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.

Decoy strategy targeting the brain-derived neurotrophic factor exon I to attenuate tactile allodynia in the neuropathic pain model of rats.

The mechanism underlying neuropathic pain is still largely unclear. Recently, much attention has been focused on the role of brain-derived neurotrophic factor (BDNF) as a neuromodulator in the spinal cord. We previously reported that the expression of Bdnf exon I mRNA was remarkably up-regulated in the dorsal root ganglion (DRG) neurons with the rat L5 spinal nerve ligation (SNL) model. In the present study, we investigated whether neuropathic pain response would be reduced by the inhibition of the Bdnf exon I in the rat SNL model. We identified the promoter region of exon I and synthesized the decoy ODNs targeting the region. Reverse transcription-polymerase chain reaction analysis confirmed that the decoy ODN treatment reduced SNL-induced Bdnf exon I mRNA up-regulation in ipsilateral L4 and L5 DRGs. Furthermore, post-treatment with the decoy ODNs significantly attenuated SNL-induced tactile allodynia. This study suggested that decoy ODNs targeting the Bdnf exon I might provide a novel analgesic strategy for the treatment of neuropathic pain.

[Acute pulmonary thromboembolism after multiple injuries, despite performing anticoagulant therapy].

We report here a patient with acute pulmonary thromboembolism after multiple injuries, despite performing an anticoagulant therapy precisely according to a guideline. A 56 year-old-woman with multiple fractures was transferred after a motor vehicle accident. She was diagnosed with a pelvic fracture, a left clavicular fracture, and a right radius fracture. For preventing deep vein thrombosis DVT, elastic stockings were attached immediately on arrival. Then we started administration of unfractionated heparin on the second day. An operation was performed for the left clavicular fracture and the right radius fracture on the fifth day. We restarted subcutaneous injection of heparin on the sixth day and 1 mg day(-1) of warfarin was added from the ninth day. On the 12th day, sudden dyspnea suggested acute pulmonary embolism and a pulmonary arteriography confirmed occlusion of the left main pulmonary artery with thombocyte. Interventional anti-thorombotic procedure was performed, and she was discharged with no complications on the 72nd day. Despite "A Guideline for Prevention of Venous Thromboembolism", arranged in Japan, was issued in June 2004, it is difficult for us to prevent DVT at the recovery phase as in this case. The guideline should be revised after further examinations.

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.

Expression changes of the neuregulin 1 isoforms in neuropathic pain model rats.

The neuregulin1 (Nrg1) gene that is expressed in the dorsal root ganglion (DRG) contains an EGF-like domain, which is known to be a direct ligand for ErbB3 and ErbB4. Multiple splice variants of the Nrg1 gene are broadly classified into 3 groups by structural features (type I, type II and type III) and their functions differ in various tissues. The Nrg1 gene has emerged as a key mediator of axon-Schwann cell interactions and as a regulator of Schwann cell development. The Nrg1 gene is indicated as a promising growth factor for neuronal development. However, the function of the Nrg1 in pain has not been clarified. We therefore, examined the expression profiles of each type of the Nrg1 transcript in the bilateral L4/L5 DRGs using L5 spinal nerve ligation (SNL) model rats and complete Freund's adjuvant (CFA) model rats. Behavior tests have shown typical mechanical hyperalgesia in both the L5SNL model and the CFA model. In the L5SNL model, expression of the Nrg1 type I and type II were significantly increased in the L5 DRG. On the other hand, the expression of the Nrg1 type III was decreased in the L5 DRG. We demonstrated that the expression changes of the Nrg1 isoforms in the ipsilateral DRGs were preferentially related to the response to nerve injury. Our findings suggest that the aberrant expression may play an important role in nerve injury, regeneration and subsequent neuropathic pain on the L5SNL.