d-ala(2)-mephe(4)-met(0)-ol-enkephalin and Morphine-Dependence

Topics: Analgesics; Animals; Brain; Castration; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Drug Tolerance; Endorphins; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Liver; Luteinizing Hormone; Male; Morphine Dependence; Naloxone; Narcotics; Opioid-Related Disorders; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Receptors, sigma; Substance Withdrawal Syndrome; Testis; Testosterone; Time Factors

The i.c.v. administration of opioid peptides having selectivity for the mu receptor (D-Ala2-NMePhe4-Gly5(ol)enkephalin and FK 33,824) produced effects on the locomotor activity of nondependent and morphine-dependent rats that differed both quantitatively and qualitatively from those effects produced by peptides having selectivity for the delta receptor (D-Ala2-D-Leu5enkephalin and metkephamid) and beta-endorphin, which has similar affinity for both receptors. Peptides selective for the mu receptor: had a biphasic effect on locomotor activity of nondependent rats, inducing an increase at low doses and an initial decrease followed by a later increase at higher doses and had an enhanced stimulant effect on locomotor activity with tolerance to the depressant effect in morphine-dependent rats. Peptides selective for the delta receptor and beta-endorphin: induced only a dose-related increase in the locomotor activity of nondependent rats and had effects on the locomotor activity of morphine-dependent rats that did not differ substantially from those in nondependent rats. Naltrexone (0.1 mg/kg s.c.) and beta-funaltrexamine (5.0 micrograms/rat i.c.v.), an irreversible antagonist, each blocked to a comparable extent the effects of D-Ala2-NMePhe4-Gly5(ol)enkephalin and DAla2-D-Leu5enkephalin on the locomotor activity of nondependent rats. Thus, effects of opioid peptides that act predominantly at mu or delta receptors on locomotor activity cannot be differentiated in nondependent rats by antagonists but can be differentiated in morphine-dependent rats. These results suggest that the depressant and stimulant effects of opioid peptides on locomotor activity are mediated by distinct neuronal sites.

Topics: Animals; beta-Endorphin; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Dose-Response Relationship, Drug; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Male; Morphine Dependence; Motor Activity; Naltrexone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

The effects of the degradation-resistant enkephalin analogs FK 33-824 and metkephamid were determined after systemic and intracerebroventricular (i.c.v.) administration in withdrawn morphine-dependent rhesus monkeys. Both peptides suppressed completely signs of 12-hr morphine deprivation, as does the prototype mu-receptor agonist morphine. The peptides were 100 and 2000 times more potent, respectively, after i.c.v. than s.c. injection. Thus, although peptidase-resistant, these compounds have restricted entrance into the central nervous system after systemic administration. The i.c.v. administration of compounds in rhesus monkeys should prove to be a valuable tool in the study of peptide ligands for opiate receptors.

Topics: Animals; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Enkephalin, Methionine; Hormones; Humans; Injections, Intraventricular; Injections, Subcutaneous; Macaca mulatta; Morphine; Morphine Dependence