Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine

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.