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

https://doi.org/10.1016/j.yfrne.2012.09.004Get rights and content

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.

Highlights

► 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.

Introduction

The influence of sex on nociception and its amelioration has been extensively documented but the underlying biology remains elusive. Multiple cross validating studies reveal that women are more likely than men to experience chronic pain as well as pain of greater severity and duration (Larijani et al., 2004, Lee et al., 2001, Mayer et al., 1999, Riley et al., 1998, Rollman and Lautenbacher, 2001, Unruh, 1996, Yunus, 2001). Chronic pain disorders that are vastly more prevalent in women than men include migraine (2:1), irritable bowel syndrome (2:1), interstitial cystitis (9:1) and fibromyalgia (6:1). Sex-dependent differences in nociception are observed across multiple modalities of nociceptive stimuli, e.g., thermal (Fillingim et al., 1998), electrical (Walker and Carmody, 1998), pressure (Ellermeier and Westphal, 1995). Moreover, epidemiological studies have consistently shown that women have greater severity and frequency of visceral pain than do men (Berkley, 1997, Berman et al., 2000, Naliboff et al., 2003).

Sex-dependent differences in nociceptive responsiveness and endogenous pain modulation have also been documented using laboratory animals (Berkley, 1997, Chesler et al., 2002, Coyle et al., 1995, Coyle et al., 1996, Kayser et al., 1996, Mogil and Chanda, 2005, Mogil et al., 1993). In particular, studies with laboratory animals reveal that females have significantly lower thresholds to experimental visceral pain than do males (Murphy et al., 2009). Despite the pervasiveness of these observations, there is little mechanistic understanding of the sex-dependent experience of either chronic or acute pain. In particular, the specific factor(s) that is (are) causally associated with sex-dependent nociception have not been delineated.

Sex is also increasingly recognized to be causally associated with antinociceptive efficacy of many opioids (Craft, 2003, Dahan et al., 2008, Kest et al., 2000, Miaskowski and Levine, 1999). There is a rapidly emerging consensus that women respond more efficaciously to opioid analgesics than do men. For example, in one study (Chia et al., 2002), females consumed significantly less morphine via patient-controlled analgesia in the first three postoperative days than was the case for males, gender being the strongest predictor for postoperative morphine requirements. The implied greater opioid antinociceptive efficacy in women vs. men was subsequently affirmed by demonstrating that women manifested greater analgesic responsiveness to three mu opioid receptor agonists (morphine, meperidine (pethidine) and hydromorphone) than their male counterparts using cold pressure as the nociceptive stimulus (Zacny, 2002).

Estrogens have a multitude of well-documented effects on opioid systems. There is considerable evidence that they play a key role in aspects of nociception and opioid antinociception that exhibit sexual dimorphism. Our understanding of the mechanisms that could underlie estrogenic modulation has been revolutionized by the recent discovery that receptors for estrogens exist in the plasma membrane and that these membrane receptors function mechanistically and temporally in a fundamentally different manner from their nuclear counterpart. The contribution of the plasma membrane estrogen receptor (ER) to estrogenic modulation of nociception and opioid antinociception is just beginning to be delineated.

Our aim in this review is to provide selective perspective on selective components of nociception and antinociception that exhibit sexually dimorphic plasticity and the roles of estrogens in that sex-dependent modulation. This review summarizes parameters of opioid functionality and nociception that are subject to modulation by estrogens with particular emphasis on estrogenic regulation that are best explained by the involvement of its plasma membrane receptors whose signaling mirrors that of G protein coupled receptors both in mechanism and temporal profile. The importance of synthesis of estrogens by the CNS as well as its rapid degradation, necessitated by the utilization of rapid membrane ER signaling will also be covered.

Section snippets

Sexually dimorphic kappa-opioid receptor (KOR)-mediated antinociception

Perhaps the most poignant example of the influence of sex on opioid antinociception in humans is the demonstration of antithetical antinociceptive/nociceptive responsiveness of females vs. males to KOR agonists–antagonists. In these studies, which made use of a clinically relevant pain model, postoperative pain resulting from the extraction of third molar teeth, butorphanol and nalbuphine were shown to have greater analgesic efficacy in women vs. men (Gear et al., 1996). The absence of any

Sex-dependent mechanistic underpinnings of opioid antinociception

Even when opioid antinociceptive responsiveness is sexually monomorphic, underlying mechanisms can still be sexually dimorphic. For example, the antinociception produced by intrathecal morphine, which does not significantly differ in magnitude between males and females, results from the sex-based differential recruitment of spinal analgesic components (Liu et al., 2007). In males, spinal morphine antinociception results from the exclusive activation of spinal MOR whereas in females, spinal

Ovarian sex steroids and nociception/antinociception

The milieu of ovarian sex steroids is thought to be a major determinant of sex-dependent nociception (Berkley, 1997, Craft et al., 2004, Kayser et al., 1996, Mogil et al., 1993) and opioid antinociception (Mogil et al., 1993, Sternberg et al., 1995). The effects of estrogens on nociception are bimodal being both pronociceptive as well as antinociceptive. Antinociceptive actions of estrogens include: (1) KOR antinociception and gene expression are enhanced by exogenous or endogenous estradiol in

