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BACKGROUND: Postoperative opioid administration has been largely replaced by regional anesthesia techniques. We aimed to determine whether intraoperative Analgesia-Nociception Index (ANI) can aid in early evaluation of the effectiveness of regional blocks such as the pectoralis muscle fascia block (PECS, pectoserratus and interpectoral plane blocks) and predicting the need for analgesics postoperatively. METHODS: This prospective observational study enrolled 30 women (age: 20-80 years) undergoing unilateral, non-intubated, breast tumor excision alone or in conjunction with sentinel lymph node biopsy. PECS block was performed following sedation. ANI readings were obtained at 1-min intervals, and polar coordinates were assigned to the distance from the nipple (0.5-cm intervals) and o'clock position (15-min intervals) for each reading. Pain scores were assessed using a numeric rating scale from 0 to 10, and analgesics were administered depending on pain score post-operatively. RESULTS: 8 (27%), 19 (63%), and 3 (10%) patients received morphine, tramadol, and no analgesics, respectively. In total, 954 ANI measurements were obtained. At the proposed cut-off of 50, the sensitivity and specificity of the ANI nadir for need of post-operative opioids were 0.875 and 0.932, respectively. Block effectiveness was most satisfactory in the upper lateral quadrant of the breast with nipple-areolar complex (NAC) sparing effect. Most average ANI measurements for the NAC were <50. No patient experienced postoperative nausea/vomiting, although one reported dizziness. CONCLUSIONS: The intraoperative ANI nadir <50 was strongly correlated with need for postoperative opioids. The ANI may aid in objectively evaluating the effectiveness of pectoralis muscle fascial blocks and predicting postoperative need for analgesics.
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Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model to explore the analgesic effects of intrathecal aaptamine administration. We also investigated cellular angiogenesis and lactate dehydrogenase A (LDHA) expression in the ipsilateral lumbar spinal cord after aaptamine administration in CCI rats by immunohistofluorescence. The results showed that aaptamine alleviates CCI-induced nociceptive sensitization, allodynia, and hyperalgesia. Moreover, aaptamine significantly downregulated CCI-induced vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and LDHA expression in the spinal cord. Double immunofluorescent staining showed that the spinal VEGF and LDHA majorly expressed on astrocytes and neurons, respectively, in CCI rats and inhibited by aaptamine. Collectively, our results indicate aaptamine's potential as an analgesic agent for neuropathic pain. Furthermore, inhibition of astrocyte-derived angiogenesis and neuronal LDHA expression might be beneficial in neuropathy.
Assuntos
Neuralgia , Fator A de Crescimento do Endotélio Vascular , Ratos , Animais , Neuralgia/metabolismo , Hiperalgesia , AnalgésicosRESUMO
Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.
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Doenças das Cartilagens , Cartilagem Articular , Osteoartrite , Ratos , Animais , Lactato Desidrogenase 5/metabolismo , Nociceptividade , Osteoartrite/metabolismo , Condrócitos/metabolismo , Cartilagem Articular/metabolismo , Doenças das Cartilagens/metabolismo , Modelos Animais de DoençasRESUMO
Prodigiosin, a secondary metabolite isolated from marine Vibrio sp., has antimicrobial and anticancer properties. This study investigated the cell death mechanism of prodigiosin in glioblastoma. Glioblastoma multiforme (GBM) is an aggressive primary cancer of the central nervous system. Despite treatment, or standard therapy, the median survival of glioblastoma patients is about 14.6 month. The results of the present study clearly showed that prodigiosin significantly reduced the cell viability and neurosphere formation ability of U87MG and GBM8401 human glioblastoma cell lines. Moreover, prodigiosin with fluorescence signals was detected in the endoplasmic reticulum and found to induce excessive levels of autophagy. These findings were confirmed by observation of LC3 puncta formation and acridine orange staining. Furthermore, prodigiosin caused cell death by activating the JNK pathway and decreasing the AKT/mTOR pathway in glioblastoma cells. Moreover, we found that the autophagy inhibitor 3-methyladenine reversed prodigiosin induced autophagic cell death. These findings of this study suggest that prodigiosin induces autophagic cell death and apoptosis in glioblastoma cells.
