Antinociceptive Effects of Intrathecal Landiolol Injection in a Rat Formalin Pain Model

Perioperative beta-blocker administration has recently been recommended for patients undergoing cardiac or other surgery due to the beneficial cardiovascular effects of these agents. In addition, some studies have reported that perioperatively administered beta-blockers also have analgesic effects. In this study, to investigate the antinociceptive effects and the analgesic profile of landiolol, we examined the effects of intrathecal landiolol administration on nociceptive pain behavior and c-fos mRNA expression (a neural marker of pain) in the spinal cord using a rat formalin model. We found that pain-related behavior was inhibited by intrathecal landiolol administration. Moreover, the increase in c-fos mRNA expression on the formalin-injected side was less pronounced in rats administered landiolol than in saline administered controls. Thus, intrathecal administration of landiolol exhibited antinociceptive effects. Further investigation of the antinociceptive mechanism of landiolol is required

Eradication of Hepatitis C Virus Subgenomic Replicon by Interferon Results in Aberrant Retinol-Related Protein Expression

Hepatitis C virus (HCV) infection induces several changes in hepatocytes, such as oxidative stress, steatosis, and hepatocarcinogenesis. Although considerable progress has been made during recent years, the mechanisms underlying these functions remain unclear. We employed proteomic techniques in HCV replicon-harboring cells to determine the effects of HCV replication on host-cell protein expression. We examined two-dimensional electrophoresis (2-DE) and mass spectrometry to compare and identify differentially expressed proteins between HCV subgenomic replicon-harboring cells and their “cured” cells. One of the identified proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Full-length HCV genome RNA replicating and cured cells were also assessed using ELISA. Replicon-harboring cells showed higher expression of retinal dehydrogenase 1 (RALDH-1), which converts retinol to retinoic acid, and the cured cells showed higher expression of retinol-binding protein (RBP), which transports retinol from the liver to target tissues. The alteration in RBP expression was also confirmed by ELISA and Western blot analysis. We conclude that protein expression profiling demonstrated that HCV replicon eradication affected retinol-related protein expression

Truncated SSX Protein Suppresses Synovial Sarcoma Cell Proliferation by Inhibiting the Localization of SS18-SSX Fusion Protein

Synovial sarcoma is a relatively rare high-grade soft tissue sarcoma that often develops in the limbs of young people and induces the lung and the lymph node metastasis resulting in poor prognosis. In patients with synovial sarcoma, specific chromosomal translocation of t(X; 18) (p11.2; q11.2) is observed, and SS18-SSX fusion protein expressed by this translocation is reported to be associated with pathogenesis. However, role of the fusion protein in the pathogenesis of synovial sarcoma has not yet been completely clarified. In this study, we focused on the localization patterns of SS18-SSX fusion protein. We constructed expression plasmids coding for the full length SS18-SSX, the truncated SS18 moiety (tSS18) and the truncated SSX moiety (tSSX) of SS18-SSX, tagged with fluorescent proteins. These plasmids were transfected in synovial sarcoma SYO-1 cells and we observed the expression of these proteins using a fluorescence microscope. The SS18-SSX fusion protein showed a characteristic speckle pattern in the nucleus. However, when SS18-SSX was co-expressed with tSSX, localization of SS18-SSX changed from speckle patterns to the diffused pattern similar to the localization pattern of tSSX and SSX. Furthermore, cell proliferation and colony formation of synovial sarcoma SYO-1 and YaFuSS cells were suppressed by exogenous tSSX expression. Our results suggest that the characteristic speckle localization pattern of SS18-SSX is strongly involved in the tumorigenesis through the SSX moiety of the SS18-SSX fusion protein. These findings could be applied to further understand the pathogenic mechanisms, and towards the development of molecular targeting approach for synovial sarcoma

Delayed Methotrexate Elimination after Administration of a Medium Dose of Methotrexate in a Patient with Genetic Variants Associated with Methotrexate Clearance

Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner

Development of a novel analgesic for cancer pain targeting brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is necessary for nerve growth. BDNF is expressed in the dorsal root ganglion (DRG) and modulates pain transduction from peripheral nociceptors. TrkB, which is a BDNF receptor with a tyrosine kinase domain, acts as a pain modulator on the cell membrane of second neuron. If an exogenous truncated TrkB lacking a tyrosine kinase domain can competitively block the binding of BDNF to endogenous TrkB, inhibitory effects on pain are expected. We constructed two expression vectors coding truncated TrkB-GFP fusion proteins, lacking intracellular tyrosine kinase domain, with and without the transmembrane domain. By transfection of the vectors to HEK293 cells, the expression and localization of the modified receptor proteins were confirmed. The truncated TrkB with the transmembrane domain, TM (+), was localized on cell membrane surface of the transfected cells, and capable of BDNF binding on cell surface. TM (-) without the transmembrane domain was secreted from the transfected cells, and the secreted TrkB protein was confirmed the capability for binding with BDNF by pull-down assay. Furthermore, we developed a rat model of cancerous osteocopic pain for evaluating an analgesic effect of the modified TrkB vectors on cancer pain. Pain-related behavior, as assessed by von Frey tests, indicated hyperalgesia after cancer cell administration. BDNF expression was higher on the affected side of the DRG at the third lumbar vertebra L3 than on the unaffected side. When the modified TrkB vectors were administrated to the cancer pain model rats, both the TM (+) and TM (-) vector administration groups exhibited an analgesic effect. These results suggest that the modified TrkB receptors and their vectors are applicable as molecular targeted drugs for pain control in cancer patients

Up-regulation of brain-derived neurotrophic factor in the dorsal root ganglion of the rat bone cancer pain model

Metastatic bone cancer causes severe pain, but current treatments often provide insufficient pain relief. One of the reasons is that mechanisms underlying bone cancer pain are not solved completely. Our previous studies have shown that brain-derived neurotrophic factor (BDNF), known as a member of the neurotrophic family, is an important molecule in the pathological pain state in some pain models. We hypothesized that expression changes of BDNF may be one of the factors related to bone cancer pain; in this study, we investigated changes of BDNF expression in dorsal root ganglia in a rat bone cancer pain model. As we expected, BDNF mRNA (messenger ribonucleic acid) and protein were significantly increased in L3 dorsal root ganglia after intra-tibial inoculation of MRMT-1 rat breast cancer cells. Among the eleven splice-variants of BDNF mRNA, exon 1–9 variant increased predominantly. Interestingly, the up-regulation of BDNF is localized in small neurons (mostly nociceptive neurons) but not in medium or large neurons (non-nociceptive neurons). Further, expression of nerve growth factor (NGF), which is known as a specific promoter of BDNF exon 1–9 variant, was significantly increased in tibial bone marrow. Our findings suggest that BDNF is a key molecule in bone cancer pain, and NGF-BDNF cascade possibly develops bone cancer pain

A Multidisciplinary Approach to the Management of Chronic Pain through a Self-managed Behavioral Exercise Program : A Pilot Study in Japan

We conducted this study to determine the short-term treatment outcomes of multidisciplinary approaches to chronic pain management for outpatients in Japan. We evaluated pain reduction and improvement in quality of life (QOL) after treatment. We analyzed 32 patients who had experienced intractable chronic pain for > 3 months. The patients received multidisciplinary therapeutic self-managed exercise instructions and then underwent evaluations 1 and 3 months after the treatment. We used the Pain Disability Short Form-36 (SF-36), Pain Catastrophizing Scale (PCS), and Pain Disability Assessment Scale (PDAS) to evaluate QOL. Although the pain levels were the same before and after the physical exercise program, the patients showed significant improvements in physical function on the SF-36 (48.5 vs. 54.5, 3 months vs. 1 month; p=0.0124), the magnification subscale on the PCS (6.8 vs. 5.9, 1 month vs. before; p=0.0164) and the PDAS (29.2 vs. 23.4, 3 months vs. before; p=0.0055). Chronic pain should be treated with a biopsychosocial approach, but time constraints and costs have limited the implementation of multidisciplinary and behavioral approaches to chronic pain management. Our findings demonstrate that clinical improvements are possible for patients with chronic pain, using multidisciplinary team resources widely available in Japanese clinical practice