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        Yokukansan, a Kampo medicine, prevents the development of morphine tolerance through the inhibition of spinal glial cell activation in rats

        Mariko Takemoto,Masataka Sunagawa,Mayumi Okada,Hideshi Ikemoto,Hiroki Suga,Ayami Katayama,Hiroshi Otake,Tadashi Hisamitsu 한국한의학연구원 2016 Integrative Medicine Research Vol.5 No.1

        Background Animal models have shown that glial cells (microglia and astrocytes) in the spinal cord undergo activation following peripheral injury associated with chronic pain, suggesting the involvement of these cells in pain diseases. We have previously reported that Yokukansan (YKS), a Japanese traditional herbal (Kampo) medicine, is effective against chronic pain through the suppression of spinal glial cell activation. Morphine is a widely-used opioid analgesic for relieving severe pain, but its repeated administration leads to the development of antinociceptive tolerance. The development of morphine tolerance is also reported to be caused by spinal glial cells activation. In the present study, we investigated the inhibitory effects of YKS on the development of morphine tolerance and the activation of the spinal microglia and astrocytes using a rat model. Methods Male Wistar rats received a subcutaneous injection of morphine hydrochloride (10 mg/kg/d) for 7 days, and the withdrawal latency to thermal stimulation was measured daily using a hot plate test. Thereafter, the appearance of activated microglia and astrocyte in the spinal cord (L5) was examined by immunofluorescence staining. Ionized calcium binding adapter molecule-1 (Iba-1) staining was used to label microglia and glial fibrillary acidic protein (GFAP) staining was performed to label astrocytes. YKS was administered mixed with powdered rodent chow at a concentration of 3%. Results The preadministration of YKS (started 3 d before the morphine injection) prevented the development of morphine tolerance. The repeated administration of morphine increased Iba-1 and GFAP immune reactivities in the spinal cord; however, these activations were inhibited by the preadministration of YKS. Conclusion These results suggest that the preadministration of YKS attenuates the development of antinociceptive morphine tolerance, and the suppression of spinal glial cell activation may be one mechanism underlying this phenomenon.

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        Acotiamide Has No Effects on Esophageal Motor Activity or Esophagogastric Junction Compliance

        Hironobu Mikami,Norihisa Ishimura,Mayumi Okada,Daisuke Izumi,Eiko Okimoto,Shunji Ishihara,Yoshikazu Kinoshita 대한소화기 기능성질환∙운동학회 2018 Journal of Neurogastroenterology and Motility (JNM Vol.24 No.2

        Background/Aims The novel prokinetic drug acotiamide is used for treatment of functional dyspepsia. It is still unclear how acotiamide has effects on esophageal motor function. Esophageal peristalsis and esophagogastric junction (EGJ) compliance has an important role for prevention of esophageal mucosal damage caused by gastroesophageal reflux, however, few studies have analyzed the effects of acotiamide on those former activities and none have investigated its effects on EGJ compliance. The aim of our research was to examine the effects of acotiamide on esophageal motility and EGJ compliance. Methods We enrolled 3 gastroesophageal reflux disease (GERD) patients as well as 9 healthy volunteers. Using high-resolution manometry, we examined esophageal motor activity parameters, including esophageal body contractions and lower esophageal sphincter (LES) pressure. While, EGJ compliance was evaluated using a functional lumen imaging probe. Following determination of baseline values for esophageal motor activities and EGJ compliance, acotiamide at a standard dose of 300 mg/day was administered for 3 days. All measurements were performed again 2 hours after the last acotiamide administration. Results In the healthy volunteers, as compared with the baseline values, acotiamide administration did not significantly change esophageal body contractions and LES pressure. And EGJ distensibility was not significantly changed (distensibility index in 40-mL distension: 3.5 ± 0.4 vs 3.3 ± 0.5 mm2/mmHg). Similarly in the GERD patients, there were no differences in either esophageal motility or EGJ compliance between before and after acotiamide administration (distensibility index in 40-mL distension: 6.2 ± 0.5 vs 6.5 ± 1.1 mm2/mmHg). Conclusion In both healthy individuals and GERD patients, standard dose acotiamide dose does not have significant effects on esophageal motor activities or EGJ compliance.

      • SCIESCOPUSKCI등재

        Effects of Metoclopramide on Esophageal Motor Activity and Esophagogastric Junction Compliance in Healthy Volunteers

        ( Hironobu Mikami ),( Norihisa Ishimura ),( Kousuke Fukazawa ),( Mayumi Okada ),( Daisuke Izumi ),( Shino Shimura ),( Eiko Okimoto ),( Masahito Aimi ),( Shunji Ishihara ),( Yoshikazu Kinoshita ) 대한소화기기능성질환·운동학회 2016 Journal of Neurogastroenterology and Motility (JNM Vol.22 No.1

        Background/Aims Prokinetic drugs such as metoclopramide are frequently used as second-line therapy for patients with gastroesophageal reflux disease. However, their beneficial effects remain unclear. Esophageal motor activities and compliance of the esophagogastric junction (EGJ) are important for prevention of gastroesophageal reflux. Although metoclopramide has been reported to increase lower esophageal sphincter (LES) pressure, its effects on EGJ compliance have not been evaluated. In the present study, we investigated the effects of metoclopramide on esophageal motor activities and EGJ compliance. Methods Nine healthy male volunteers without abdominal symptoms were enrolled. Peristaltic esophageal contractions and LES pressure were examined using high-resolution esophageal manometry, while EGJ compliance was evaluated with an endoluminal functional lumenimaging probe. After obtaining baseline values for esophageal motor activities and EGJ compliance, metoclopramide (10 mg) was intravenously administered, then all measurements were repeated at 15 minutes after administration in each subject. Results Following administration of metoclopramide, mean resting LES pressure was significantly increased as compared with the baseline (13.7 ± 9.2 vs 26.7 ± 8.8 mmHg, P < 0.05). In addition, metoclopramide significantly augmented peristaltic contractions, especially in the distal esophageal segment (P < 0.05). On the other hand, distensibility index did not change after administration (4.5 ± 0.5 vs 4.1 ± 0.5 mm2/mmHg), suggesting no significant effect of metoclopramide on EGJ compliance. Conclusions Metoclopramide augmented esophageal contractions without changing EGJ compliance in healthy adults. (J Neurogastroenterol Motil 2016;22:112-117)

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