Inhibition by Z-Pro-D-Leu of development of tolerance to and physical dependence on morphine in mice.

Abstract

The peptide Z-Pro-D-Leu, injected daily in mice receiving morphine chronically, was found to prevent development of physical dependence as measured by changes in body temperature and body weight due either to abrupt or to naloxone-induced withdrawal. On the other hand, administration of Z-Pro-D-Leu only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily administration of Z-Pro-D-Leu was also effective in blocking the development of tolerance to the analgesic and the hypothermic effects of subsequent challenge doses of morphine. However, the peptide treatment did not alter the acute effects of a challenge dose of morphine on either analgesia or body temperature. No effects on memory were noted, as evaluated in a one-trial passive avoidance task. Clinical implications of the use of Z-Pro-D-Leu are discussed.Certain neurohypophyseal hormones, their analogs, and disulfide-containing cyclic fragments of these hormones facilitate development of physical dependence on and tolerance to actions of morphine (1-3). Several of these peptides, notably vasopressin and its analogs, can modify various aspects of behavior including acquisition and extinction of conditioned responses in lower species as well as of memory in man (4-10). In addition, non-disulfide-containing linear hormone fragments, such as Pro-Leu-Gly-NH2 (melanotropin-release inhibiting factor) (11), Z-Pro-Leu-Gly-NH2 (7), the enzymatically stable cyclo(LeuGly) (12), and Pro-Arg-Gly-NH2 (13) also exhibit these effects (7,8,13).Recently, in comparing the relative potencies of these peptides in facilitating the development of physical dependence on and tolerance to morphine, van Ree and de Wied (3) found not only that oxytocin and 8-arginine vasotocin are more effective than 8-arginine vasopressin but, moreover, that ProLeu-Gly-NH2 and cyclo(Leu-Gly) are as effective as oxytocin in these tests.Replacement of an L residue in a peptide hormone or agonistic analog by the D isomer has been reported to produce, in certain instances, a competitive inhibitor or partial agonist-findings that might be explained by steric misplacement of an "active element" (14) from its preferred orientation in the "active site" (15) such that intrinsic activity is decreased or even lost with retention of receptor affinity (14, 16).On the basis of this background it was decided, as a first step in a series of studies, to evaluate the effect of Z-Pro-D-Leu on the development of physical dependence on and tolerance to morphine. MATERIALS AND METHODSThe Z-Pro-D-Leu (17) used was prepared in these laboratories (18). Male C57BL/6J, Swiss Webster, and ICR mice weighing 26 ± 4 g (±SD) were used in these studies.Mice were randomly divided into two groups. One group received subcutaneous injections of water (vehicle); the other group received Z-Pro-D-Leu (50 ,jg per mouse on day 1). Two hours later, the mice were then further subdivided and each subgroup was implanted with placebo or morphine pellets. The injections of vehicle and Z-Pro-D-Leu were repe...

The Effect of Melanotrophin Release Inhibiting Factor (Mif) and Cyclo (Leu‐gly) on the Tolerance to Morphine‐induced Antinociception in the Rat: A Dose‐response Study

“…These data are also consistent with work in mice with MIF and cyclo (Leu-Gly) and with another analogue of MIF, Z-Pro-D-Leu (Walter et al, 1978).…”

“…Additional studies (van Ree & de Wied, 1976) indicated that not only DG-AVP, but oxytocin and its C-terminal tripeptide prolylleucyl-glycinamide (MIF) and cyclo (Leu-Gly) facilitated morphine dependence (as measured by the loss of body weight following naloxone administration to dependent rats) as well as development of tolerance to the analgesic effect of morphine. Other studies, however, indicate that oxytocin and vasopressin (Schmidt, Holaday, Loh & Way, 1978) and cyclo (Leu-Gly) (Bhargava, 1980a) Previous studies have demonstrated that an analogue of MIF, Z-Pro-D-Leu, (Walter, Ritzmann, Bhargava, Rainbow, Flexner & Krivoy, 1978), MIF and cyclo (Leu-Gly) (Walter, Ritzmann, Bhargava & Flexner, 1979; inhibit the development of tolerance to and physical dependence on morphine in mice. Additionally, it was found that cyclo (Leu-Gly) also inhibited morphine tolerance in the rat (Bhargava, 1980b).…”

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

“…Although we obtained similar results in mice in the case of oxytocin (unpublished data) with the method of morphine implantation as described (1,2), the current results with MIF and cyclo(Leu-Gly) in mice are apparently in disagreement with those reported by van Ree and de Wied (13) for these compounds in rats. The disparity between the two studies may be due to differences of species, routes of morphine administration, or doses used.…”

“…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.…”

“…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.…”