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OtherANALGESIA AND DRUGS OF ABUSE

Delta Opioid Receptor Enhancement ofMu Opioid Receptor-Induced Antinociception in Spinal Cord

Li He and Nancy M. Lee
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1181-1186;
Li He
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Abstract

Although the mu selective agonist [d-Ala2-MePhe4-Gly-ol5]enkephalin (DAMGO) and the delta selective agonist [d-Pen2,d-Pen5]enkephalin (DPDPE) are both antinociceptive when administered directly into the spinal cord of mice, 50% of antinociceptive dose (AD50) of DAMGO is about 2 orders of magnitude lower than the AD50 of DPDPE. In contrast, the two ligands show similar affinities for their respective receptors in in vitro binding assays. One possible explanation for this discrepancy is that DPDPE antinociception in the spinal cord is mediated through not delta butmu receptors, for which it has an several hundred-fold lower affinity than DAMGO. In support of this, we found that DPDPE-mediated antinociception was blocked by the muselective antagonistd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2(CTAP). The pA2 value of CTAP for DPDPE was virtually identical with that for DAMGO. However, because its action also was blocked by naltrindole, an antagonist selective fordelta receptors, the latter must also play a role in antinociception. When DAMGO and DPDPE were administered i.t. together at ratios ranging from 1:200 to 1:500, the AD50 of DAMGO was lowered as much as 10-fold relative to its AD50 when given alone. Thus DPDPE had a potentiating effect on DAMGO, although the reverse was not observed. This potentiation was lost in animals made tolerant to systemic morphine. The loss of potentiation seemed to be caused by changes in the delta receptors, because a) the AD50 of DAMGO (i.t.) given alone to tolerant animals was virtually the same as for naive animals, whereas the AD50 of DPDPE given alone increased by 4-fold; and b) the AD50 of DPDPE given alone in the tolerant animal was increased only slightly by naltrindole, whereas CTAP was still a very potent antagonist. We conclude that DPDPE, a selectivedelta agonist, mediates antinociception in the spinal cord through mu receptors, consistent with results of recent studies of “knock-out” mice lacking mureceptors. At the same time, however, the delta agonist acting through delta receptors can potentiate themu receptor-mediated antinociceptive action of eithermu or delta agonists. This potentiating effect, like the synergistic effect observed between mureceptors at spinal and supraspinal sites, is lost during tolerance.

Footnotes

  • Send reprint requests to: Dr. Nancy M. Lee, Geraldine Brush Cancer Research Institute, California Pacific Medical Center, Research Institute, 2330 Clay Street, San Francisco, CA 94115.

  • ↵1 This work was supported in part by National Institute on Drug Abuse grants DA-02643 and DA-10048.

  • Abbreviations:
    DAMGO
    [d-Ala2-MePhe4-Gly-ol5]enkephalin
    DPDPE
    [d-Pen2,d-Pen5]enkephalin
    CTAP
    d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2
    NTI
    naltrindole
    AD50
    50% of antinociceptive dose
    i.t.
    intrathecal
    i.c.v.
    intracerebroventricular
    • Received September 4, 1997.
    • Accepted February 20, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherANALGESIA AND DRUGS OF ABUSE

Delta Opioid Receptor Enhancement ofMu Opioid Receptor-Induced Antinociception in Spinal Cord

Li He and Nancy M. Lee
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1181-1186;

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OtherANALGESIA AND DRUGS OF ABUSE

Delta Opioid Receptor Enhancement ofMu Opioid Receptor-Induced Antinociception in Spinal Cord

Li He and Nancy M. Lee
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1181-1186;
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