17β-Estradiol and Progesterone Positively Modulate Spinal Cord Dynorphin: Relevance to the Analgesia of Pregnancy

Abstract

Pregnancy and parturition are associated with opioid-mediated elevations in maternal pain thresholds. This analgesia is subserved by a spinal cord dynorphin/K-opiate receptor system. During gestation, elevated pain thresholds are paralleled by a significant increase in the content of dynorphin (1–17 and 1–8) in the lumbar spinal cord. An additional increment in lumbar dynorphin (1–17) concentration, but not that of dynorphin (1–8), occurs in parturient animals. Simulation of the pregnancy blood concentration profile of 17β-estradiol and progesterone (‘hormone-simulated pregnancy’) also results in an opioid analgesia, the magnitude and temporal pattern of which closely approximates that of actual gestation. The current study demonstrates that during hormone-simulated pregnancy, the spinal cord content of dynorphin (1–17) [but not dynorphin (1–8)] is positively modulated. This regulation is time- (or dose-)-dependent and region-specific. Significant elevations in spinal levels of dynorphin (1–17) are observed during steroid dose periods 3 and 4, corresponding to the last week of actual gestation and parturition, respectively. Increased dynorphin (1–17) content is observed in only the lumbar spinal region. These changes are temporally and anatomically identical to those which occur during actual gestation and parturition. It is concluded that changes in circulating 17β-estradiol and progesterone, that occur as a natural consequence of gestation, activate a dynorphin system in the lumbar spinal cord. This attenuates the pain associated with late pregnancy and labor. The pattern of circulating sex steroids can be an important determinant of the activity of central opioid analgesic systems.

Activation of Opioid Receptor Like-1 Receptor in the Spinal Cord Produces Sex-Specific Antinociception in the Rat: Estrogen Attenuates Antinociception in the Female, whereas Testosterone Is Required for the Expression of Antinociception in the Male

“…There are a number of possible molecular mechanisms via which estrogen might diminish OFQ-induced antinociception, including decreasing the expression of the ORL 1 receptor (Flores et al, 2003) and/or its coupling to G-proteins (for review, see Kelly and Wagner, 1999;Malyala et al, 2005), which would secondarily modify the affinity of OFQ to the ORL 1 receptor. Estrogen receptors (ER␣/ER␤) are present in spinal dorsal horn neurons (Amandusson et al, 1996(Amandusson et al, , 1999Shughrue et al, 1997), and estrogen, in addition to altering the expression of opioid peptides (Medina et al, 1993;Micevych et al, 1997;Amandusson et al, 1999;Micevych and Sinchak, 2001) (for review, see Craft et al, 2004), has also been shown by us and others to alter the expression of the ORL 1 receptor gene and protein in the trigeminal region and the hypothalamus (Sinchak et al, 1997;Flores et al, 2003;Sinchak et al, 2006).…”

Placenta ingestion by rats enhances δ- and κ-opioid antinociception, but suppresses μ-opioid antinociception

“…During late pregnancy and parturition, changes in hormonal and sensory aspects of maternal physiology induce a significant increase in pain threshold [11,15,33,53]. Opioid mechanisms play a pivotal role in the mediation of this effect [23,78], and provide, presumably, the endogenous analgesic substrate(s) for ingested POEF at parturition [45].…”

Estrogenic influences in pain processing

“…Spinal dynorphin-and metenkephalin pathways are activated concomitantly but are subject to individual regulation (Gupta and Gintzler, 2003). As pregnancy progresses, the level of spinal met-enkephalin gradually increases throughout the spinal cord whereas the increase in dynorphin is restricted to the lumbar regions receiving pelvic afferents (Medina et al, 1993). It has been suggested that met-enkephalin therefore is of importance to the basal opioid tone and serves to facilitate spinal dynorphin activity, which is required for antinociception to occur (Gupta and Gintzler, 2003).…”

“…Even though progesterone receptors have not been detected in the dorsal horn of the spinal cord (Kastrup et al, 1999), the possibility that progesterone also contributes to the effects of estrogen must be considered. Progesterone has indeed been shown to alter the nociceptive effects of estrogens (Drury and Gold, 1978;Kuba et al, 2006) at a spinal level (McCarthy et al, 1990;Medina et al, 1993;Ren et al, 2000) and to regulate nociception-related P2X3-receptor function in dorsal root ganglion neurons (Fan et al, 2011). Pregnancy-induced analgesia requires progesterone to become manifest so this analgesia is not seen in response to estrogens alone (Gintzler and Liu, 2001).…”