Antinociceptive interactions of opioid delta receptor agonists with morphine in mice: supra- and sub-additivity

Life Sci. 1992;50(20):1535-41. doi: 10.1016/0024-3205(92)90144-e.


In this study, the antinociceptive interactions of fixed ratio combinations of intracerebroventricularly (i.c.v.) given morphine and subantinociceptive doses of the delta agonists, [D-Pen2, D-Pen5]enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin (DELT) or [Met5]enkephalin (MET) were examined using the mouse warm water tail flick test. When morphine was coadministered with DPDPE or DELT in a 4:1 and 9:1 mixture, respectively, a synergistic antinociceptive effect was observed. In contrast, when morphine was coadministered with MET in a 1:2 fixed ratio mixture, a subadditive interaction occurred. These results demonstrate both positive and negative modulatory interactions of delta agonists with morphine in an antinociceptive endpoint and that these interactions can be either supra- or subadditive. The data support the concept of a functional interaction between opioid mu and delta receptors and a potential regulatory role for the endogenous ligands of the opioid delta receptor.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Drug Synergism
  • Enkephalin, D-Penicillamine (2,5)-
  • Enkephalin, Methionine / pharmacology*
  • Enkephalins / pharmacology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Morphine / pharmacology*
  • Oligopeptides / pharmacology*
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid, delta


  • Analgesics
  • Enkephalins
  • Oligopeptides
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • deltorphin II, Ala(2)-
  • Enkephalin, Methionine
  • Morphine
  • Enkephalin, D-Penicillamine (2,5)-