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

Abstract

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.

Estrogenic influences in pain processing

“…This mechanism may be particularly important for dynorphin-related nociceptive signaling in the spinal cord (Gintzler and Liu, 2012b). As previously described, dynorphin is an essential component of pregnancy-induced analgesia in rats.…”

“…However, other studies, particularly those carried out by Alan Gintzler and collaborators have shown that under certain conditions, such as during pregnancy, dynorphin produces pain inhibition (for refs. see Gintzler and Liu, 2012a). Amandusson et al 1996.…”

“…The distribution of dynorphin largely follows that of enkephalins (Khachaturian et al, 1982;Weber et al, 1982), but while both are densely expressed in the superficial dorsal horn, they seem to constitute distinct populations (Marvizon et al, 2009). Dynorphin is both pro-and antinociceptive (Gintzler and Liu, 2012a). Dynorphin is released in the spinal cord upon peripheral tissue damage (Kajander et al, 1990;Malan et al, 2000), and intrathecal administration of dynorphin in animals has repeatedly been shown to induce pain (for refs.…”

“…Dynorphin is released in the spinal cord upon peripheral tissue damage (Kajander et al, 1990;Malan et al, 2000), and intrathecal administration of dynorphin in animals has repeatedly been shown to induce pain (for refs. see Gintzler and Liu, 2012a). Furthermore, studies in dynorphin knock-out mice have demonstrated that dynorphin is necessary for the maintenance of sustained neuropathic pain (Wang et al, 2001).…”

Activation of Estrogen Receptor α Enhances Bradykinin Signaling in Peripheral Sensory Neurons of Female Rats

“…Among the many possible reasons for the disparity in pain responsiveness between men and women, which include cognitive and sociocultural differences, several studies have shown the importance of the sex hormone estrogen in regulating nociception (Craft, 2007;Fillingim et al, 2009;Gintzler and Liu, 2012).…”