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Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Prodigiosina/farmacologia , Antineoplásicos , Calnexina/metabolismo , Caspase 3/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Prodigiosina/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Previous studies have demonstrated that the marine compound austrasulfone, isolated from the soft coral Cladiella australis, exerts a neuroprotective effect. The intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, attenuates several inflammatory responses. The present study uses in vitro and in vivo methods to investigate the neuroprotective effect of dihydroaustrasulfone alcohol-modified 1-tosylpentan-3-one (1T3O). Results from in vitro experiments show that 1T3O effectively inhibits 6-hydroxydopamine-induced (6-OHDA-induced) activation of both p38 mitogen-activated protein kinase (MAPK) and caspase-3 in SH-SY5Y cells; and enhances nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling. Hoechst staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining results reveal that 1T3O significantly inhibits 6-OHDA-induced apoptosis. In addition, the addition of an Akt or HO-1 inhibitor decreases the protective effect of 1T3O. Thus, we hypothesize that the anti-apoptotic activity of 1T3O in neuronal cells is mediated through the regulation of the Akt and HO-1 signaling pathways. In vivo experiments show that 1T3O can reverse 6-OHDA-induced reduction in locomotor behavior ability in zebrafish larvae, and inhibit 6-OHDA-induced tumor necrosis factor-alpha (TNF-α) increase at the same time. According to our in vitro and in vivo results, we consider that 1T3O exerts its anti-apoptotic activities at SH-SY5Y cells after 6-OHDA challenges, probably via the regulation of anti-oxidative signaling pathways. Therefore, this compound may be a promising therapeutic agent for neurodegenerations.
Assuntos
Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxidopamina/efeitos adversos , Pentanos/farmacologia , Pentanonas/farmacologia , Compostos de Tosil/farmacologia , Animais , Antozoários/química , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Humanos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pentanos/química , Pentanonas/química , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos de Tosil/química , Peixe-Zebra , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
OBJECTIVE: Developing a new measurement index is the first step in evaluating pain relief outcomes. Although the percentage difference in pain intensity (%PID) is the most popular indicator, this indicator does not take into account the goal of pain relief. Therefore, the aims of this study were to develop a pain relief index (PRI) for outcome evaluation and to examine the index using demographic characteristics of cancer inpatients with clinically significant pain. DESIGN: Retrospective cohort study. SETTING: A national hospital. SUBJECTS: All cancer inpatients. METHODS: Pain intensity was assessed using a numerical rating scale, a faces pain scale or the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Tool. Using a nursing information system, a pain score database containing data from 2011 through 2013 was analyzed. RESULTS: Cancer patients representing 93,812 hospitalizations were considered in this study. We focused on cancer patients for whom the worst pain intensity (WPI) was ≥ 4 points. PRI values of -62.02% to -72.55% were observed in the WPI ≥ 7 and 4 ≤ WPI ≤ 6 groups. Significant (P < 0.05) effects on PRI values were observed among patients who were > 65 years old, those who were admitted to the medicine or gynecology and those who had a hospital stay > 30 days. CONCLUSION: This hospital-based study demonstrated that the PRI is an effective and valid measure for evaluating outcome data using an electronic nursing information system. We will further define the meaningful range of percentage difference in PRI from various perspectives.
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Registros Eletrônicos de Saúde/tendências , Hospitalização/tendências , Neoplasias/diagnóstico , Enfermagem/tendências , Medição da Dor/métodos , Dor/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/terapia , Enfermagem/métodos , Dor/epidemiologia , Manejo da Dor/métodos , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
Six new 9-hydroxybriarane diterpenoids, briarenolides ZI-ZVI (1-6), were isolated from a gorgonian coral Briareum sp. The structures of briaranes 1-6 were elucidated by spectroscopic methods and by comparison of their spectroscopic data with those of related analogues. Briarenolides ZII (2) and ZVI (6) were found to significantly inhibit the expression of the pro-inflammatory inducible nitric oxide synthase (iNOS) protein of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells.
