Satellite glial cell-secreted exosomes after in-vitro oxaliplatin treatment presents a pro-nociceptive effect for dorsal root ganglion neurons and induce mechanical hypersensitivity in naïve mice.

BACKGROUND: The pathophysiological mechanism underlying chemotherapy-induced neuropathic pain (CINP) remains unclear. Sensory neuronal hypersensitivity in the dorsal root ganglion (DRG) is essential for the onset and maintenance of chronic pain. Satellite glial cells (SGCs) in the DRG potentially affect the function of sensory neurons, possibly by mediating extracellular or paracrine signaling. Exosomes play an essential role in cell-cell communication. However, the role of SGC-secreted exosomes in glia-neuron communication and CINP remains unclear. METHODS: SGCs and sensory neurons were cultured from the DRG of mice. The SGCs were treated with 4 µM oxaliplatin for 24 h. Glial fibrillary acid protein (GFAP) and connexin-43 (Cx-43) expressions in the SGCs were examined with immunocytochemistry (ICC). Enzyme-linked immunosorbent assay (ELISA) detected cytokine release in the SGCs after oxaliplatin treatment. Subsequently, SGC-secreted exosomes were collected using ultracentrifugation and identified by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Subsequently, DRG neurons were incubated with SGC-secreted exosomes for 24 h. The percentage of reactive oxygen species (ROS)-positive neurons was detected using flow cytometry, and acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) expression were examined by western blotting. SGC-secreted exosomes were intrathecally injected into naïve mice. The mechanical withdrawal threshold was assessed 24, 48, and 72 h following the injection. TRPV1 expression in the DRG was examined 72 h after intrathecal injection. Furthermore, differentially expressed (DE) miRNAs within the SGC-secreted exosomes were detected using RNA sequencing and bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses were performed to predict the function of the target genes of DE miRNAs. Finally, the DE miRNAs with pain regulation potential were identified in silico. RESULTS: After in-vitro oxaliplatin treatment, ICC showed an increase in the immunoreactivity of GFAP and Cx-43 in the SGCs. ELISA results suggested an increased release of tumor necrosis factor-α and interleukin (IL)-1ß, but a decreased release of IL-10. Oxaliplatin treatment increased the secretion of exosomes in the SGCs from 4.34 to 5.99 × 1011 (particles/ml). The exosome-specific markers CD9 and TSG101 were positive, whereas calnexin was negative for the obtained exosomes. Additionally, the SGC-secreted exosomes were endocytosed by DRG neurons after co-incubation. Moreover, after incubation with conditioned SGC-secreted exosomes (after 4 µM oxaliplatin treatment), the percentage of ROS-positive DRG neurons increased and ASIC3 and TRPV1 expressions were upregulated. After the intrathecal injection of the conditioned SGC-secreted exosomes, the mice presented with mechanical hypersensitivity and TRPV1 expression upregulation in the DRG. Notably, 25 and 120 significantly upregulated and downregulated miRNAs, respectively, were identified in the conditioned SGC-secreted exosomes. When predicting the function of target genes of DE miRNAs, certain GO terms, such as synapse organization, neurogenesis regulation, histone modification, and pain-related KEGG or Reactome pathways, including vascular endothelial growth factor A-vascular endothelial growth factor receptor 2, mammalian target of rapamycin, and mitogen-activated protein kinase signaling pathways, related to nervous system function were predicted. Finally, 27 pain regulation-related miRNAs, including miR-324-3p, miR-181a-5p, and miR-122-5p, were identified in silico. CONCLUSION: Our study demonstrates that SGC-secreted exosomes after in-vitro oxaliplatin treatment present a pro-nociceptive effect for DRG neurons and induce mechanical hypersensitivity in naïve mice, possibly via the contained miRNA cargo. Identifying the candidate miRNAs and verifying their functions in vivo are required to elucidate the exosomes mediating 'glia-neuron' communication under CINP condition.

Concomitant Gastric Acid Suppressants on the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Meta-Analysis.

