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, M. Szücs, Alan R. Gintzler

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1213-1220
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number3
Publication statusPublished - 2001

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Dynorphins
Opioid Analgesics
Steroids
Spinal Cord
Guanosine 5'-O-(3-Thiotriphosphate)
nociceptin
Pregnancy
Opioid Receptors
Progesterone
Estradiol
Ligands
Neurons

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ovarian sex steroid-dependent plasticity of nociceptin/orphanin FQ and opioid modulation of spinal dynorphin release. / Gupta, Daya S.; Kelson, Andrew B.; Polgar, Willma E.; Toll, Lawrence; Szücs, M.; Gintzler, Alan R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 298, No. 3, 2001, p. 1213-1220.

Research output: Contribution to journalArticle

Gupta, Daya S. ; Kelson, Andrew B. ; Polgar, Willma E. ; Toll, Lawrence ; Szücs, M. ; Gintzler, Alan R. / Ovarian sex steroid-dependent plasticity of nociceptin/orphanin FQ and opioid modulation of spinal dynorphin release. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 298, No. 3. pp. 1213-1220.
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