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Antozoários/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Diterpenos/isolamento & purificação , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Camundongos , Modelos Moleculares , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/imunologiaRESUMO
BACKGROUND: Transforming growth factor-ßs (TGF-ßs) are a group of multifunctional proteins that have neuroprotective roles in various experimental models. We previously reported that intrathecal (i.t.) injections of TGF-ß1 significantly inhibit neuropathy-induced thermal hyperalgesia, spinal microglia and astrocyte activation, as well as upregulation of tumor necrosis factor-α. However, additional cellular mechanisms for the antinociceptive effects of TGF-ß1, such as the mitogen-activated protein kinase (MAPK) pathway, have not been elucidated. During persistent pain, activation of MAPKs, especially p38 and extracellular signal-regulated kinase (ERK), have crucial roles in the induction and maintenance of pain hypersensitivity, via both nontranscriptional and transcriptional regulation. In the present study, we used a chronic constriction injury (CCI) rat model to explore the role of spinal p38 and ERK in the analgesic effects of TGF-ß1. METHODS: We investigated the cellular mechanisms of the antinociceptive effects of i.t. injections of TGF-ß1 in CCI induced neuropathic rats by spinal immunohistofluorescence analyses. RESULTS: The results demonstrated that the antinociceptive effects of TGF-ß1 (5 ng) were maintained at greater than 50 % of the maximum possible effect in rats with CCI for at least 6 h after a single i.t. administration. Thus, we further examined these alterations in spinal p38 and ERK from 0.5 to 6 h after i.t. administration of TGF-ß1. TGF-ß1 significantly attenuated CCI-induced upregulation of phosphorylated p38 (phospho-p38) and phosphorylated ERK (phospho-ERK) expression in the dorsal horn of the lumbar spinal cord. Double immunofluorescence staining illustrated that upregulation of spinal phospho-p38 was localized to neurons, activated microglial cells, and activated astrocytes in rats with CCI. Additionally, increased phospho-ERK occurred in activated microglial cells and activated astrocytes. Furthermore, i.t. administration of TGF-ß1 markedly inhibited phospho-p38 upregulation in neurons, microglial cells, and astrocytes. However, i.t. injection of TGF-ß1 also reduced phospho-ERK upregulation in microglial cells and astrocytes. CONCLUSIONS: The present results demonstrate that suppressing p38 and ERK activity affects TGF-ß1-induced analgesia during neuropathy.
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Constrição Patológica/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/patologia , Traumatismos dos Nervos Periféricos/patologia , Proteínas Serina-Treonina Quinases/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Receptor do Fator de Crescimento Transformador beta Tipo I , Regulação para CimaRESUMO
BACKGROUND: Many cancer research studies have extensively examined the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathway. There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain. Here, we report a role for PTEN in a rodent model of neuropathic pain. RESULTS: We found that chronic constriction injury (CCI) surgery in rats could elicit downregulation of spinal PTEN as well as upregulation of phosphorylated PTEN (phospho-PTEN) and phosphorylated mammalian target of rapamycin (phospho-mTOR). After examining such changes in endogenous PTEN in neuropathic rats, we explored the effects of modulating the spinal PTEN pathway on nociceptive behaviors. The normal rats exhibited mechanical allodynia after intrathecal (i.t.) injection of adenovirus-mediated PTEN antisense oligonucleotide (Ad-antisense PTEN). These data indicate the importance of downregulation of spinal PTEN for nociception. Moreover, upregulation of spinal PTEN by i.t. adenovirus-mediated PTEN (Ad-PTEN) significantly prevented CCI-induced development of nociceptive sensitization, thermal hyperalgesia, mechanical allodynia, cold allodynia, and weight-bearing deficits in neuropathic rats. Furthermore, upregulation of spinal PTEN by i.t. Ad-PTEN significantly attenuated CCI-induced microglia and astrocyte activation, upregulation of tumor necrosis factor-α (TNF-α) and phospho-mTOR, and downregulation of PTEN in neuropathic rats 14 days post injury. CONCLUSIONS: These findings demonstrate that PTEN plays a key, beneficial role in a rodent model of neuropathic pain.
