Abstract

The concomitant activation of spinal κ- and δ-opioid systems is a prerequisite for the antinociception of gestation and its hormonal simulation [via 17β-estradiol and progesterone administration; hormone-simulated pregnancy (HSP)]. However, it is not known whether the release of κ- and δ-opioids is also concomitantly regulated. This study investigates whether the release of methionine-enkephalin and modulation thereof is altered during HSP, as has been reported for dynorphin. K⁺-stimulated release of spinal methionine-enkephalin from lumbar spinal tissue obtained from control animals is negatively modulated by nociceptin (orphanin FQ; N/OFQ) in a dose-dependent manner, but not by opioids. Conversely, selective blockade of spinal N/OFQ, but not opioid receptors, augments the K⁺-induced increase in methionine-enkephalin release, indicating that endogenous N/OFQ also functions as a negative modulator of methionine-enkephalin release. The magnitude of K⁺-evoked methionine-enkephalin release from spinal tissue obtained from ovarian steroid-treated animals remains unchanged, consistent with the insensitivity of its modulation by N/OFQ to the ovarian sex steroid milieu. These characteristics of methionine-enkephalin release stand in sharp contrast to those previously reported for the evoked release of spinal dynorphin. Dynorphin release is subject to negative modulation by opioid (predominantly δ) as well as N/OFQ, both of which are offset during HSP, resulting in an ≈2-fold increase in the magnitude of its release. These observations reveal that regulation of spinal dynorphin/κ- and methionine-enkephalin/δ-spinal opioid antinociceptive systems is independent, divergent, and not symmetrical and support the formulation that spinal methionine-enkephalin/δ-opioid tone acts in a permissive/facilitative capacity to accentuate spinal dynorphin/κ-activity.