Ovarian sex steroid-dependent plasticity of nociceptin/orphanin FQ and opioid modulation of spinal dynorphin release.
Pregnancy and its hormonal simulation via 17beta-estradiol (E(2)) and progesterone (P) are associated with spinal opioid antinociception, primarily driven by augmented dynorphin/kappa-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 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, 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 E(2)/P, basal and stimulated rates of dynorphin release increase approximately 2-fold. Moreover, evoked dynorphin release is no longer negatively modulated by kappa- or delta-opioid agonists or N/OFQ. Interestingly, in these preparations, release 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-[(35)S]-thio triphosphate binding analyses indicate a reduction in functional N/OFQ receptors. These data indicate that at least part of the E(2)/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.
Gupta
D S
DS
Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, New York 11203, USA.
Kelson
A B
AB
Polgar
W E
WE
Toll
L
L
Szücs
M
M
Gintzler
A R
AR
D000818:Animals; D004399:Dynorphins / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D018847:Opioid Peptides / Q000494:pharmacology* / Q000502:physiology*; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000097629:Nociceptin
D004399:Dynorphins; D004958:Estradiol; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018847:Opioid Peptides; D011188:Potassium; D011374:Progesterone; D000097629:Nociceptin