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

Abstract

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) 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 ϩ -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.Pharmacological and behavioral studies have suggested a functional association between spinal ␦-and -opioid antinociceptive systems and their modulation by ovarian sex steroids (Dawson-Basoa and Gintzler, 1998). Response thresholds to somatic and visceral noxious stimuli are elevated during gestation (gestational antinociception, GSA) in rats, mice, sows (Toniolo et al., 1987;Gintzler and Bohan, 1990;Iwasaki et al., 1991), and humans (Cogan and Spinnato, 1986). Simulation of the concentration profiles of 17␤-estradiol (estrogen, E 2 ) and progesterone (P) found in the blood during pregnancy (i.e., hormone-simulated pregnancy, HSP) also increases thresholds for responsiveness to aversive stimuli (HSP analgesia, HSPA). Moreover, the magnitude, temporal pattern of onset, and duration, and spinal opioid receptor profile of HSPA are essentially identical to those of physiological pregnancy Gintzler, 1993, 1998;Liu and Gintzler, 1999).In rats, pharmacological blockade of either spinal -opioid receptors (KOR) or ␦-opioid receptors (DOR) abolishes GSA and HSPA (Dawson-Basoa and Gintzler, 1998;Liu and Gintzler, 2000). This indicates that ovarian sex steroids can induce activation of spinal KOR and DOR analgesic systems and that both of these effects are essential for the manifestation of GSA and HSPA. Functional interactions between spinal...

Estradiol Treatment Prevents Injury Induced Enhancement in Spinal Cord Dynorphin Expression

“…PRDN/ERα co-expression was shown previously in the intact lumbar and sacral spinal cord segments of female rats (Gintzler et al, 2008). The co-expression of PRDN and ERα provides a morphological basis for the effect of EB treatment on the tissue levels of PRDN in the at level spinal cord.…”

Regulation of Spinal Dynorphin 1-17 Release by Endogenous Pituitary Adenylyl Cyclase-Activating Polypeptide in the Male Rat: Relevance of Excitation via Disinhibition

“…The content of Dyn in intrathecal perfusate was quantified by using a competitive enzyme immunoassay performed as instructed in the kit (Peninsula Laboratories, Belmont, CA). The anti-Dyn antibody used is highly selective for Dyn 1-17; it does not recognize either Dyn 1-13, Dyn 1-8, ␣-NeoEndorphin, ␤-endorphin, Dyn B, or Leu-enkephalin (see Gintzler et al, 2008 for further characterization). A standard curve (0.5-32 pg/assay well) in which the percentage of inhibition of binding was plotted against the log concentration of unlabeled Dyn in the reaction well was generated in each assay.…”

Mu Opioids and Their Receptors: Evolution of a Concept

“…7), including methadone, heroin, fentanyl, and morphine-6b-glucuronide Chang et al, 1998;Pasternak, 2004Pasternak, , 2010. Additional studies have explored the roles of genetic backgrounds and sex issues in more detail (Kepler et al, 1991;Gear et al, 1999;Kest et al, 1999;Lariviere et al, 2002;Wilson et al, 2003a,b;Gintzler et al, 2008;Chakrabarti et al, 2010;Mogil and Bailey, 2010). Thus, these preclinical studies suggest a genetic basis for differing sensitivities of individuals to each opiate and to different relative potencies of mu opiates from patient to patient.…”