Attempt of obstinacy pain easing by spinal cord GABA-B receptor continuation activation.

尝试通过脊髓 GABA-B 受体持续激活来缓解顽固性疼痛。

• 批准号: 17500254
• 负责人: UEZONO Yasuhito
• 金额: $ 2.24万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500254/
• 关键词: Desensitization of GABA_B receptors; GRK4; Ketamine; FRET; Immunochemistry; Persistent analgesia; 持続的鎮痛緩和; 接続的鎮痛緩和

Recent reports have shown that intrathecal administration of GABA_B receptor agonist baclofen (ITB, intrathecal baclofen) is effective for intolerable pain such as neuropathic pain. Even such effective ITB therapy, prolonged application of baclofen causes tolerance and then decreases analgesic effects in patients. The main cause of the tolerance of ITB therapy arises from desensitization of GABA_B receptors due to continuous activation of the receptors. We have recently reported that G protein-coupled receptor kinase 4 (GRK4) and GRK5 are involved in the desensitization processes of GABA_B receptors (Kanaide et al., J Cell Physiol. (2007)). In the present study we sought to find drugs that inhibit GRK4 and GRK5 activity to persistently stimulate GABA_B receptors.Our findings suggest that ketamine, an anesthetic and an inhibitor of NMDA receptors, efficiently inhibited the properties of GRK4 and GRK5 to finally cause attenuation of desensitization of GABA_B receptors induced by prolonged application of baclefen in the Xenopus oocyte and baby hamster kidney cell expression systems.These results imply that co-administration of both baclofen and ketamine may inhibit desensitization of GABA_B receptors and eventually cause persistent analgesic effects without tolerance in the ITB therapy. Further studies with the whole body animals and preliminary clinical trials would be required to confirm the 'safe and effective ITB therapy' for patients suffering from severe pain.

最近的报道表明，鞘内注射GABA_B受体激动剂巴氯芬(ITB，鞘内巴氯芬)对神经病理性疼痛等难以忍受的疼痛是有效的。即使是如此有效的ITB疗法，长期应用巴氯芬也会引起患者的耐受性，进而降低患者的止痛效果。ITB治疗耐受的主要原因是由于GABA_B受体的持续激活而使其脱敏。我们最近报道了G蛋白偶联受体激酶4(GRK4)和GRK5参与了GABA_B受体的脱敏过程(Kanaide等人，J Cell Physiol)。(2007))。在本研究中，我们试图寻找抑制GRK4和GRK5活性的药物来持续刺激GABA_B受体。我们的研究结果表明，麻醉剂和NMDA受体的抑制剂氯胺酮有效地抑制了GRK4和GRK5的特性，最终导致巴克莱芬在非洲爪哇卵母细胞和幼鼠肾细胞表达系统中引起的GABA_B受体脱敏的减弱。这些结果表明，联合应用巴氯芬和氯胺酮可能抑制GABA_B受体的脱敏，最终在ITB治疗中产生无耐受性的持续镇痛效应。需要对全身动物进行进一步的研究和初步的临床试验，才能确认对患有严重疼痛的患者使用ITB疗法是安全有效的。

项目成果

The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes

• DOI: 10.1159/000093179
• 发表时间: 2006-01-01
• 期刊: PHARMACOLOGY
• 影响因子: 3.1
• 作者: Horishita, Takafumi;Minami, Kouichiro;Shigematsu, Akio
• 通讯作者: Shigematsu, Akio

自律神経は消化管運動のmajor regulatorか?

自主神经系统是胃肠蠕动的主要调节者吗？

• 发表时间: 2006
• 期刊: 分子消化器病 3 (4)
• 作者: 谷山紘太郎;上園保仁
• 通讯作者: 上園保仁

Inhibition by selenium compounds of catecholamine secretion due to inhibition of Ca2+ influx in cultured bovine adrenal chromaffin cells.

• DOI: 10.1254/jphs.fp0060204
• 发表时间: 2006
• 期刊: Journal of pharmacological sciences
• 影响因子: 3.5
• 作者: Y. Uezono;Y. Toyohira;N. Yanagihara;A. Wada;K. Taniyama

Coupling of the GABA_B receptor GABA_<B2> subunit to G protein : Evidence from the Xenopus oocyte and baby hamster kidney cell expression system.

GABA_B 受体 GABA_<B2> 亚基与 G 蛋白的偶联：来自非洲爪蟾卵母细胞和幼仓鼠肾细胞表达系统的证据。

• 发表时间: 2006
• 期刊: American Journal of Physiology - Cell Physiology 269
• 作者: Uezono Y;et al.
• 通讯作者: et al.

Inhibition by selenium compounds of catecholamine secretion due to inhibition of Ca^<2+> influx in bovine adrenal chromaffin cells.

由于抑制牛肾上腺嗜铬细胞中的Ca 2+ 流入，硒化合物对儿茶酚胺分泌的抑制。

• 发表时间: 2006
• 期刊: Journal of Pharmacological Sciences 101
• 作者: Uezono Y;et al.
• 通讯作者: et al.