Tolerance to morphine bradycardia in the rat.

Intravenous injection of opiate agonists produces in the rat a precipitous but transient fall in heart rate. This bradycardia, which may be a vagal chemoreflex, appears to originate from peripheral opiate receptors because the onset is faster after injections of morphine into the peripheral circulation than after central injections. The bradycardia is blocked by i.v. administration of tertiary and quaternary naloxone at doses which are not effective centrally. Tolerance develops to morphine bradycardia after s.c. infusions of morphine sulfate (e.g., 74 nmol/hr/rat s.c. for 2 days elevated the morphine ED50 by 22 times), but not after central infusions of morphine at doses which are sufficient to produce physical dependence and tolerance to morphine analgesia. Subcutaneously infused morphine animals are cross-tolerant to FK33,824 (Tyr-D-Ala-Gly-NMePhe-Met(O)-ol), a potent enkephalin analog, and vice versa, but are not tolerant to serotonin or phenyldiguanide. Vagal bradycardia may be a convenient index for studying the peripheral action of opioid agonists.