Analysis of the antinociceptive actions of the κ-opioid agonist enadoline (CI-977) in neonatal and adult rats: comparison to κ-opioid receptor mRNA ontogeny

Abstract

Earlier reports indicate that κ-opioid agonists may be especially potent in the formalin test of tonic nociception, and that neonatal rat pups are more sensitive to μ-agonists, when compared to adults. We have assessed the potency of enadoline (CI-977), a novel and selective κ-opioid agonist, in the formalin and tail-flick nociceptive tests in 3-day-old rat pups and compared their responses to adults in the same tests. In addition, the recent cloning of the κ-opioid receptor has allowed us to make the first evaluation of the ontogeny of κ-opioid receptor mRNA in an effort to elucidate a possible mechanism for differences in sensitivity to κ-opioid agonists. Enadoline was found to be a potent antinociceptive agent in the formalin test; the neonates were eight times more sensitive than the adults. κ-Opioid receptor mRNA, however, is present in whole brain at adult levels as early as postnatal day 3. Previous studies have shown κ-opioid receptor levels, as measured by radioligand binding and receptor autoradiography, to be present at postnatal day 3 as well. Consequently, it is unlikely that gross differences in receptor number subserved the modest increase in sensitivity to enadoline observed in the neonates in the formalin test. Enadoline was less potent and less effective in the tail-flick test in the neonates. The adults were similarly insensitive to the antinociceptive effects of enadoline in the tail-flick test. Additional studies indicated that enadoline significantly increased locomotor activity, as assessed by the open-field test, in neonates, while decreasing activity in the adults. Studies with U50.488 (U50), and nor-binaltorphamine ( nor-BNI) suggest that these increases in activity observed in the neonates may be κ-mediated. Although the open-field studies do not relate directly to κ-opioid antinociception, the observation of behavioral activation in the neonates may limit the use of κ-agonists in pediatric populations.