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Regulação da Expressão Gênica/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Ciática/patologia , Medula Espinal/metabolismo , Animais , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hiperalgesia , Masculino , PTEN Fosfo-Hidrolase/genética , Limiar da Dor , Ratos , Ratos Wistar , Ciática/fisiopatologia , Sirolimo/metabolismo , Fatores de Tempo , Transdução GenéticaRESUMO
Two new cembranes, columnariols A (1) and B (2), were isolated from the cultured soft coral Nephthea columnaris. The structures of cembranes 1 and 2 were elucidated by spectroscopic methods. In the anti-inflammatory effects test, cembranes 1 and 2 were found to significantly inhibit the accumulation of the pro-inflammatory iNOS and COX-2 protein of the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Compound 1 exhibited moderate cytotoxicity toward LNCaP cells with an IC50 value of 9.80 µg/mL.
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Antozoários/química , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Diterpenos/administração & dosagem , Diterpenos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI) model of neuropathic pain. First, we found that a single intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-µg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-ß1 (TGF-ß1) at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-ß type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-ß1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide.
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Analgésicos/farmacologia , Antozoários/metabolismo , Anti-Inflamatórios/farmacologia , Lactonas/farmacologia , Neuralgia/tratamento farmacológico , Fator de Crescimento Transformador beta1/fisiologia , Animais , Hiperalgesia/tratamento farmacológico , Masculino , Neuroglia/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ratos , Ratos Wistar , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Regulação para CimaRESUMO
STUDY OBJECTIVE: This study aimed to compare the analgesic effects of anesthesiologist-administrated erector spinae plane block (ESPB) and surgeon-administrated intercostal nerve block (ICNB) following video-assisted thoracoscopic surgery (VATS). DESIGN: Randomized, controlled, double-blinded study. SETTING: Operating room, postoperative recovery room and ward in two centers. PATIENTS: One hundred patients, ASA I-III and scheduled for elective VATS. INTERVENTIONS: The anesthesiologist-administrated ESPB under ultrasound guidance or surgeon-administrated ICNB under video-assisted thoracoscopy was randomly provided during VATS. Regular oral non-opioid analgesic combined with intravenous rescue morphine were prescribed for multimodal analgesia after surgery. MEASUREMENTS: The primary outcomes were the pain score and morphine consumption during 48 h after surgery. Postoperative pain intensity were assessed using the 10-cm visual analogue scale at 1 h, 24 h, and 48 h after surgery. Morphine consumption at these time points was compared between the two study groups. Furthermore, oral weak opioid rescue analgesic was also provided at 24 h after surgery. Postoperative quality of recovery at 24 h was also assessed using the QoR-15 questionnaire, along with duration of chest tube drainage and hospital stay were compared as secondary outcomes. MAIN RESULTS: Patients in the two study groups had comparable baseline characteristics, and surgical types were also similar. Postoperative VAS changes at 1 h, 24 h, and 48 h after surgery were also comparable between the two study groups. Both groups had low median scores (<4.0) at all time points (all p > 0.05). Patients in the ESPB group required statistically non-significant higher 48-h morphine consumption [3 (0-6) vs. 0 (0-6) mg in the ESPB group and ICNB group respectively; p = 0.135] and lower numbers of oral rescue analgesic (0.4 ± 1.2 vs. 1.0 ± 1.8 in the ESPB group and ICNB group respectively; p = 0.059). Additionally, patients in the two study groups had similar QoR15 scores and lengths of hospital stay. CONCLUSIONS: Both anesthesiologist-administered ultrasound-guided ESPB and surgeon-administered VATS ICNB were effective analgesic techniques for patients undergoing VATS for tumor resection.
