Relationship of spinal dynorphin neurons to δ-opioid receptors and estrogen receptor α: Anatomical basis for ovarian sex steroid opioid antinociception

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.