This study determined whether the modulation of morphine antinociception by [Leu5]enkephalin, a compound which does not produce detectable antinociception when given i.p., was additive or synergistic. Co-administration of graded i.p. doses of morphine and [Leu5]enkephalin 20 min before testing resulted in a progressive leftward and parallel displacement of the i.p. morphine dose-response line. The increase in potency produced by i.p. [Leu5]enkephalin, but not the antinociception of i.p. morphine alone, was blocked by i.c.v. ICI 174,864. The data demonstrate strong and dose-related synergism between the two compounds, supporting the view that (a) peripheral administration of [Leu5]enkephalin can modulate morphine antinociception, apparently at the level of the brain and (b) that the interaction between μ and δ opioid agonists is not the result of simple additive action at the same (i.e., μ) receptor. Further evidence is thus provided for the existence of functional μ-δ interactions.
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