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Analgésicos Opioides , Nervos Intercostais , Morfina , Bloqueio Nervoso , Medição da Dor , Dor Pós-Operatória , Cirurgia Torácica Vídeoassistida , Ultrassonografia de Intervenção , Humanos , Cirurgia Torácica Vídeoassistida/efeitos adversos , Cirurgia Torácica Vídeoassistida/métodos , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/etiologia , Bloqueio Nervoso/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Nervos Intercostais/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Idoso , Adulto , Músculos Paraespinais/inervação , Resultado do Tratamento , Tempo de Internação/estatística & dados numéricosRESUMO
OBJECTIVE: Postoperative pain remains one of the most common complaints after surgery, and appropriate treatments are limited. METHODS: We therefore investigated the effect of the anti-nociceptive properties of magnesium sulfate (MgSO4), an N-methyl-D-aspartate (NMDA) receptor antagonist, on incision-induced postoperative pain and peripheral and central nervous system inflammation. RESULTS: We found that local MgSO4 administration dose-dependently increases paw withdrawal latency, indicating reduced peripheral postoperative pain. Furthermore, MgSO4 inhibited the expression of interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) and phosphorylation of the NMDA receptor NR1 subunit in injured paw tissue and significantly attenuated microglial and astrocytic activation in the ipsilateral lumbar spinal cord dorsal horn. CONCLUSION: Locally administered MgSO4 has potential for development as an adjunctive therapy for preventing central nociceptive sensitization.
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Inflamação , Sulfato de Magnésio , Nociceptividade , Dor Pós-Operatória , Ratos Sprague-Dawley , Animais , Sulfato de Magnésio/farmacologia , Sulfato de Magnésio/administração & dosagem , Masculino , Nociceptividade/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ratos , Modelos Animais de Doenças , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Sensibilização do Sistema Nervoso Central/fisiologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Interleucina-1beta/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
BACKGROUND CONTEXT: Postoperative pain control following spine surgery can be difficult. The Enhanced Recovery After Surgery (ERAS) programs use multimodal approaches to manage postoperative pain. While an erector spinae plane block (ESPB) is commonly utilized, the ideal distance for injection from the incision, referred to as the ES (ESPB to mid-surgical level) distance, remains undetermined. PURPOSE: We evaluated the impact of varying ES distances for ESPB on Numerical Rating Scale (NRS) measures of postoperative pain within the ERAS protocol. STUDY DESIGN/SETTING: Retrospective observational study. PATIENT SAMPLE: Adult patients who underwent elective lumbar spine fusion surgery. OUTCOME MEASURES: Primary outcome measures include the comparative postoperative NRS scores across groups at immediate (T1), 24 (T2), 48 (T3), and 72 (T4) hours postsurgery. For secondary outcomes, a propensity matching analysis compared these outcomes between the ERAS and non-ERAS groups, with opioid-related recovery metrics also assessed. METHODS: All included patients were assigned to one of three ERAS groups according to the ES distance: Group 1 (G1, ES > 3 segments), Group 2 (G2, ES = 2-3 segments), and Group 3 (G3, ES<2 segments). Each patient underwent a bilateral ultrasound-guided ESPB with 60 mL of diluted ropivacaine or bupivacaine. RESULTS: Patients within the ERAS cohort reported mild pain (NRS < 3), with no significant NRS variation across G1 to G3 at any time. Sixty-five patients were matched across ERAS and non-ERAS groups. The ERAS group exhibited significantly lower NRS scores from T1 to T3 than the non-ERAS group. Total morphine consumption during hospitalization was 26.7 mg for ERAS and 41.5 mg for non-ERAS patients. The ERAS group resumed water and food intake sooner and had less postoperative nausea and vomiting. CONCLUSIONS: ESPBs can be effectively administered at or near the mid-surgical level to the low thoracic region for lumbar spine surgeries. Given challenges with sonovisualization, a lumbar ESPB may be preferred to minimize the risk of inadvertent pleural injury.
Assuntos
Recuperação Pós-Cirúrgica Melhorada , Vértebras Lombares , Bloqueio Nervoso , Dor Pós-Operatória , Humanos , Masculino , Feminino , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Pessoa de Meia-Idade , Vértebras Lombares/cirurgia , Estudos Retrospectivos , Idoso , Fusão Vertebral/métodos , Fusão Vertebral/efeitos adversos , Músculos Paraespinais/inervação , Adulto , Medição da Dor , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Anestésicos Locais/administração & dosagem , Resultado do Tratamento , Manejo da Dor/métodosRESUMO
Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis.
