Neuro-humoral mechanisms of relexive respiratory suppression mediated by endogenous opiated system.

内源性阿片系统介导的反射性呼吸抑制的神经体液机制。

• 批准号: 60440027
• 负责人: KUMAZAWA Takao
• 金额: $ 6.98万
• 依托单位: Res. Inst. of Environ. Med. Nagoya Univ.
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1985
• 资助国家: 日本
• 起止时间: 1985 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-60440027/
• 关键词: Thin-fiber muscular afferent; Polymodal receptor; Respiratory suppression Proglumide; Enkephalin; ELISA; Opioid; 結合腕傍核; オピオイド; 酵素標識免疫測定法; モルフィン; プログロマイド

Our previous works have revealed naloxone-reversible respiratory suppression induced by stimulation of thin-fiber muscular afferents: polymodal receptor inputs. The present work is aimed to elucidate the following questions provided by those previous works. 1)Whether N. parabrachialis (PBN) is implicated in the respiratory inhibition, since previous decerebration experiment suggested the importance of the rostral pons. 2)What kinds of modulation factors are involved, since repeated stimulation reduced the magnitude of the respiratory inhibition. 3) What opioid peptide(s) may be really concerned. In addition the receptor characteristics of polymodal receptors are investigated in detail.Results. 1)Both repetitive electrical stimulation of PBN and microinjection of morphine into PBN produced naloxone-reversible, long lasting respiratory supression, which is similar to that induced by peripheral muscular afferent stimulation. 2)Respiratory suppression produced by morphine did not reduce by its repetitive application, suggesting that opioid tolerance is not the cause of the tachyphylaxis of the reflex res[piratory suppression. Since the tachyphylaxis was antagonized by proglumide, an antagonist of cholecystokinin (CCK), it may be caused by a temporal summation of activities in facilitatory systems such as CCK, which would be simultaneously stimulated by muscular afferents. Effectiveness of the stimulation was shown to be respiratoy-phase dependent; influence of vagal inputs was also suggested. 3)Perfusion through the 4th ventricle-cisterna magna with solution containing enkephalinase inhibitors caused significantly larger reflex respiratory suppression. Concentration of enkephalin determined by ELISA was higher in the elute during and after stimulation than before.The present result reveals an enkephalinergic respiratory regulation mechanism triggered by peripheral polymodal receptor inputs.

我们以前的工作揭示了纳洛酮可逆的呼吸抑制引起的刺激细纤维肌肉传入：多模态受体输入。目前的工作是为了阐明这些以前的工作提供了以下问题。1)无论N.臂旁肌（PBN）参与呼吸抑制，因为先前的去大脑实验表明了头侧脑桥的重要性。2)由于重复刺激降低了呼吸抑制的幅度，因此涉及哪些类型的调制因素。3)什么样的阿片肽（S）可能真正关心。此外，还对多模式受体的受体特性进行了详细的研究。1)重复电刺激PBN和PBN内微量注射吗啡均能产生纳洛酮可逆的、持久的呼吸抑制，与刺激外周肌传入神经引起的呼吸抑制相似。2)吗啡引起的呼吸抑制并不因反复应用而减少，提示阿片耐受不是反射性呼吸抑制快速耐受的原因。由于这种快速耐受可被缩胆囊素（CCK）拮抗剂丙谷胺所拮抗，因此可能是由CCK等易化系统的活动在时间上叠加而引起的，这些易化系统同时受到肌肉传入的刺激。刺激的有效性被证明是依赖性的，迷走神经输入的影响也被建议。3)通过第四脑室枕大池灌注含有脑啡肽酶抑制剂的溶液引起明显更大的反射性呼吸抑制。ELISA法测定的脑啡肽浓度在刺激过程中和刺激后均高于刺激前，提示脑啡肽能呼吸调节机制是由外周多模态受体输入触发的。

项目成果

K. Mizumura: "Respiratory changes induced by activation of testicular afferents in dogs." Pflugers Arch. - Eur. J. Physiol.411. 27-33 (1988)

K. Mizumura：“狗睾丸传入神经的激活引起的呼吸变化。”

D. Simbulan: "Phrenic responses to muscle afferent nerve stimulation applied to different respiratory phases." Environ. Med.31. 61-67 (1987)

D. Simbulan：“膈对应用于不同呼吸阶段的肌肉传入神经刺激的反应。”

Y.Takesue: Neurochemical reseaech. 11. 147 (1986)

Y. Takesue：神经化学研究。

E.Tadaki: Environ. Med.30. 47-53 (1986)

E.Tadaki：环境。

D.Simbulan: Environ. Med.31. 61-67 (1987)

D.Simbulan：环境。