Ovarian sex steroid-dependent plasticity of nociceptin/orphanin FQ and opioid modulation of spinal dynorphin release

Pregnancy and its hormonal simulation via 17 beta -estradiol (E-2) and prog esterone (P) are associated with spinal opioid antinociception, primarily d riven by augmented dynorphin/kappa -opioid activity. This study addresses t he ovarian sex steroid-activated mechanism(s) that underlie this activation using an ex vivo spinal cord preparation. In lumbar spinal cord obtained f rom control animals, exogenous kappa (-) or delta -opioid agonists (but not mu), as well as nociceptin (orphanin FQ; N/OFQ), dose dependently inhibit the stimulated release of dynorphin. Consistent with these observations, st imulated dynorphin release is enhanced following selective blockade of opio id or N/OFQ receptors, indicating that their endogenous ligands are negativ e modulators of dynorphin release. In lumbar spinal cord obtained from ovar iectomized animals exposed to pregnancy blood levels of E-2/P, basal and st imulated rates of dynorphin release increase approximate to2-fold. Moreover , evoked dynorphin release is no longer negatively modulated by kappa (-) o r delta -opioid agonists or N/OFQ. Interestingly, in these preparations, re lease can be facilitated by delta -opioid receptor activation, and neither spinal opioid nor N/OFQ receptor blockade enhances evoked dynorphin release . Consistent with these observations, guanosine-5'-O-3-[S-35]-thio triphosp hate binding analyses indicate a reduction in functional N/OFQ receptors. T hese data indicate that at least part of the E-2/P-induced augmented activi ty of lumbar dynorphin neurons results from their disinhibition via the rem oval of negative opioid and N/OFQ modulation. These results underscore the plasticity of spinal opioid and N/OFQ systems and their dependence on the o varian sex steroid milieu. Ovarian sex steroid-activated antinociception re veals mechanisms that enable sustained opioid activation without concomitan t tolerance formation.