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NEUROPHARMACOLOGY

Relationship of Spinal Dynorphin Neurons to -Opioid Receptors and Estrogen Receptor : Anatomical Basis for Ovarian Sex Steroid Opioid Antinociception

Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, New York (A.R.G., D.S.G., N.-J.L.) and Department of Neuroscience (S.A.S., M.W.W.), University of Minnesota, Minneapolis, Minnesota

Pharmacological and behavioral studies suggest that spinal - and -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 -opioid receptors or -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 (ER) share anatomical relationships that permit their direct interaction. Coexpression of DOR or ER by DYN neurons was assessed using fluorescence immunohistochemistry and a synaptosomal release assay. Findings show that ER 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, ER-ir cells, cells double-labeled for DYN-ir and ER-ir and the proportion of DYN-ir cells coexpressing ER. 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.

Address correspondence to: Dr. Alan Gintzler, Box 8, Department of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail: alan.gintzler{at}downstate.edu