Vol. 298, Issue 3, 1213-1220, September 2001

Ovarian Sex Steroid-Dependent Plasticity of Nociceptin/Orphanin FQ and Opioid Modulation of Spinal Dynorphin Release

Daya S. Gupta, Andrew B. Kelson, Willma E. Polgar, Lawrence Toll, Maria Szücs¹ and Alan R. Gintzler

Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, New York (D.S.G., M.S., A.R.G.); and SRI International, Menlo Park, California (A.B.K., W.E.P., L.T.)

Pregnancy and its hormonal simulation via 17-estradiol (E₂) and progesterone (P) are associated with spinal opioid antinociception, primarily driven by augmented dynorphin/-opioid activity. This study addresses the ovarian sex steroid-activated mechanism(s) that underlie this activation using an ex vivo spinal cord preparation. In lumbar spinal cord obtained from control animals, exogenous - or -opioid agonists (but not µ), as well as nociceptin (orphanin FQ; N/OFQ), dose dependently inhibit the stimulated release of dynorphin. Consistent with these observations, stimulated dynorphin release is enhanced following selective blockade of opioid or N/OFQ receptors, indicating that their endogenous ligands are negative modulators of dynorphin release. In lumbar spinal cord obtained from ovariectomized animals exposed to pregnancy blood levels of E₂/P, basal and stimulated rates of dynorphin release increase 2-fold. Moreover, evoked dynorphin release is no longer negatively modulated by - or -opioid agonists or N/OFQ. Interestingly, in these preparations, release can be facilitated by -opioid receptor activation, and neither spinal opioid nor N/OFQ receptor blockade enhances evoked dynorphin release. Consistent with these observations, guanosine-5'-O-3-[³⁵S]-thio triphosphate binding analyses indicate a reduction in functional N/OFQ receptors. These data indicate that at least part of the E₂/P-induced augmented activity of lumbar dynorphin neurons results from their disinhibition via the removal of negative opioid and N/OFQ modulation. These results underscore the plasticity of spinal opioid and N/OFQ systems and their dependence on the ovarian sex steroid milieu. Ovarian sex steroid-activated antinociception reveals mechanisms that enable sustained opioid activation without concomitant tolerance formation.