Am. J. Respir. Crit. Care Med., Volume 162, Number 3, September 2000, 994-999

Differential Cardiorespiratory Effects of Endomorphin 1, Endomorphin 2, DAMGO, and Morphine

MARC A. CZAPLA, DAVID GOZAL, OSCAR A. ALEA, ROBERT C. BECKERMAN, and JAMES E. ZADINA

Constance S. Kaufman Pediatric Pulmonary Research Laboratory and Departments of Pediatrics, Physiology, Neuroscience, and Medicine, Tulane University School of Medicine, and Veterans Affairs Medical Center, New Orleans, Louisiana

The novel endogenous µ-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 ( E), heart rate (HR) and mean arterial blood pressure (BP) were measured. The threshold dose for analgesia was similar for all 3 peptides (~ 900 nmol/kg). All 3 compounds elicited biphasic E responses, with marked, short-lived E depressions (4-6 s) followed by more sustained E increases (10-12 min). However, compared with responses elicited by EM2 or DAMGO, EM1 decreased E only at higher doses, and produced greater E stimulation. Morphine produced a E decrease, but no subsequent 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 E, HR, and BP were blocked by the MOR antagonist, naloxone HCI (NIx). Only the HR and BP responses, however, were blocked by naloxone-methiodide (MeNIx), indicating central mediation of E 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.

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