We have previously demonstrated that both
endomorphin-1 and
endomorphin-2 produce their antinociception by the stimulation of
mu-opioid receptors. However, the antinociception induced by
endomorphin-2 contains an additional component, which is mediated by the release of
dynorphin A (1-17) acting on
kappa-opioid receptors. These studies were done to determine whether the antinociception induced by
endomorphin-1 and
endomorphin-2 given supraspinally was mediated by the activation of different descending
pain control pathways in the mouse. Specific receptor antagonists or
antisera against endogenous
opioid peptides were injected intrathecally to block the receptors or bind the released endogenous
opioid peptides, and
endomorphin-1 or
endomorphin-2 was then administered i.c.v. to activate the descending
pain control systems to produce antinociception. The tail-flick response was used as antinociceptive test. The blockade of the alpha(2)-adrenoceptors and
5-hydroxytryptamine receptors in the spinal cord by i.t. injection of
yohimbine and
methysergide, respectively, inhibited the antinociception induced by i.c.v.-administered
endomorphin-1 and
endomorphin-2. However, the antinociception induced by
endomorphin-2 was inhibited by i.t. pretreatment with delta(2)-opioid receptor antagonist
naltriben or
kappa-opioid receptor antagonist
nor-binaltorphimine, but not by the
mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH(2) or the delta(1)-opioid receptor antagonist 7-benzylidene naltrexamine. Intrathecal pretreatment with antiserum against
Met-enkephalin attenuated the antinociception induced by i.c.v.-administered
endomorphin-2, but not
endomorphin-1. Furthermore, i.t. pretreatment with antiserum against
dynorphin A (1-17) also inhibited the antinociception induced by i.c.v.-administered
endomorphin-2, but not
endomorphin-1. Intrathecal pretreatment with antiserum against
Leu-enkephalin or
beta-endorphin did not inhibit i.c.v.-administered endomorphin-1- or endomorphin-2-induced antinociception. The results indicate that, like other
opioid micro-receptor agonists,
morphine, and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-
enkephalin,
endomorphin-1 and
endomorphin-2 given i.c.v. produce antinociception by activating spinipetal noradrenergic and serotonergic pathways for producing antinociception. However, the antinociception induced by
endomorphin-2 given i.c.v. also contains other components, which are mediated by the release of
Met-enkephalin and
dynorphin A (1-17) acting on
opioid delta(2)- and
kappa-receptors, respectively, in the spinal cord.