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Biomedical subjects

Tomohiko Aoe

Publications and source records attributed to Tomohiko Aoe.

7 recordsLinked to original sources
PubMed2006

Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain.

PURPOSE: Not all bone cancer pain can be effectively treated with current therapies. In the present study, the effects of ip administration of alpha-2 agonists (dexmedetomidine and clonidine), N-methyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), an N-acetylaspartylglutamate peptidase inhibitor (ZJ-43), and morphine were examined in a mouse bone cancer pain model. METHODS: A bone cancer pain model was produced by injection of murine sarcoma cells into the medullary cavity of the distal femur. To estimate the level of bone cancer pain, the number of pain-related behaviours induced by repeated applications of a von Frey monofilament (0.166 g) to the site of tumour cells implantation was counted. Drugs were administered two weeks after the implantation. RESULTS: Morphine produced a significant analgesic effect (P < 0.001). The alpha-2 agonists produced analgesic effects (P < 0.001) with an efficacy similar to that of morphine, but only at doses that produced severe sedation. MK-801 had only limited analgesic effects, while ketamine produced an analgesic effect (P < 0.001) with the same efficacy as morphine. ZJ-43 (100 mg.kg(-1)) had a significant analgesic effect (P < 0.05) and the effect of ZJ-43 was antagonized by the selective group II metabotropic glutamate receptor (mGluR) antagonist. CONCLUSION: These data suggest that alpha-2 agonists produce an analgesic effect only at a sedative dose and that ketamine, but not MK-801, is associated with an analgesic response without overt side effects. The effect of ZJ-43 is mediated by activating group II mGluRs.

Adrenergic alpha-Agonists↗
PubMed2005

Analgesic effects of nonsteroidal antiinflammatory drugs, acetaminophen, and morphine in a mouse model of bone cancer pain.

PURPOSE: Bone metastasis is one of the major causes of cancer-related pain, and not all bone cancer pain can be effectively treated. Recently, a mouse model of bone cancer pain was introduced. To test the analgesic effects of nonsteroidal antiinflammatory drugs on bone cancer pain, the authors examined the effects of oral administration of a cyclooxygenase-1 (COX-1) selective inhibitor (SC560), a COX-2 selective inhibitor (celecoxib), and a nonselective COX inhibitor (indomethacin) on bone cancer pain and compared these effects to the effect of orally administered acetaminophen and morphine. METHODS: An animal model of bone cancer pain was induced by injecting osteolytic murine sarcoma cells in the mouse femur. Drugs were administered orally 2 weeks after tumor-cell implantation, and the level of bone cancer pain was assessed 30, 60, 90, 120, and 180 min after drug administration. RESULTS: Oral administration of acetaminophen, indomethacin, and morphine, but not of SC560 or celecoxib, produced an analgesic effect on bone cancer pain. Co-administration of a subanalgesic does of morphine with acetaminophen enhanced the analgesic effect of acetaminophen. CONCLUSION: These data suggest that bone cancer pain is effectively treated by oral administration of indomethacin, acetaminophen, and morphine and that the co-administration of acetaminophen and an opioid provides a beneficial effect when treating of bone cancer pain.

Acetaminophen↗
PubMed2004

Reduction of SNAP25 in acid secretion defect of Foxl1-/- gastric parietal cells.

Foxl1 is a winged helix transcription factor expressed in the mesenchyme of the gastrointestinal tract. In the absence of Foxl1, parietal cells fail to secrete gastric acid in response to various secretagogue stimuli including cAMP. A marked decrease in H+,K(+)-ATPase expression was observed even though a substantial number of parietal cells still existed in Foxl1-deficient mice. Ultrastructural analysis suggested that the gastric acid secretion defect in Foxl1-deficient mice is mainly due to impairment in the fusion of cytoplasmic tubulovesicular structures to the apical canalicular plasma membrane. Among the molecules involved in the membrane fusion event, only SNAP25 showed a significant decrease in mRNA expression, which likely caused the impairment in acid secretion from parietal cells in Foxl1-deficient mice, with the reduction in H+,K(+)-ATPase expression contributing to additional effect.

Animals↗
PubMed2004

Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice.

Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca(2+) current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.

Animals↗
PubMed2003

Anti-mechanical allodynic effect of intrathecal and intracerebroventricular injection of orexin-A in the rat neuropathic pain model.

Orexin-A has been reported to produce an analgesic effect in the hot plate test and in the inflammatory pain models. In the present study, the authors examined the effect of orexin-A on the mechanical allodynia induced by partial sciatic nerve ligation (a model of neuropathic pain) in the rat. Partial sciatic nerve ligation is created by tight ligation of one-third or one-half of the right sciatic nerve. Orexin-A was administered intrathecally or intracerebroventricularly 7 days after a partial sciatic nerve injury. Either intrathecal or intracerebroventricular injection of orexin-A attenuated the level of mechanical allodynia induced by partial sciatic nerve ligation. These data suggest that either intrathecal or intracerebroventricular injection of orexin-A is a new therapeutic approach to treating mechanical allodynia caused by nerve injury.

Animals↗
PubMed2003

The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response. The resultant outcomes are cytoprotective but also proapoptotic. ER chaperones and misfolded proteins exit to the secretory pathway and are retrieved to the ER, during which process the KDEL receptor plays a significant role. Using an expression of a mutant KDEL receptor that lacks the ability for ligand recognition, we show that the impairment of retrieval by the KDEL receptor led to a mis-sorting of the immunoglobulin-binding protein BiP, an ER chaperone that has a retrieval signal from the early secretory pathway, which induced intense ER stress response and an increase in susceptibility to ER stress in HeLa cells. Furthermore, we show that the ER stress response accompanied the activation of p38 mitogen-activated protein (MAP) kinases and c-Jun amino-terminal kinases (JNKs) and that the expression of the mutant KDEL receptor suppressed the activation of p38 and JNK1 but not JNK2. The effect of the expression of the mutant KDEL receptor was consistent with the effect of a specific inhibitor for p38 MAP kinases, because the inhibitor sensitized HeLa cells to ER stress. We also found that activation of the KDEL receptor by the ligand induced the phosphorylation of p38 MAP kinases. These results indicate that the KDEL receptor participates in the ER stress response not only by its retrieval ability but also by modulating MAP kinase signaling, which may affect the outcomes of the mammalian ER stress response.

Carrier Proteins↗