Background: The influence of concomitant use of gastric acid suppressants (AS) on survival of patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inconsistent according to previous studies. We performed a meta-analysis to evaluate the effect of additional AS in patients with NSCLC taking TKIs. Methods: Relevant observational studies were identified by a search of Medline, Embase, and Web of Science databases. Only studies with multivariate analyses were included. A random-effect model was used to combine the results. Results: Thirteen retrospective studies with 12259 patients were included. Pooled results showed that concomitant use of AS was associated with worse progression-free survival (PFS, adjusted hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.31 to 1.89, P < 0.001; I 2 = 65%) and overall survival (OS, adjusted HR: 1.38, 95% CI: 1.19 to 1.61, P < 0.001; I 2 = 70%) in NSCLC patients taking TKIs. Sensitivity analysis limited to studies including NSCLC with EGFR mutation showed consistent results (HR for PFS: 1.53, P=0.003; HR for OS: 1.43, P=0.001). Subgroup analyses indicated that the association between concomitant use of AS and poor survival was not significantly affected by the category of AS used (proton pump inhibitors or histamine type-2 receptor antagonists) or the country of the study (Asian or non-Asian, P for subgroup analysis all >0.05). Conclusions: Concomitant use of AS in patients with NSCLC taking TKIs may be associated with poor survival outcomes.

PTEN-Induced Putative Kinase 1 (PINK1)/Parkin-Mediated Mitophagy Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity.

BACKGROUND The pathogenesis of chemotherapy-induced neuropathy, a dose-dependent adverse effect of cisplatin, involves mitochondrial dysfunction. PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy removes damaged mitochondria under various pathological conditions. The objective of this study was to determine mitophagy status and its effects on mitochondrial function and neuronal cell damage after cisplatin treatment using an in vitro model of cisplatin-induced neurotoxicity. MATERIAL AND METHODS PC12 cells were transfected with Parkin or Parkin siRNA using lentiviral particles and Lipofectamine 3000™, respectively, and then were exposed to 10 µM cisplatin. The expression of autophagic proteins was measured by Western blot analysis. Mitophagy in PC12 cells was detected by confocal microscopy analysis of mitochondria-lysosomes colocalization and autophagic flux. The effects of PINK1/Parkin-mediated mitophagy on cisplatin-induced neurotoxicity were assessed via mitochondrial function, neuritic length, nuclear diameter, and apoptosis. RESULTS Cisplatin activated PINK1/Parkin-mediated mitophagy in PC12 cells. Autophagic flux analysis revealed that cisplatin inhibits the late stage of the autophagic process. The knockdown of Parkin suppressed cisplatin-induced mitophagy, aggravating cisplatin-induced depolarization of mitochondria, cellular ATP deficits, reactive oxygen species outburst, neuritic shortening, nuclear diameter reduction, and apoptosis, while Parkin overexpression enhanced mitophagy and reversed these effects. CONCLUSIONS PINK1/Parkin-regulated mitophagy can protect against cisplatin-related neurotoxicity, suggesting therapeutic enhancement of mitophagy as a potential intervention for cisplatin-induced peripheral neuropathies. The interference of cisplatin with autophagosome-lysosome fusion may be partly responsible for cisplatin-induced neurotoxicity.

Regular intermittent bolus provides similar incidence of maternal fever compared with continuous infusion during epidural labor analgesia.

OBJECTIVES: To compare the effects of regular intermittent bolus versus continuous infusion for epidural labor analgesia on maternal temperature and serum interleukin-6 (IL-6) level. METHODS: This randomized trial was performed in Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China between October 2012 and February 2014. Either regular intermittent bolus (RIB, n=66) or continuous infusion (CI, n=66) was used for epidural labor analgesia. A bolus dose (10 ml of 0.08% ropivacaine + 0.4 ug·ml-1 sufentanil) was manually administrated once an hour in the RIB group, whereas the same solution was continuously infused at a constant rate of 10 ml·h-1 in the CI group. Maternal tympanic temperature and serum IL-6 level were measured hourly from baseline to one hour post partum. The incidences of fever (>/=38 degree celsius ) were calculated. RESULTS: The incidence of maternal fever was similar between the 2 groups. There was a rising trend in mean temperature over time in both groups, but no statistical difference was detected between the groups at respective time points; maternal serum IL-6 showed similar changes. CONCLUSION: Compared with continuous infusion, regular intermittent bolus presents with the same incidence of maternal fever for epidural labor analgesia. Interleukin-6 elevation could be involved in mean maternal temperature increase. 

Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain.

