Pregnancy and its hormonal simulation via 17β-estradiol (E2) and progesterone (P) are associated with spinal opioid an3tinociception, 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.
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - aug. 29 2001|
ASJC Scopus subject areas
- Molecular Medicine