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

In this study, the antinociceptive interactions of fixed ratio combinations of intracerebroventricularly (i.c.v.) given morphine and subantinociceptive doses of the δ 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 δ 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 μ and δ receptors and a potential regulatory role for the endogenous ligands of the opioid δ receptor.