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Research ArticleArticle

Delta Opioid Peptide [d-Ala2,d-leu5]Enkephalin Blocks the Long-term Loss of Dopamine Transporters Induced by Multiple Administrations of Methamphetamine: Involvement of Opioid Receptors and Reactive Oxygen Species

Li-I Tsao, Bruce Ladenheim, Anne M. Andrews, Chuang C. Chiueh, Jean Lud Cadet and Tsung-Ping Su
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 322-331;
Li-I Tsao
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Bruce Ladenheim
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Anne M. Andrews
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Chuang C. Chiueh
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Jean Lud Cadet
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Tsung-Ping Su
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Abstract

Delta opioid peptide [d-Ala2,d-leu5]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 METH-induced 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.

Footnotes

  • Send reprint requests to: Dr. Tsung-Ping Su, Molecular Neuropsychiatry Section, IRP, NIDA/NIH, P.O. Box 5180, Baltimore, MD 21224.

  • 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-Ala2,d-leu5]enkephalin
    DAT
    dopamine transporter(s)
    2
    3-DHBA and 2,5-DHBA, 2,3- and 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
    α-phenyl-N-tert-butyl nitrone
    PD
    Parkinson’s disease
    ROS
    reactive oxygen species
    RTI-121
    3β-(4-[125I]iodophenyl)tropane-2β-carboxylic acid isopropyl ester
    TBA
    thiobarbituric acid
    TBARS
    thiobarbituric acid reactive substances
    TH
    tyrosine hydroxylase
    ANOVA
    analyses of variance
    • Received February 16, 1998.
    • Accepted June 1, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 1998
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Research ArticleArticle

Delta Opioid Peptide [d-Ala2,d-leu5]Enkephalin Blocks the Long-term Loss of Dopamine Transporters Induced by Multiple Administrations of Methamphetamine: Involvement of Opioid Receptors and Reactive Oxygen Species

Li-I Tsao, Bruce Ladenheim, Anne M. Andrews, Chuang C. Chiueh, Jean Lud Cadet and Tsung-Ping Su
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 322-331;

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Research ArticleArticle

Delta Opioid Peptide [d-Ala2,d-leu5]Enkephalin Blocks the Long-term Loss of Dopamine Transporters Induced by Multiple Administrations of Methamphetamine: Involvement of Opioid Receptors and Reactive Oxygen Species

Li-I Tsao, Bruce Ladenheim, Anne M. Andrews, Chuang C. Chiueh, Jean Lud Cadet and Tsung-Ping Su
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 322-331;
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