Ovarian sex steroid-dependent plasticity of nociceptin/orphanin FQ and opioid modulation of spinal dynorphin release.
J Pharmacol Exp Ther
; 298(3): 1213-20, 2001 Sep.
Article
in En
| MEDLINE
| ID: mdl-11504823
ABSTRACT
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Progesterone
/
Spinal Cord
/
Dynorphins
/
Opioid Peptides
/
Estradiol
Limits:
Animals
Language:
En
Journal:
J Pharmacol Exp Ther
Year:
2001
Document type:
Article
Affiliation country:
United States