RESUMO
OBJECTIVE: This study tested the hypothesis that adding tenoxicam (T) to intravenous patient-controlled analgesia (IV-PCA) with morphine (M) would improve postoperative pain relief and wound inflammatory responses compared with M alone after spine surgery. DESIGN: Randomized, prospective, double-blind, controlled study. SUBJECTS: Ninety-four patients eligible for elective spine surgery. SETTING: Teaching hospital. METHODS: Patients were randomized to one of three groups: the M group (PCA regimen with M), the TM group (PCA regimen with T and M), or the T+TM group (20 mg T administered 30 minutes before wound closure in addition to the TM regimen). The primary end point was the numeric rating scale score for pain intensity, and secondary end points pertaining to postoperative pain management included M consumption, PCA demand/delivery, use of rescue analgesics, adverse events, and levels of inflammatory mediators in wound drainages. RESULTS: PCA demand was reduced in both the TM and T+TM groups compared with the M group (both P ≤ 0.001). The incidence of skin itching was significantly reduced in the T+TM group compared with the other groups (both P ≤ 0.05). PGE2 and interleukin-6 levels in wound drainages were reduced in the TM and T+TM groups compared with the M group (both P ≤ 0.001). CONCLUSIONS: The combination of T and M for IV-PCA was not more efficacious than IV-PCA with M alone in reducing postoperative pain after spine surgery but reduced PCA demand and suppressed local inflammation at the surgical site. Administration of T before wound closure may ameliorate IV-PCA M-induced skin itching.
Assuntos
Inflamação/tratamento farmacológico , Inflamação/epidemiologia , Morfina/administração & dosagem , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/prevenção & controle , Piroxicam/análogos & derivados , Fusão Vertebral/estatística & dados numéricos , Analgésicos Opioides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Comorbidade , Método Duplo-Cego , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Dor Pós-Operatória/diagnóstico , Piroxicam/administração & dosagem , Prevalência , Medição de Risco , Autoadministração , Taiwan/epidemiologia , Resultado do TratamentoRESUMO
Glioblastoma multiforme (GBM) is a common central nervous system disease with a poor prognosis; its five-year survival rate is <5 %, and its median survival of 15 months. Current treatment includes chemotherapy with temozolomide, which is ineffective against GBM, suggesting an urgent need to develop novel therapies. This study evaluated isoaaptamine and aaptamine in the GBM cell lines for cell viability; GBM 8401, U87 MG, U138 MG, and T98G. Our findings showed that isoaaptamine was more potent than its iso-form aaptamine in these four cell lines, and GBM 8401 was most sensitive to isoaaptamine. The study in GBM 8401 cells showed that apoptosis was induced by isoaaptamine with increased cleaved caspase 3 and poly ADP-ribose polymerase (PARP). Moreover, isoaaptamine enhanced oxidative stress by increasing the levels of reactive oxygen species (ROS), inhibiting mitochondrial and cellular superoxidase dismutases (SOD1&2), peroxidase and an anti-apoptotic protein (Bcl-2), and disrupting mitochondrial membrane potential. In addition, the oxygen consumption rates and activities of mitochondrial complexes I-V were significantly reduced. Mitochondrial dynamics were prone to fission instead of fusion after isoaaptamine treatment, and ATP synthesis was ablated. Also, autophagy-related acidic organelle vesicles were formed, indicating autophagy was triggered. Overall, isoaaptamine-induced ROS overproduction in mitochondria could cause mitochondrial dysfunction, apoptosis, and autophagy in the GBM cells.
