ANALYSIS OF THE ANTINOCICEPTIVE ACTIONS OF THE KAPPA-OPIOID AGONIST ENADOLINE (CI-977) IN NEONATAL AND ADULT-RATS - COMPARISON TO KAPPA-OPIOID RECEPTOR MESSENGER-RNA ONTOGENY

Earlier reports indicate that kappa-opioid agonists may be especially potent in the formalin test of tonic nociception, and that neonatal ra t pups are more sensitive to mu-agonists, when compared to adults. We have assessed the potency of enadoline (CI-977), a novel and selective kappa-opioid agonist, in the formalin and tail-flick nociceptive test s in 3-day-old rat pups and compared their responses to adults in the same tests. In addition, the recent cloning of the kappa-opioid recept or has allowed us to make the first evaluation of the ontogeny of K-op ioid receptor mRNA in an effort to elucidate a possible mechanism for differences in sensitivity to kappa-opioid agonists. Enadoline was fou nd to be a potent antinociceptive agent in the formalin test; the neon ates were eight times more sensitive than the adults. kappa-Opioid rec eptor mRNA, however, is present in whole brain at adult levels as earl y as postnatal day 3. Previous studies have shown kappa-opioid recepto r levels, as measured by radioligand binding and receptor autoradiogra phy, to be present at postnatal day 3 as well. Consequently, it is unl ikely that gross differences in receptor number subserved the modest i ncrease in sensitivity to enadoline observed in the neonates in the fo rmalin test. Enadoline was less potent and less effective in the tail- flick test in the neonates. The adults were similarly insensitive to t he antinociceptive effects of enadoline in the tail-flick test. Additi onal studies indicated that enadoline significantly increased locomoto r activity, as assessed by the open-field test, in neonates, while dec reasing activity in the adults. Studies with U50,488 (U50), and nor-bi naltorphamine (nor-BNI) suggest that these increases in activity obser ved in the neonates may be kappa-mediated. Although the open-field stu dies do not relate directly to kappa-opioid antinociception, the obser vation of behavioral activation in the neonates may limit the use of k appa-agonists in pediatric populations.