Sensitivity to morphine-evoked bradycardia in rats is modified by dynorphin (1-13), Leu- and Met-enkephalin.

Intravenous injection of morphine evokes, in the rat, a vagal chemoreflex resulting in bradycardia, hypotension and transient apnea. The morphine ED50 for producing bradycardia was utilized here as an index of the sensitivity to opioid stimulation of the organism. The potency of morphine for producing bradycardia can be modified by dynorphin (1-13), Leu- and Met-enkephalin. Both dynorphin (1-13) and Leu-enkephalin administered s.c. to normal and morphine-tolerant rats, 30 min before blood vessel cannulation and testing, lowered the morphine ED50 for bradycardia. Dynorphin (1-13) was 3 times more potent than Leu-enkephalin. Under the same test conditions, Met-enkephalin, given s.c. (0.45-0.9 mumol/kg) 30 min before morphine challenge, produced only desensitization to morphine-evoked bradycardia. The effects of dynorphin (1-13) were biphasic with respect to time of injection. When dynorphin (1-13) (0.3 mumol/kg s.c.) was injected s.c. 2 hr before morphine challenge, animals were desensitized to morphine by 2.5 times. Dynorphin (1-13) (0.19-0.77 nmol/hr s.c.) co-infused with morphine (74 nmol/hr s.c.) for 2 days accelerated tolerance development to morphine bradycardia. These results confirm previous studies which suggest that opioid peptides having Leu- or Met-enkephalin at its N-terminus manifest different pharmacological properties in vivo.