enkephalin--leucine-2-alanine and deltakephalin

The effects of i.c.v. injected selective ligands for mu and delta opioid receptors on histamine (HA) turnover in the mouse brain were investigated to determine the receptor subclasses involved in the neurochemical response to opioids. HA turnover was measured by the accumulation of tele-methylhistamine, a major metabolite of brain HA, after pargyline injection (65 mg/kg i.p.). The increase in the HA turnover induced by [D-Ala2,D-Leu5] enkephalin (0.5 microgram i.c.v.) was antagonized by naloxone (0.3 microgram i.c.v.) but not by ICI 174,864 (5 micrograms i.c.v.), a selective delta receptor antagonist. [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO; 0.1-0.5 microgram i.c.v.), a selective mu receptor agonist, produced an increase in the HA turnover, whereas [D-Thr2-Leu5]enkephalin, Thr (0.1-1.0 microgram i.c.v.), a selective delta receptor agonist, had little effect on the HA turnover. DAGO (0.1 microgram i.c.v.) also increased the steady-state level of tele-methylhistamine but not that of HA. The effect of DAGO was observed in various brain regions except for the hypothalamus, and it was the most marked in the striatum. DAGO (10(-7) and 10(-6) M) significantly increased the K+ (30 mM)-evoked HA release from mouse cerebral cortical slices without influencing on the spontaneous HA release. The enhancement of HA release induced by DAGO (10(-6) M) was blocked completely by naloxone (10(-6) M) but not by tetrodotoxin (10(-6) M). These results suggest that opioids with mu agonist activity increase brain HA turnover by facilitating HA release from nerve endings.

Topics: Animals; Brain; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Histamine; Male; Methylhistamines; Methylhistidines; Mice; Naloxone; Oligopeptides; Receptors, Opioid; Receptors, Opioid, mu; Tetrodotoxin

In order to specifically direct cytotoxic agents against tumor cells bearing delta opioid receptors, the DNA intercalating agents ellipticine and 9-OH-ellipticine were coupled by quaternarization of the pyridine nitrogen to an enkephalin modified pentapeptide through a short chemical linker. The ellipticine ring of these conjugates was shown to intercalate into DNA, with DNA affinity constants close to those of the non-conjugated ellipticines. Despite the addition of a polycyclic ring to the C-terminal amino acid, the D-Ala2-D-Leu5-enkephalin-ellipticine conjugates bind to the opioid receptor from rat brain and NG 108-15 cells with an affinity constant close to 10(8) M-1. Other derivatives were synthesized as a control using a tripeptide which does not bind to the opioid receptor.

Topics: Alkaloids; Animals; Brain; Cell Line; DNA; Ellipticines; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Humans; Oligopeptides; Rats; Receptors, Opioid

The opioid receptors involved in the supraspinal and spinal actions of [D-Pen2, D-Pen5]enkephalin (DPDPE) for production and/or modulation of analgesia were investigated in two thermal analgesic tests, the mouse warm water (55 degrees C) tail-withdrawal assay and the radiant heat tail-flick test. Two approaches were used at supraspinal and spinal sites: determination of possible cross-tolerance between morphine and a variety of receptor selective/nonselective agonists (DPDPE, [D-Pen2, L-Pen5]enkephalin (DPLPE), [D-Ala2, MePhe4, Gly-ol]enkephalin, [D-Ala2, Met5]enkephalin amide, [D-Ser2, Leu5, Thr6]enkephalin and [D-Thr2 Leu, Thr6]enkephalin) and possible potentiation of morphine (mu) analgesia by proposed delta agonists (DPDPE, DPLPE and [D-Ala2, D-Leu5]enkephalin) in naive and morphine-tolerant mice. Additionally, proposed mu (morphine) and delta (DPDPE) agonists were evaluated for their i.c.v. analgesic effectiveness in the absence, and in the presence, of the proposed delta antagonist ICI 174,864. The present communication now reports that after i.c.v. administration analgesic cross-tolerance could be demonstrated between morphine and a variety of relatively selective or nonselective opioids but not to the highly delta selective DPDPE and DPLPE. This result was consistent with direct antagonism of i.c.v. DPDPE, but not morphine analgesia, by ICI 174,864. Furthermore, i.c.v. DPDPE and DPLPE were able to potentiate morphine analgesia in either naive or morphine-tolerant mice. In contrast, after intrathecal administration, cross-tolerance could be demonstrated between DPDPE or DPLPE and morphine, and no potentiation of morphine by DPDPE could be observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesia; Anesthesia, Spinal; Animals; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Male; Mice; Morphine; Oligopeptides; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

The characteristics of opiate binding sites in the retina of the chick, rabbit and goldfish have been investigated. In the newly hatched chick retina, 131 fmol/mg of binding sites for [D-Ala2-D-Leu5]-[3H]enkephalin are present; competition studies with the delta selective peptide [D-Thr-Leu5]-enkephalin (DTLET) and the mu selective peptide morphiceptin show that all of the [D-Ala2-D-Leu5]-[3H]-enkephalin binding sites are of the delta subtype. Dihydro[3H]morphine binds poorly to the chick retina; 13.2 fmol/mg of this binding is displaceable by morphiceptin and corresponds to mu binding sites. Benzomorphan sites are defined as sites occupied by [3H]diprenorphine which is displaceable by low concentrations of ethylketocyclozacine but not by high concentrations of D-Ala2-D-Leu5-enkephalin and morphiceptin. At least 88 fmol/mg of benzomorphan sites are present in the chick retina. [3H]diprenorphine binding to the rabbit and fish retina was measured. The rabbit retina bound 60 fmol/mg, and the fish retina 42 fmol/mg of [3H]diprenorphine. These findings are discussed in the light of the studies on the localization and physiological effects of enkephalin in the retina.

Topics: Animals; Benzomorphans; Chickens; Dihydromorphine; Diprenorphine; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Goldfish; Oligopeptides; Rabbits; Receptors, Opioid; Retina; Species Specificity

It has recently been reported that the hamster vas deferens contains only delta-opioid receptors. We have demonstrated that three delta-receptor agonists [D-Ala2, D-Leu5]enkephalin (DADLE), [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Thr2, Leu5, Thr6] enkephalin (DTLET) appear to mediate their effects via the delta-receptor since they are readily reversed by the selective delta-receptor antagonist ICI 174864. In addition, a number of classical mu and k receptor compounds were devoid of activity in this preparation. However it was observed that some compounds such as etorphine and MR 2034 reported to possess delta-receptor affinity in other assay systems were weak or inactive on the hamster vas deferens.

Topics: Animals; Cricetinae; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; In Vitro Techniques; Male; Mesocricetus; Muscle, Smooth; Naloxone; Narcotic Antagonists; Narcotics; Oligopeptides; Receptors, Opioid; Receptors, Opioid, delta; Vas Deferens