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OtherANALGESIA AND DRUGS OF ABUSE

Nonopioid Motor Effects of Dynorphin A and Related Peptides: Structure Dependence and Role of the N-Methyl-d-aspartate Receptor

Vijay K. Shukla, Jyoti A. Prasad and Simon Lemaire
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 604-610;
Vijay K. Shukla
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Jyoti A. Prasad
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Simon Lemaire
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Abstract

Dynorphin (Dyn) A and related opioid and nonopioid peptides were tested for their ability to produce motor effects in mice. Central (intracerebroventricular) administration of Dyn A in mice produced marked motor effects characterized by wild running, jumping, circling and/or barrel rolling with an ED50 value of 14.32 (95% confidence limits, 10.09–20.32) nmol/mouse. The order of potency of the various Dyn A-related peptides and fragments in producing motor effects was Dyn A ≃ Dyn A-(1–13) > [Ala1]Dyn A-(1–13) ≃ Dyn A-(2–13) > α-Neo-End > Dyn A-(1–8) ≃ Dyn B ≃ Dyn A-(2–8) >>> Dyn A-(3–8). Dyn A-(1- 5) (or Leu-Enk) and Dyn A-(6–10) displayed no motor effect at doses up to 100 nmol/mouse. The potencies of Dyn A and Dyn A-(2–13) were not affected by preadministration of naloxone (5 mg/kg s.c.), but the motor effects of Dyn A-(1–13) (20 nmol/mouse i.c.v.) were significantly reduced by coadministration of low doses (0.2–0.6 nmol/mouse) of the N-methyl-d-aspartate (NMDA) receptor antagonists dextrorphan, MK-801 and CPP. Dyn A was also a potent inhibitor of the binding of the phencyclidine receptor ligand, [3H]MK-801, to rat brain membranes, with a Kivalue of 0.41 μM. However, the order of potency of the various Dyn A-related peptides and fragments in inhibiting [3H]MK-801 binding did not correlate with their ability to produce motor effects. On the other hand, Dyn A and related peptides produced a significant potentiation of the binding of the competitive NMDA antagonist [3H]CGP-39653 to rat brain membranes, an effect that correlated well (r = 0.91) with their potency in producing motor effects. These results indicate that the nonopioid motor effects of Dyn A and related peptides are structure dependent, with Dyn A-(2–8) being the minimal core peptide for motor activity. In addition, these effects most likely involve the participation of the excitatory amino acid binding domain on the NMDA receptor complex.

Footnotes

  • Send reprint requests to: Simon Lemaire, Ph.D., Department of Pharmacology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.

  • ↵1 This work was supported by the Medical Research Council of Canada.

  • Abbreviations:
    i.c.v.
    intracerebroventricular
    s.c.
    subcutaneous
    CL
    confidence limit
    EEG
    electroencephalographic
    Dyn A
    dynorphin A
    Leu-Enk
    Leu-enkephalin
    α-Neo-End
    α-Neo-endorphin
    NMDA
    N-methyl-d-aspartate
    AMPA
    α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate
    PCP
    phencyclidine
    • Received March 27, 1997.
    • Accepted July 11, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherANALGESIA AND DRUGS OF ABUSE

Nonopioid Motor Effects of Dynorphin A and Related Peptides: Structure Dependence and Role of the N-Methyl-d-aspartate Receptor

Vijay K. Shukla, Jyoti A. Prasad and Simon Lemaire
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 604-610;

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OtherANALGESIA AND DRUGS OF ABUSE

Nonopioid Motor Effects of Dynorphin A and Related Peptides: Structure Dependence and Role of the N-Methyl-d-aspartate Receptor

Vijay K. Shukla, Jyoti A. Prasad and Simon Lemaire
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 604-610;
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