Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

Abstract

Pro-Leu-Gly-NH2 (MIF) and several structural analogues, all injected in 50jsg doses daily in mice receiving morphine chronically, were found to prevent development of physical dependence as measured by changes in body temperature associated with naloxone-induced withdrawal. Doseresponse studies, using again a protocol of daily injections of peptide at 50, 5, 0.5, 0.05, or 0.005 ,ug per mouse revealed MIF and cyclo(Leu-ly) to be the most potent peptides and to be effective In lockng physical dependence to morphine at a dose as low as 0.5 and 0.05 ,g per mouse, respectively. The benzyloxycarbonyl derivative of MIF, Pro-Leu, and Pro--Leu exhibited significant activities down to a dose of 5 1Ag of peptide per mouse.Recent evidence (1) indicates that the dipeptide benzyloxycarbonyl-Pro-D-Leu is capable of blocking the development of tolerance to and physical dependence on morphine in mice; these effects were achieved without altering the analgesic potency of morphine.In light of the potential clinical importance of these observations and their significance for the study of the mechanism of action of central nervous system-active peptides, it was decided to investigate whether more potent inhibitors could be found. The inhibitory properties of a selected number of peptides was evaluated over a broader dose range. Because, in our original studies, Z-Pro-D-Leu was equally effective in blocking tolerance, abrupt withdrawal, or naloxone-precipitated withdrawal (1), it was decided to use naloxone-precipitated withdrawal in mice as the bioassay in the current investigation for an evaluation of structure-function and dose-response relationships.MATERIAL AND METHODS A double-blind procedure was used for all experiments, and each peptide was tested in at least two independent experiments. Male Swiss Webster mice (Scientific Small Animal Farm, Inc., Melrose Park, IL) weighing 24 ± 2 g (mean E SD) were used. The mice were housed five or six per cage in temperature (23 ± 1"C) and light (light 0600-1800 hr) controlled rooms and were kept in our laboratory for a minimum of 7 days prior to the initiation of experiments. Food (Purina Laboratory Chow) and water were available ad lib.Mice were randomly divided into two groups. One group received subcutaneous injections of 0.1 ml of water (vehicle). The other group received peptide dissolved in 0.1 ml of water; in the case of the structure-activity studies, a single dose of 50 ,ug of peptide per mouse was given on day 1, and in the doseresponse studies 50, 5, 0.5, or 0.005 tig of peptide was administered to the respective groups of mice. Two hours later the mice were implanted with morphine pellets. The injections ofThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 518 vehicle and respective peptides were repeated 24 and 48 hr after the first injection in their respective groups. Morphine pellets, containing 75 mg of mo...

Cyclo(Phe-Pro) Modulates the Expression ofompUinVibriospp

“…Cyclo(Leu-Gly) produced by the fungus Rosellinia necatrix inhibits the development of physical dependence on morphine (52), and cFP produced by Lactobacillus plantarum has antifungal activity (49), while a stereoisomer, cyclic(D-Phe-D-Pro), produced by marine bacteria, inhibits the growth of the fish pathogen Vibrio anguillarum (13). cFP together with cyclo(Lleucine-L-proline) inhibits the growth of pathogenic yeasts and is antimutagenic in a Salmonella mutation assay (43).…”

Opioid Diketopiperazines: Synthesis and Activity of a Prototypic Class of Opioid Antagonists

“…For instance, c(His-Pro) has a range of distinct neurobiological properties (Prasad and Peterkofsky, 1976), including suppression of prolactin regulation (Jikihara ef a/., 1993), modulation of hypothermia (Bhargarva et a/., 1980;Shulkaef a/., 1994;Carltonet a/., 1995), and acts as a dopamine blocker (Jikihara et a/., 1993;Kaakkola and Wurtman, 1993) among other central mediated effects (Banks ef a/., 1993). Similarly, c(Leu-Gly) antagonized the development of the physical dependence on morphine and puromycin-induced amnesia (Walter et a/., 1979) and cfTyr-Arg) exhibited opioid analgesic activity greater than kyotorphin or [Met 5 ]enkephalin (Sakuradaef a/., 1982).…”

Opioid and anti‐opioid peptides

“…The C-terminal tripeptide of oxytocin (Pro-Leu-Gly-NH,) is a melanocyte inhibiting factor (MIF-1) (Celis et al, 1971; Nair et al, 1971) with antiopioid properties (Galina and Kastin, 1986, see below). The hypothalamus contains an exopepti-dase which can produce MIF-1 from oxytocin (Walter et al, 1979). Other peptides, structurally related to MIF-1, but which do not derive from oxytocin, also have anti-opioid properties.…”