Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors

Estrogens have a multitude of effects on opioid systems and are thought to play a key role in sexually dimorphic nociception and opioid antinociception. Heretofore, classical genomic actions of estrogens are largely thought to be responsible for the effects of these steroids on nociception and opioid antinociception. The recent discovery that estrogens can also activate estrogen receptors that are located in the plasma membrane, the effects of which are manifest in seconds to minutes instead of hours to days has revolutionized our thinking concerning the ways in which estrogens are likely to modulate pain responsiveness and the dynamic nature of that modulation. This review summarizes parameters of opioid functionality and nociception that are subject to modulation by estrogens, underscoring the added dimensions of such modulation that accrues from rapid membrane estrogen receptor signaling. Implications of this mode of signaling regarding putative sources of estrogens and its degradation are also discussed.

► Rapid membrane estrogen receptor signaling influences pain regulation.
► Membrane estrogen receptors modulate μ- and κ-opioid receptor heterodimerization.
► Membrane estrogen receptors regulate pro- vs. anti-nociceptive functions of dynorphin.
► Spinal estrogen via its membrane receptor regulates dynorphin effects on nociception.
► Membrane estrogen receptor activity influences sex difference in pain process.