BACKGROUND: Our previous work found that tumor suppressor menin potentiates spinal synaptic plasticity in the context of peripheral nerve injury-induced neuropathic hypersensitivity, but the underlying molecular mechanisms are not clear. We hereby assessed the role of menin in regulating the spinal balance between glutamate and GABA and its contribution to the pathological condition of nerve injury-induced hypersensitivity. METHODS: In spared nerve injury induced C57BL/6 mice, mechanical withdrawal threshold was measured with von Frey filaments after intrathecal administration of small interfering RNA (siRNA) of MEN1 or/and subcutaneous histone deacetylase (HDAC) inhibitors to control the level of glutamic acid decarboxylase 65 (GAD65). Immunoblotting and high-performance liquid chromatography were used to detect the level of protein expression and spinal glutamate and GABA, respectively. RESULTS: Genetic knockdown of spinal menin alleviated nerve injury evoked mechanical hypersensitivity, which was strongly associated with the alteration of the spinal level of GAD65 that resulted in an imbalance of glutamate/GABA ratio from the baseline ratio of 5.8 ± 0.9 (×10(-4)) to the peak value of 58.6 ± 11.8 (×10(-4)) at the day 14 after SNI (p < 0.001), which was reversed by MEN1 siRNA to 14.7 ± 2.1 (×10(-4)) at the day 14 after nerve injury (p < 0.01). In further, selective inhibitors of HDACs considerably reversed the ratio of spinal glutamate and GABA, and also alleviated the mechanical withdrawal threshold markedly. CONCLUSION: Our findings provide mechanistic insight into the contribution of the upregulated spinal menin to peripheral nerve injury induced neuropathic hypersensitivity by regulating glutamate-GABA balance through deactivating GAD65.

Pesando riscos e benefícios: lições aprendidas com as intervenções terapêuticas de um caso com pré-eclâmpsia grave / Balancing the benefits and risks: lessons learned from the therapeutic interventions of a case with severe preeclampsia / Balance entre beneficios y riesgos: lecciones aprendidas con las intervenciones terapéuticas de un caso con preclampsia grave

JUSTIFICATIVA E OBJETIVO: A pré-eclâmpsia é uma síndrome da disfunção de múltiplos órgãos (SDMO) devido a suas manifestações típicas e atípicas que incluem hipertensão, proteinúria, síndrome HELLP, encefalopatia hipertensiva e coagulopatia. O manejo ideal desses pacientes requer uma avaliação do balanço entre os benefícios e riscos das estratégias terapêuticas, anestésicas e obstétricas. RELATO DE CASO: Paciente grávida de 35 anos, com uma gravidez anterior sem complicações, deu entrada em nosso instituto médico em caráter de emergência às 29 semanas de gravidez. A paciente apresentava-se com tontura, angústia no peito, palpitação, visão embaçada e sangramento vaginal. Após exame físico e laboratorial, a paciente foi diagnosticada com pré-eclâmpsia grave, síndrome HELLP, descolamento prematuro da placenta e SDMO. A paciente também apresentava deformidade da coluna vertebral e pélvica, fixação da articulação mandibular e deslocamento traqueal por causa de um acidente de trânsito ocorrido havia 11 anos. Portanto, uma cesariana de urgência foi feita sob anestesia geral com intubação nasotraqueal usando fio-guia. A paciente recebeu alta diretamente da unidade de terapia intensiva obstétrica no sétimo dia pós-operatório, com pressão arterial normal e recuperação completa das funções orgânicas. CONCLUSÕES: Este caso merece uma discussão mais detalhada sobre as considerações anestésicas no momento de se tomar uma decisão clínica para o tratamento de tal paciente. O bloqueio do neuroeixo é a primeira escolha para pacientes com pré-eclâmpsia submetidas à cesariana quando existe uma trombocitopenia moderada, mas não progressiva. Quando se opta pela anestesia geral, sedação e analgesia adequadas são necessárias para o bom controle da resposta do estresse à intubação, especialmente em pacientes com sinais neurológicos, e para evitar complicações cerebrais sérias.

BACKGROUND AND OBJECTIVE: Preeclampsia is a multiple organ dysfunction syndrome (MODS) for its typical and atypical manifestations including hypertension, proteinuria, HELLP syndrome, hypertensive encephalopathy and coagulopathy. Optimal management for such patients is determined from an assessment of the balance between benefits and risks of anesthetic and obstetric therapeutic strategies. CASE REPORT: A 35-year-old pregnant woman, with one past uncomplicated pregnancy presented at 29 weeks to our medical institute as an emergency with dizziness, chest distress, palpitation, blurred vision and vaginal bleeding. After physical examination and laboratory tests, the patient was diagnosed with severe preeclampsia, HELLP syndrome, placental abruption, and MODS. The patient also presented spinal and pelvic deformity, fixation of articulus mandibularis, and tracheal displacement because of a traffic accident 11 years ago. Therefore, urgent cesarean section was performed under general anesthesia with nasal tracheal intubation using a guide wire. The patient was discharged directly home from the obstetric intensive care unit on the 7th postoperative day with normal blood pressure and full recovery of organic function. CONCLUSIONS: This case merits further discussion on the anesthesia considerations concerning how to make a clinical decision when treating such a patient. Neuraxial block is the first choice for preeclampsia patients undergoing cesarean section when a moderate but not progressive thrombocytopenia exists. When general anesthesia is decided, adequate sedation and analgesia is needed to better control the stress response to intubation especially in patients with neurological signs, and to prevent major cerebral complications.

