Enhancement of morphine antinociception by a CCKB antagonist in mice is mediated via opioid delta receptors

Todd W. Vanderah, Robert N. Bernstein, Henry I. Yamamura, Victor J. Hruby, Frank Porreca

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32 Scopus citations


This study investigated the possible involvement of opioid δ receptors in the modulation of morphine antinociceptive potency produced by L365,260, a CCKB antagonist, Intracerebroventricular (i.c.v.), intrathecal (i.th.) or subcutaneous (s.c.) L365,260 alone did not produce any antinociceptive actions in the mouse warm-water tail-flick test. Treatment with L.365,260 by any of these routes produced a leftward shift of the corresponding morphine dose-effect curve that was blocked by pretreatment with a receptor-selective dose of s.c. naltrindole, an opioid δ receptor antagonist. Pretreatment with i.c.v. antisera to [Leu5]enkephalin also blocked the leftward displacement of the i.c.v. morphine dose-effect curve resulting from L.365,260 but did not directly alter the i.c.v. morphine doseeffect curve; antisera to [Met5]enkephalin did not alter the effects of morphine or the modulation of morphine antinociception produced by L365,260. Repeated pretreatment with L365,260 resulted in a progressive decrease in the magnitude of the morphine modulatory action (i.e., L365,260 "tolerance"). In these "L365,260-tolerant" mice, the dose-effect curve for i.c.v. [D-Ala2, Glu4]deltorphin (a selective δ agonist) was displaced to the right by approximately 8.2-fold. The i.c.v. administration of [Leu5]enkephalin produced a leftward displacement of the i.c.v. morphine dose-effect curve that diminished after repeated administration (i.e., [Leu5]enkephalin "tolerance"). In "[Leu5]enkephalin-tolerant" mice, L.365,260 failed to produce the leftward shift of the morphine dose-effect curve seen in control animals. That is, two-way antinociceptive cross-tolerance was observed between an opioid δ agonist and a CCKB receptor antagonist. Intracerebroventricular thiorphan, a peptidase inhibitor, did not elicit antinociception directly. Co-administration of thiorphan with L365,260 elicited significant antinociception that was blocked by naltrindole or antisera to [Leu5]enkephalin; antisera to [Met5]enkephalin had no effect. Repeated administration of i.c.v. [D-Ala2, Glu4]deltorphin resulted in a progressively decreasing antinociceptive effect (i.e., [D-Ala2, Glu4]deltorphin "tolerance"). In "[D-Ala2, Glu4]deltorphintolerant" mice, the thiorphan/L365,260 antinociceptive effect was inhibited. Collectively, these data suggest that CCK interacts at the CCKB receptor to inhibit tonically the release and/or availability of an endogenous substance acting at opioid δ receptors. The subsequent enhancement of morphine antinociceptive potency may reflect the well-known modulation of morphine antinociception produced by opioid δ receptor agonists. In this case, the latter may be [Leu5]enkephalin or a [Leu5]enkephalin-like substance.

Original languageEnglish (US)
Pages (from-to)212-219
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jul 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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