Delta Opioid Peptide [D-Ala,D-leu]Enkephalin Blocks the Long-term Loss of Dopamine Transporters Induced by Multiple Administrations of Methamphetamine: Involvement of Opioid Receptors and Reactive Oxygen Species

Delta opioid peptide [D-Ala,D-leu]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine(METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METHinduced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical. Endogenous opioid peptides and their receptors are known to participate in many pharmacological and physiological functions. For example, DADLE, a metabolically stable analog of the endogenous delta opioid peptide enkephalin, can induce hibernation when injected into summer-active ground squirrels—in the months when they do not usually hibernate (Oeltgen et al., 1988). Moreover, DADLE can dramatically extend the organ survival time in a multiorgan block preparation, including the heart, lung, liver, spleen and kidney, from an average of 14 to 46 hr—the longest in the history of organ preservation (Chien et al., 1994). Lungs preserved in such a fashion functioned normally when transplanted into the host animals 24 hr after the preservation (Oeltgen et al., 1996). DADLE also enhanced the hypothermic preservation time of isolated rat lungs (Wu et al., 1996). Further, using isolated rabbit hearts, a recent report demonstrated that DADLE can promote myocardial tolerance to ischemia in a fashion far superior to the standard cardioplegic procedure (Bolling et al., 1997). The exact mechanism(s) underlying the protective property of DADLE in peripheral organs is(are) not completely understood at present. However, because the survival of organs depends largely on the oxidative state of the tissue, it is possible that the protective property of DADLE may involve, via as yet unknown mechanism, reactive oxygen species (ROS). As such, it is not unreasonable to speculate that DADLE might be a tissue protective agent Received for publication February 16, 1998. 1 This work was supported by the Basic Neurobiology and Biological Systems Research Branch, Division of Basic Research, NIDA. ABBREVIATIONS: BPT, bathophenanthroline disulfonic acid; CNS, central nervous system; DA, dopamine or dopaminergic; DADLE, [D-Ala,Dleu]enkephalin; DAT, dopamine transporter(s); 2,3-DHBA and 2,5-DHBA, 2,3and 2,5-dihydroxybenzoic acid; DOPAC, 3,4-dihydroxyphenylacetic acid; DTT, dithiothreitol; GSH, glutathione; HPLC-ECD, high performance liquid chromatography utilizing electrochemical detection; HVA, homovanillic acid; METH, methamphetamine; 6-MPH4, 6-methyl-5,6,7,8-tetrahydropterin; PTBN, a-phenyl-N-tert-butyl nitrone; PD, Parkinson’s disease; ROS, reactive oxygen species; RTI-121, 3b-(4-[I]iodophenyl)tropane-2b-carboxylic acid isopropyl ester; TBA, thiobarbituric acid; TBARS, thiobarbituric acid reactive substances; TH, tyrosine hydroxylase; ANOVA, analyses of variance. 0022-3565/98/2871-0322$00.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 287, No. 1 Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 287:322–331, 1998