JUSTIFICATIVA Y OBJETIVOS: La preclampsia es un síndrome de la disfunción de múltiples órganos (SDMO) debido a sus manifestaciones típicas y atípicas que incluyen hipertensión, proteinuria, síndrome HELLP, encefalopatía hipertensiva y coagulopatía. El manejo ideal de esos pacientes necesita una evaluación del balance entre los beneficios y riesgos de las estrategias terapéuticas, anestésicas y obstétricas. RELATO DE CASO: Paciente embarazada de 35 años, con un embarazo anterior sin complicaciones, llegó a nuestro instituto médico en carácter de urgencia a las 29 semanas de embarazo. La paciente estaba con mareos, molestias en el pecho, cardiopalmia, visión nublada y sangramiento vaginal. Posteriormente al examen físico y laboratorial, la paciente fue diagnosticada con preclampsia grave, síndrome HELLP, desplazamiento prematuro de la placenta y SDMO. La paciente también presentaba una deformidad de la columna vertebral y pélvica, fijación de la articulación mandibular y desplazamiento traqueal debido a un accidente de tránsito ocurrido hacía 11 años. Por tanto, se realizó una cesárea de urgencia con anestesia general con intubación nasotraqueal usando un cable guía. La paciente recibió alta directamente de la unidad de cuidados intensivos obstétrica (UCI-OB) al séptimo día del postoperatorio, con una presión arterial normal y la recuperación completa de las funciones orgánicas. CONCLUSIONES: Este caso merece una discusión más detallada sobre las consideraciones anestésicas al momento de tomar una decisión clínica para el tratamiento de tal paciente. El bloqueo del neuro eje es la primera elección para pacientes con preclampsia sometidas a la cesárea cuando existe una trombocitopenia moderada, pero no progresiva. Cuando se opta por la anestesia general, una sedación y una analgesia adecuadas se hacen necesarias para el buen control de la respuesta del estrés a la intubación, especialmente en los pacientes con signos neurológicos, y para evitar las complicaciones cerebrales serias.

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans.

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease.

Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine.

In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and used it to study the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective; cocaine had no effect on nicotine-induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data from mice. If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction.

A cardiolipina é o alvo da cardiotoxicidade dos anestésicos locais?: [revisão] / Is cardiolipin the target of local anesthetic cardiotoxicity?: [review]

JUSTIFICATIVA E OBJETIVOS: Os anestésicos locais são amplamente utilizados na prevenção ou na reversão de dor aguda e no tratamento de dor crônica. A reação de cardiotoxicidade induzida pelos anestésicos locais é um evento acidental sem terapia farmacológica, exceto a infusão de intralípides relatados recentemente cujo mecanismo de ação ainda não é bem compreendido. CONTEÚDO: A cardiolipina, um fosfolipídio aniônico, desempenha papel relevante na determinação de reação respiratória mitocondrial, metabolismo de ácidos graxos e apoptose celular. A disfunção do metabolismo energético mitocondrial é sugerida em associação com a cardiotoxicidade dos anestésicos locais, a partir de um estudo in vitro de que ela talvez se deva a fortes ligações eletrostáticas entre os anestésicos locais e a cardiolipina na membrana mitocondrial. Não há, contudo, evidência experimental. Portanto, levantamos a hipótese de que as interações anestésico-cardiolipina sejam o principal determinante associado à reação de cardiotoxicidade, o que pode ser estabelecido com a adoção de métodos teóricos e biológicos estruturais. Esse modelo de interação nos daria uma pista sobre o mecanismo da cardiotoxicidade dos anestésicos locais, visando a futuras pesquisas na área de desenvolvimento de fármacos de prevenção a esse evento na prática clínica. CONCLUSÕES: A interação entre a cardiolipina mitocondrial e os anestésicos locais pode ser a principal fonte de sua cardiotoxicidade, em função de seus efeitos sobre o metabolismo energético e o estado eletrostático.

