Differential antinociception induced by spinally administered endomorphin-1 and endomorphin-2 in the mouse

We have previously demonstrated that the antinociception induced by either endomorphin-1 or endomorphin-2 given supraspinally is mediated by the stimulation of mu-opioid receptors. However, the antinociception induced by endomorphin-2 given supraspinally contains additional components, which are mediated by the spinal release of dynorphin A (1-17) acting on kappa-opioid receptors and the spinal release of [Met5]enkephalin acting on delta2-opioid receptors in the spinal cord. The present studies were performed to determine whether there are any differential effects on the tail-flick inhibition induced by endomorphin-1 and endomorphin-2 given intrathecally (i.t.) in mice. Endomorphin-1 or endomorphin-2 given i.t. inhibited the tail-flick response in a dose-dependent manner. The tail-flick inhibition induced by endomorphin-1 was blocked by i.t. pretreatment with mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2 (CTOP), but not kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI), delta1-opioid receptor antagonist 7-benzylidene naltrexamine (BNTX), or delta2-opioid receptor antagonist naltriben (NTB). In contrast, the tail-flick inhibition induced by endomorphin-2 given i.t. was blocked by i.t. pretreatment with CTOP or nor-BNI, but not BNTX or NTB. Intrathecal pretreatment with antiserum against dynorphin A (1-17), but not antiserum against [Met5]enkephalin, [Leu5]enkephalin, or beta-endorphin, blocked the tail-flick inhibition induced by i.t.-administered endomorphin-2. None of these antisera attenuated the i.t.-administered endomorphin-1-induced tail-flick inhibition. It is concluded that the tail-flick inhibition induced by endomorphin-1 and endomorphin-2 given spinally is mediated by the stimulation of mu-opioid receptors. However, the tail-flick inhibition induced by spinally injected endomorphin-2 contains an additional component, which is mediated by the spinal release of dynorphin A (1-17) acting on kappa-opioid receptors in the spinal cord. We propose that there are at least two different subtypes of micro-opioid receptors for endomorphin-1 and endomorphin-2 to produce antinociception in the spinal cord.