Abstract
Pharmacological and behavioral studies suggest that spinal δ- and κ-opioid antinociceptive systems are functionally associated with ovarian sex steroids. These interactions can be demonstrated specifically during pregnancy or hormone-simulated pregnancy (HSP). The analgesia associated with both conditions can be abolished by blockade of either spinal κ-opioid receptors or δ-opioid receptors (DOR). Furthermore, both dynorphin (DYN) release (J Pharmacol Exp Ther 298:1213–1220, 2001) and the processing of the DYN precursor (J Neurochem 65:1374–1380, 1995) are significantly increased in the spinal cord during HSP. We undertook the current study to determine whether DYN, DOR, and estrogen receptor α (ERα) share anatomical relationships that permit their direct interaction. Coexpression of DOR or ERα by DYN neurons was assessed using fluorescence immunohistochemistry and a synaptosomal release assay. Findings show that ERα and DYN are coexpressed. Moreover, in the spinal cord of HSP animals, there were significant increases in the number of DYN-immunoreactive (DYN-ir) cells, ERα-ir cells, cells double-labeled for DYN-ir and ERα-ir and the proportion of DYN-ir cells coexpressing ERα. Some varicose fibers in the spinal cord dorsal horn and intermediate gray matter that expressed DYN-ir also expressed DOR-ir. Activation of DORs located on DYN terminals was sufficient to inhibit K+-evoked DYN release. These data define, at least in part, the anatomical substrates that may be relevant to the antinociception of gestation and its hormonal simulation. Furthermore, they provide a framework for understanding sex-based nociception and antinociception and suggest novel strategies for treating pain.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.139816.
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ABBREVIATIONS: GSA, gestational antinociception; DYN, dynorphin; DYN-ir, dynorphin immunoreactivity; ERα, estrogen receptor α;ERα-ir, estrogen receptor α immunoreactivity; HSP, hormone-simulated pregnancy; HSPA, HSP analgesia; DOR, δ-opioid receptor; DOR-ir, δ-opioid receptor immunoreactivity; E2, 17β-estradiol, estrogen; P, progesterone; KOR, κ-opioid receptor; NA, numerical aperture; DPDPE, d-Pen5-enkephalin; PBS, phosphate-buffered saline.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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↵1 Current affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky.
- Received April 9, 2008.
- Accepted June 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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