Differential antinociceptive effects of endomorphin-1 and endomorphin-2 in the mouse.

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous mu-opioid receptor ligands. We determined the antinociceptive effects of these two ligands at the supraspinal level in mice with the tail-flick and hot-plate responses. The i.c.v. injection of endomorphin-1 and -2 inhibited the tail-flick and hot-plate responses in a dose-dependent manner. The endomorphin-1 was found to be 3.3- and 2.4-fold more potent than endomorphin-2 in inhibiting the tail-flick and hot-plate responses, respectively. The antinociception induced by endomorphin-1 was blocked by i.c.v. pretreatment with the mu-opioid receptor antagonist beta-funaltrexamine but not by the kappa-opioid receptor antagonist nor-binaltorphimine, the delta(1)-opioid antagonist 7-benzylidene naltrexamine, or the delta(2)-opioid receptor antagonist naltriben. In contrast, the antinociception induced by endomorphin-2 was blocked by i.c.v. pretreatment with beta-funaltrexamine or nor-binaltorphimine but not by 7-benzylidene naltrexamine or naltriben. The inhibition of the tail-flick response induced by endomorphin-2 was blocked by pretreatment with an antiserum against dynorphin A(1-17) but not by antisera against Met-enkephalin, Leu-enkephalin, or beta-endorphin. None of these antisera reduced the endomorphin-1-induced tail-flick inhibition. We propose that endomorphin-1 produces antinociception by stimulating one type of mu-opioid receptor, whereas endomorphin-2 initially stimulates different mu-opioid receptors, which subsequently induce the release of dynorphins that act on kappa-opioid receptors to produce antinociception.