Electroencephalographic and behavioral tolerance to and cross-tolerance between D-Ala2-methionine-enkephalinamide and morphine in the rat.

Rats were given repeated intraventricular (i.vt.) injections of D-enkephalin (20 microgram/4 hr) or morphine (20 microgram/4 hr) for 72 to 96 hr during electroencephalograman(EEG) recording. Initial epileptiform EEG and associated wet-dog shakes occurred following D-enkephalin but not morphine. The epileptoid EEG progressed to a continous high-voltage EEG synchrony similar to morphine and was associated with behavioral stupor. Rapid eye movement sleep was also suppressed. Repeated administration of D-enkephalin or morphine produced tolerance to their effects. When challenged with i.vt. morphine, D-enkephalin-tolerant rats were cross-tolerant to morphine. Likewise, morphine-tolerant rats were cross-tolerant to D-enkephalin. While the morphine-tolerant rats demonstrated a marked abstinence syndrome when challenged with naloxone (10 mg/kg i.p.), no abstinence signs were observed in the D-enkephalin-tolerant rats. The demonstration of tolerance and cross-tolerance between morphine and D-enkephalin suggests a similar mechanism of action, but the differential development of physical dependence may entail different mechanisms or receptor sensitivities for this effect. These findings of similarities and differences in the acute and chronic effects of D-enkephalin and morphine support the contention that heterogenous opiate receptors may mediate their pharmacologic actions.