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, f reely behaving rats. After systemic (intravenous) administration of EM1, EM 2, or the selective MOR agonist DAMGO, analgesia, minute ventilation ((V) o ver dot E), heart rate (HR) and mean arterial blood pressure (BP) were meas ured. The threshold dose for analgesia was similar for all 3 peptides (simi lar to 900 nmol/kg). All 3 compounds elicited biphasic (V) over dot E respo nses, 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 w ith responses elicited by EM2 or DAMGO, EM1 decreased (V) over dot E only a t higher doses, and produced greater (V) over dot E stimulation. Morphine p roduced a (V) over dot E decrease, but no subsequent (V) over dot E increas e. EM2 and DAMGO decreased HR and BP, while EM1 decreased HR, but did not d ecrease 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 c ardiovascular responses. We conclude that MOR-selective compounds vary in t heir cardiorespiratory response characteristics which could be linked to di fferential cellular actions. The results support the concept that the analg esic, respiratory, and cardiovascular effects of MOR agonists can be dissoc iated and that EM1-like compounds could provide the basis for novel, safer analgesics.