PT  - JOURNAL ARTICLE
AU  - Daya S. Gupta
AU  - Andrew B. Kelson
AU  - Willma E. Polgar
AU  - Lawrence Toll
AU  - Maria Szücs
AU  - Alan R. Gintzler
TI  - Ovarian Sex Steroid-Dependent Plasticity of Nociceptin/Orphanin FQ and Opioid Modulation of Spinal Dynorphin Release
DP  - 2001 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1213--1220
VI  - 298
IP  - 3
4099  - http://jpet.aspetjournals.org/content/298/3/1213.short
4100  - http://jpet.aspetjournals.org/content/298/3/1213.full
SO  - J Pharmacol Exp Ther2001 Sep 01; 298
AB  - Pregnancy and its hormonal simulation via 17β-estradiol (E2) and progesterone (P) are associated with spinal opioid antinociception, primarily driven by augmented dynorphin/κ-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 κ- or δ-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 κ- or δ-opioid agonists or N/OFQ. Interestingly, in these preparations, release can be facilitated by δ-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. The American Society for Pharmacology and Experimental Therapeutics