de Doenças , Hiperalgesia/etiologia , Masculino , Camundongos , Neuralgia/etiologia , Traumatismos dos Nervos Periféricos/complicações , Traumatismo por Reperfusão/complicações
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