Assuntos
Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias , Autofagia , Apoptose , Linhagem Celular TumoralRESUMO
We previously demonstrated that intrathecal IL-1ß caused thermal hyperalgesia in rats. This study was conducted to examine the effects and cellular mechanisms of glial inhibitors on IL-1ß-induced nociception in rats. The effects of minocycline (20 µg), fluorocitrate (1 nmol), and SB203580 (5 µg) on IL-1ß (100 ng) treatment in rats were measured by nociceptive behaviors, western blotting of p38 mitogen-activated protein kinase (MAPK) and inducible nitric oxide synthase (iNOS) expression, cerebrospinal fluid nitric oxide (NO) levels, and immunohistochemical analyses. The results demonstrated that intrathecal IL-1ß activated microglia and astrocytes, but not neurons, in the dorsal horn of the lumbar spinal cord, as evidenced by morphological changes and increased immunoreactivity, phosphorylated p38 (P-p38) MAPK, and iNOS expression; the activation of microglia and astrocytes peaked at 30 min and lasted for 6 h. The immunoreactivities of microglia and astrocytes were significantly increased at 30 min (6.6- and 2.7-fold, respectively) and 6 h (3.3- and 4.0-fold, respectively) following IL-1ß injection, as compared with saline controls at 30 min (all P < 0.01). IL-1ß induced P-p38 MAPK and iNOS expression predominantly in microglia and less in astrocytes. Minocycline, fluorocitrate, or SB203580 pretreatment suppressed this IL-1ß-upregulated P-p38 MAPK mainly in microglia and iNOS mainly in astrocytes; minocycline exhibited the most potent effect. Minocycline and fluorocitrate pretreatment abrogated IL-1ß-induced NO release and thermal hyperalgesia in rats. In conclusion, minocycline, fluorocitrate, and SB203580 effectively suppressed the IL-1ß-induced central sensitization and hyperalgesia in rats.
Assuntos
Citratos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/fisiologia , Minociclina/uso terapêutico , Medição da Dor/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Injeções Espinhais , Masculino , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/métodos , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
BACKGROUND: The COVID-19 outbreak disrupted medical access for patients receiving chronic opioid therapy. This study investigated their prescription opioid dosages before and after the 2020 outbreak in Taiwan. METHODS: A prospective questionnaire survey was conducted among registered outpatients receiving long-term opioids before July 2019 in Taiwan. The questionnaire included items from the Taiwanese Brief Pain Inventory and quality of life assessment. Follow-up surveys in outpatient departments through October 2020 were conducted to collect opioid prescription data. RESULTS: After a mean of 531 days, the questionnaire responses of 103 of the initial 117 respondents were reviewed. Daily opioid doses decreased for 31 respondents (30.1%), remained roughly equivalent (defined as ±2.5%) for 27 (26.2%), and increased for 45 (43.7%) after the first wave of the pandemic. The use of strong opioids and nonopioid medications did not significantly differ among the three groups, but less fentanyl patch use was noted in the decreased-dose group after the outbreak. More than 70% of the patients received daily high-dose opioids (≥90 morphine milligram equivalents); moreover, 60% reported constipation. No deaths due to opioid overdose occurred during the study period. CONCLUSIONS: The COVID-19 outbreak in 2020 did not interrupt access to long-term opioid prescriptions for most registered patients with chronic pain in Taiwan. Less fentanyl patch use was observed in participants whose opioid dose was tapering.
RESUMO
The investigators previously found that the administration of lemnalol, a natural marine compound isolated from the Formosan soft coral Lemnalia cervicorni, produced anti-inflammatory and analgesic effects in carrageenan-injected rats. Recently, several studies have demonstrated that the development and maintenance of neuropathic pain are accompanied by releasing of proinflammatory mediators from activated glial cells in the spinal cord. In this study, we investigated the antinociceptive properties of lemnalol, a potential anti-inflammatory compound, on chronic constriction injury (CCI) in a well-established rat model of neuropathic pain. Our results demonstrated that a single intrathecal administration of lemnalol (0.05-10 µg) significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, 14 days postsurgery. Furthermore, immunohistofluorescence analyses showed that lemnalol (10 µg) also significantly inhibits CCI-induced upregulation of microglial and astrocytic immunohistochemical activation markers in the dorsal horn of the lumbar spinal cord. Double immunofluorescent staining demonstrated that intrathecal injection of lemnalol (10 µg) markedly inhibited spinal proinflammatory mediator tumor necrosis factor-α expression in microglial cells and astrocytes in neuropathic rats. Collectively, our results indicate that lemnalol is a potential therapeutic agent for neuropathic pain, and that further exploration of the effects of lemnalol on glial proinflammatory responses is warranted.