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

我们以前的工作已经揭示了纳洛酮可逆呼吸抑制引起的刺激薄纤维肌肉传入：多模态受体输入。目前的工作旨在阐明这些先前的工作提供了以下问题。1)由于以往的实验表明了桥侧吻侧的重要性，是否与呼吸抑制有关。2)由于反复刺激降低了呼吸抑制的程度，这涉及到哪些调节因子。3)哪些阿片肽可能是真正值得关注的。此外，还对多模受体的受体特性进行了详细的研究。1)反复电刺激PBN和向PBN微注射吗啡均产生纳洛酮可逆的、持续时间较长的呼吸抑制，与外周肌肉传入刺激引起的呼吸抑制相似。2)吗啡引起的呼吸抑制不因反复使用而减轻，提示阿片类药物耐受性不是反射性呼吸抑制快速反应的原因。由于速速反应是由一种胆囊收缩素（CCK）拮抗剂丙氨酸拮抗剂引起的，它可能是由CCK等促进系统的活动的时间累积引起的，这些系统将同时受到肌肉传入的刺激。刺激的效果与呼吸期有关；迷走神经输入的影响也被提出。3)脑啡肽酶抑制剂溶液经第四脑室大池灌注后，反射性呼吸抑制明显增强。ELISA法测定刺激前后洗脱液中脑啡肽浓度均高于刺激前。本研究结果揭示了由外周多模态受体输入触发的脑啡能呼吸调节机制。

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.