Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine
Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine
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DOI：
10.1164/ajrccm.162.3.9911102
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发表时间：
2000-09-01
影响因子：
24.7
通讯作者：
Zadina, JE
中科院分区：
文献类型：
--
作者：
Czapla, MA;Gozal, D;Zadina, JE
研究了新型内源性mu-阿片受体（MOR）激动剂内啡肽1 （EM1）和内啡肽2 （EM2）对有意识、自由行为大鼠的心肺作用。在全身（静脉）给药EM1、EM2或选择性MOR激动剂DAMGO后，测量镇痛、分钟通气量（(V) /点E）、心率（HR）和平均动脉血压（BP）。所有3种肽的镇痛阈值剂量相似（相似于900 nmol/kg）。所有3种化合物都引起了双相(V)过点E反应，有明显的，短暂的(V)过点E下降（4-6秒），然后是更持续的(V)过点E增加（10-12分钟）。然而，与EM2或DAMGO引起的反应相比，EM1仅在较高剂量下降低(V)超过点E，并产生更大的(V)超过点E刺激。吗啡引起(V)过E点下降，但随后没有(V)过E点增加。在9600 nmol/kg的剂量下，EM2和DAMGO降低了清醒大鼠的HR和血压，而EM1降低了HR，但没有降低血压。在麻醉大鼠中，这3种肽均能降低心率和血压。(V) / dot E、HR和BP的降低被MOR拮抗剂盐酸纳洛酮（NIx）阻断。然而，只有HR和BP反应被纳洛酮-甲氧基醚（MeNIx）阻断，表明VE反应具有中枢介导作用，心血管反应具有外周介导作用。我们得出结论，莫尔选择性化合物的心肺反应特征不同，这可能与不同的细胞作用有关。这些结果支持MOR激动剂的镇痛、呼吸和心血管作用可以分离的概念，并且em1样化合物可以为新型、更安全的镇痛药提供基础。
The novel endogenous mu-opioid receptor (MOR) agonists endomorphin 1 (EM1) and 2 (EM2) were tested for their cardiorespiratory effects in conscious, freely behaving rats. After systemic (intravenous) administration of EM1, EM2, or the selective MOR agonist DAMGO, analgesia, minute ventilation ((V) over dot E), heart rate (HR) and mean arterial blood pressure (BP) were measured. The threshold dose for analgesia was similar for all 3 peptides (similar to 900 nmol/kg). All 3 compounds elicited biphasic (V) over dot E responses, with marked, short-lived (V) over dot E depressions (4-6 s) followed by more sustained (V) over dot E increases (10-12 min). However, compared with responses elicited by EM2 or DAMGO, EM1 decreased (V) over dot E only at higher doses, and produced greater (V) over dot E stimulation. Morphine produced a (V) over dot E decrease, but no subsequent (V) over dot E increase. EM2 and DAMGO decreased HR and BP, while EM1 decreased HR, but did not decrease BP in conscious rats at doses up to 9,600 nmol/kg. In anesthetized rats, all 3 peptides decreased HR and BP. The decreases in (V) over dot E, HR, and BP were blocked by the MOR antagonist, naloxone HCl (NIx). Only the HR and BP responses, however, were blocked by naloxone-methiodide (MeNIx), indicating central mediation of VE responses and peripheral mediation of cardiovascular responses. We conclude that MOR-selective compounds vary in their cardiorespiratory response characteristics which could be linked to differential cellular actions. The results support the concept that the analgesic, respiratory, and cardiovascular effects of MOR agonists can be dissociated and that EM1-like compounds could provide the basis for novel, safer analgesics.