BACKGROUND AND OBJECTIVES: Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. Local anesthetic-induced cardiotoxic reaction has been considered the accidental event without currently effective therapeutic drugs except for recently reported intralipid infusion whose possible mechanism of action is not well known. CONTENTS: Cardiolipin, an anionic phospholipid, plays a key role in determining mitochondrial respiratory reaction, fatty acid metabolism and cellular apoptosis. Mitochondrial energy metabolism dysfunction is suggested as associated with local anesthetic cardiotoxicity, from an in vitro study report that the local anesthetic cardiotoxicity may be due to the strong electrostatic interaction of local anesthetics and cardiolipin in the mitochondria membrane, although there is a lack for experimental evidence. Herein we hypothesized that local anesthetic-cardiolipin interactions were the major determinant of local anesthetic-associated cardiotoxic reaction, established by means of theoretic and structural biological methods. This interacting model would give an insight on the underlying mechanism of local anesthetic cardiotoxicity and provide clues for further in depth research on designing preventive drugs for such inadvertent accidence in routine clinical practice. CONCLUSIONS: The interaction between local anesthetic and mitochondrial cardiolipin may be the underlying mechanism for cardiotoxicity affecting its energy metabolism and electrostatic status.

Continuous infusion of butorphanol combined with intravenous morphine patient-controlled analgesia after total abdominal hysterectomy: a randomized, double-blind controlled trial.

BACKGROUND AND OBJECTIVE: Postoperative pain therapy is still a problem for clinicians. Continuous basal infusion of drugs combined with standard patient-controlled analgesia (PCA) is considered to be an effective means of postoperative acute pain management. This study was designed to investigate the analgesic efficacy, morphine-sparing effects and side effects of butorphanol delivered as a continuous infusion adjunct to intravenous morphine PCA after abdominal hysterectomy. METHODS: One hundred and eighty-six ASA physical status I-II patients, undergoing total abdominal hysterectomy, were allocated to this randomized double-blind controlled study and assigned to one of two groups. In the butorphanol (n = 96) group, patients received an intravenous loading dose of 10 microg kg(-1) butorphanol followed by infusion of 2 microg kg(-1) h(-1) butorphanol combined with intravenous PCA set at a bolus of 0.02 mg kg(-1) morphine after surgery. The control group (n = 90) received a physiological saline infusion combined with the same morphine PCA. Pain intensity on movement and at rest, sedation, satisfaction with analgesia, morphine consumption and side effects were recorded. RESULTS: A total of 164 patients completed the study. The butorphanol group had analgesia superior to the physiological saline control (P < 0.001). The butorphanol infusion group produced higher sedation ratings (P < 0.001) and better satisfaction (P < 0.05) and a lower incidence of side effects (P < 0.001) with the exception of sweating and dry mouth (P < 0.05) than the physiological saline group. The butorphanol group consumed less morphine over 48 h, 24.6 mg (95% confidence interval, 18.7-46.6), than the physiological saline group, 58.5 mg (95% confidence interval, 41.5-79.2; P = 0.006). There were no differences between urinary catheterization of more than 24 h, first time out of bed and time to discharge to home. CONCLUSION: Basal infusion of butorphanol combined with intravenous morphine PCA in patients undergoing abdominal hysterectomy shows effective analgesia with sedation and fewer side effects.

Preoperative tramadol combined with postoperative small-dose tramadol infusion after total abdominal hysterectomy: a double-blind, randomized, controlled trial.

This double blind, randomized, controlled trial investigated whether a single preoperative intravenous (iv) dose of tramadol (100 mg) given 30 min before abdominal hysterectomy resulted in improved analgesic efficacy, reduced postoperative morphine patient-controlled analgesia (PCA) use and reduced side effects when combined with a postoperative small-dose tramadol infusion. Two-hundred twenty-four patients undergoing elective abdominal hysterectomy were randomly allocated to one of two groups: the tramadol group (n = 113) received iv tramadol (100 mg) 30 min before surgery, and the control group (n = 111) received an equivalent volume of normal saline. Upon awakening from general anesthesia, all patients received a loading dose of 0.5 mg/kg of tramadol and a small-dose infusion of tramadol (0.1 mg/kg/h) for 48 h. In addition, all patients were connected to morphine PCA delivering a morphine bolus of 0.02 mg/kg with a 6-min lock-out. Data on pain intensity at rest and during movement, morphine consumption, side-effects and overall patient satisfaction were recorded. A total of 189 patients completed the study. Preemptive tramadol was associated with superior analgesia at rest and with movement in the first 24 h after surgery (p < 0.01), a longer interval to first morphine PCA request (p = 0.019), and reduced morphine PCA use (p = 0.017). The tramadol group had reduced nausea (p = 0.015), dizziness (p = 0.001) and drowsiness (p = 0.0001), while other side-effects were similar. In conclusion, a single dose of iv tramadol (100 mg) 30 min prior to abdominal hysterectomy improves analgesia, and reduces morphine PCA requirements, nausea, dizziness and drowsiness when combined with a postoperative small-dose tramadol infusion and morphine PCA when compared to the same analgesic regimen that omitted the preemptive tramadol.