Biochemical bases for effects of estrogens on nociception/antinociception

ER activation can also result in modification of signaling cascades known to mediate opioid receptor signaling. For example, ER-coupled actions can result in activation of protein kinase A (Auger et al., 2001, Gu and Moss, 1996, Mize and Alper, 2002, Moss and Gu, 1999), protein kinase C (Qiu et al., 2003), mitogen-activated protein kinase (MAPK) (Zhang et al., 2002), extracellular signal-regulated kinase 1/2 (ERK1/2) (Setalo et al., 2002) and Akt proteins (Vertes et al., 2004). All of these

Regulation by estradiol of interactions among opioid receptors

Surprisingly, treatment of orchiectomized male rats with pregnancy levels of ovarian sex steroids also produces spinally mediated opioid antinociception, the temporal profile and magnitude of which is indistinguishable from that observed in females (Liu and Gintzler, 2000). But this antinociception results from the additive, not synergistic, contributions of spinal opioid systems (Liu and Gintzler, 2000). In males, the antinociception resulting from ovarian steroid treatment results from the

Genomic effects of estrogens on opioid antinociception

Classically, the ER was considered to be a ligand-activated transcription factor (Couse and Korach, 1999, McKenna et al., 1999, Paech et al., 1997). This was based on the nuclear localization of ERs (King and Greene, 1984, Welshons et al., 1984), its binding to estrogen response elements on DNA (Nawaz et al., 1992) and the dependence of the actions of estrogens on gene expression and protein synthesis (Rainbow et al., 1980). Activation of gene expression and de novo protein synthesis by

Plasma membrane ERs and nociception/antinociception

The more recently discovery that estrogens exert effects by acting at ERs located in the plasma membrane (as well as nucleus ERs) (Bondar et al., 2009, Rai et al., 2005, Zheng and Ramirez, 1997), the effects of which are manifest within seconds to min, instead of hours/days, enormously broadens the physiological functions that could be modulated by estrogens. This mode of action was foreshowed by the report that within seconds of application, estradiol alters excitability of neurons in the

Integration of the effects resulting from rapid membrane ER and genomic ER signaling

It is important to realize that genomic and plasma membrane actions of estrogens are not mutually exclusive. There is a complex interaction between the functional consequences of activating ERs in different subcellular compartments that can be modulated by cell context-specific environments. This enables the fine-tuning of estradiol function. For example, one consequence of rapid membrane initiated ER signaling is the enhancement of genomic effects of estradiol function; activation of

Membrane ERs are co-expressed and act cooperatively to regulate MOR/KOR

The effects of doses of spinal ER type-selective antagonists that produced submaximal reductions in spinal MOR/KOR heterodimerization or in the KOR component of spinal morphine antinociception are not additive. Instead, reductions in either the content of MOR/KOR or the KOR component of spinal morphine antinociception produced by the individual submaximal antagonism of ERα, ERβ, or GPR30 are indistinguishable from that produced by the concomitantly blocking combinations of ERs (ERα + GPR30 and ERα

Spinal membrane ERs and sexually dimorphic nociceptive/antinociceptive effects of Dyn/KOR

Regulation by rapid plasma membrane ER signaling of the equilibrium between monomeric KOR and KOR heterodimerized with MOR enables modulation of nociception by utilizing the bimodal functionality inherent in Dyn/KOR signaling. Dyn has long been considered to be an endogenous KOR substrate (Chavkin and Goldstein, 1981a, Chavkin and Goldstein, 1981b, Chavkin et al., 1982, Lord et al., 1977). The actions of Dyn are very complex, if not contradictory (see Lai et al. (2001) for overview). It is now

Aromatase and nociception/antinociception

The data mentioned above regarding the ability of rapid membrane ER signaling to modulate nociception/antinociception constitutes proof of principle and defines a specific physiological state (proestrus) in which rapid membrane ER signaling is of particular relevance to antinociception. A more generalized relevance to nociception of rapid membrane ER signaling requires their access to dynamically regulated nuanced levels of estrogens that fluctuate within a time frame comparable to that of

Rapid catabolism of estrogens

The physiological importance of rapid membrane ER signaling requires the ability to rapidly degrade estrogens in addition to the ability to acutely regulate aromatase activity. In this regard, it should be noted that the CNS contains high levels of two enzymes that can degrade estrogens. The preoptic-hypothalamic region contains 2- and 4-hydroxylases that convert estrogens to 2- and 4-hydroxyestrogens (Balthazart et al., 1994, Timmers et al., 1988, Zhu and Conney, 1998), which are subsequently

Conclusion

This new-found complexity and sexual dimorphism thereof could provide solid ground for understanding the sex divide in the experience of pain and its treatment, the growing examples of which outpace our comprehension. This newly appreciated complexity could also provide a starting point for interpreting the spectrum of contradictory findings that pervade the sex/pain literature. The importance of estrogens in pain modulation can only be fully comprehended within the context of the male female

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