Comparison of the analgesic efficacy of preemptive and preventive tramadol after lumpectomy.

The aim of this study was to investigate the analgesic efficacy of tramadol administrated preemptively or preventively in the earlier period of lumpectomy. Four hundred American Society of Anesthesiologists (ASA) physical status I-II patients, undergoing lumpectomy, were screened and 317 were randomly assigned into one of two groups. In the preemptive tramadol (n = 158) group, patients received an iv injection of tramadol 100 mg 15 min before operation. The preventive group (n = 159) received the same dose of tramadol 15 min before the end of the operation. Pain intensity at rest, overall satisfaction score, morphine consumption and side effects were recorded. A total of 299 patients completed the study. Preemptive and preventive subjects experienced similar analgesic effect and feeling of satisfaction at the first 24 h after surgeries. The similar amount of additional morphine was consumed [4.6 mg (95% CI 1.5-7.2) vs. 4.1 mg (95% CI 1.2-6.3), p = 0.811]. No intergroup difference was observed in the incidence of side effects. In conclusion, preemptive and preventive administration of tramadol expressed analgesia of similar efficacy up to 24 h after lumpectomy. The additional morphine requirement, the overall satisfaction and the frequency of side effects all did not display significant difference between the two groups. This implies that the administration of tramadol either before the start or before the end of the surgical procedures all can produce effective postoperative analgesia.

CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum.

Remodeling chromatin is essential for cAMP-regulated gene expression, necessary not only for development but also for memory storage and other enduring mental states. Histone acetylation and deacetylation mediate long-lasting forms of synaptic plasticity in Aplysia as well as cognition in mice. Here, we show that histone acetylation by the cAMP-response element binding protein (CREB)-binding protein (CBP) mediates sensitivity to cocaine by regulating expression of the fosB gene and its splice variant, DeltafosB, a transcription factor previously implicated in addiction. Using the chromatin immunoprecipitation assay with antibodies against histone H4 or CBP, we find that CBP is recruited to the fosB promoter to acetylate histone H4 in response to acute exposure to cocaine. We show that mutant mice that lack one allele of the CBP gene and have normal levels of fosB expression are less sensitive to chronic (10-day) administration of cocaine than are wild-type mice. This decreased sensitivity is correlated with decreased histone acetylation and results in decreased fosB expression and diminished accumulation of DeltafosB. Thus, CBP, which forms part of the promoter complex with CREB, mediates sensitivity to cocaine by acetylating histones.

p38 MAP kinase mediates both short-term and long-term synaptic depression in aplysia.

At Aplysia sensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers. We find that FMRFa leads to the phosphorylation and activation of p38 mitogen-activated protein (MAP) kinase. Short-term depression and the release of arachidonate are blocked by the specific p38 kinase inhibitor SB 203580. Both the inhibitor and an affinity-purified antibody raised against recombinant Aplysia p38 kinase injected into sensory neurons prevented long-term depression, which depends on the phosphorylation of translation factors cAMP response element-binding protein 2 (CREB2) and activating transcription factor 2. Facilitation produced by 5-HT, on the other hand, inactivates p38 kinase. Chromatin immunoprecipitation assays indicate that p38 kinase activates CREB2. p38 kinase also is pivotal in the bidirectional regulation of synaptic plasticity: when the kinase is inhibited, brief treatment with 5-HT that normally produces only short-term facilitation now results in long-term facilitation. Conversely, in sensory neurons injected with the activated kinase, long-term facilitation is blocked, and brief exposure to FMRFa, which normally results in short-term depression, results in long-term depression. We conclude that p38 kinase, which itself is bidirectionally regulated by FMRFa and 5-HT, acts as a modulator of synaptic plasticity by positively regulating depression and serving as an inhibitory constraint for facilitation.