ReviewImportance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors
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
References (207)
- et al.
The role of the uterus in regulation of heat duration in cycling rats
Horm. Behav.
(1985) - et al.
Estradiol and testosterone differently affect visceral pain-related behavioural responses in male and female rats
Eur. J. Pain
(2010) - et al.
Estrogen-induced alterations of spinal cord enkephalin gene expression
Pain
(1999) - et al.
Brain aromatase and the control of male sexual behavior
J. Steroid Biochem. Mol. Biol.
(1993) - et al.
Immunocytochemical localization of aromatase in the brain
Brain Res.
(1990) - et al.
Distribution and regulation of estrogen-2-hydroxylase in the quail brain
Brain Res. Bull.
(1994) - et al.
Phosphorylation processes mediate rapid changes of brain aromatase activity
J. Steroid Biochem. Mol. Biol.
(2001) - et al.
Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level
J. Steroid Biochem. Mol. Biol.
(2003) - et al.
Oestrogen receptor-immunoreactive neurons in the trigeminal sensory system of male and cycling female rats
Arch. Oral Biol.
(2005) - et al.
Gender differences in regional brain response to visceral pressure in IBS patients
Eur. J. Pain
(2000)
Molecular cloning and tissue expression of a novel orphan G protein-coupled receptor from rat lung
Biochem. Biophys. Res. Commun.
Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus
Brain Res. Mol. Brain Res.
Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer
Genomics
Estradiol inhibits atp-induced intracellular calcium concentration increase in dorsal root ganglia neurons
Neuroscience
Electrophysiological and neurochemical characterization of neurons of the medial preoptic area in Japanese quail (Coturnix japonica)
Brain Res.
Female rats are more susceptible to the development of neuropathetic pain using the partial sciatic nerve ligation (PSNL) model
Neurosci. Lett.
Intact female rats are more susceptible to the development of tactile allodynia than ovariectomized female rats following partial sciatic nerve ligation (PSNL)
Neurosci. Lett.
Sex differences in pain and analgesia: the role of gonadal hormones
Eur. J. Pain
17-b-Estradiol and progesterone modulate an intrinsic opioid analgesic system
Brain Res.
Involvement of spinal cord d opiate receptors in the antinociception of gestation and its hormal simulation
Brain Res.
Gestational and ovarian sex steroid antinociception: synergy between spinal k and d opioid systems
Brain Res.
Up-regulation of opioid gene expression in spinal cord evoked by experimental nerve injuries and inflammation
Brain Res.
Gender differences in pain ratings and pupil reactions to painful pressure stimuli
Pain
Peripheral estradiol induces temporomandibular joint antinociception in rats by activating the nitric oxide/cyclic guanosine monophosphate signaling pathway
Neuroscience
Cloning of a novel member of the G protein-coupled receptor family related to peptide receptors
Biochem. Biophys. Res. Commun.
Sex differences in temporal summation but not sensory-discriminative processing of thermal pain
Pain
The influence of sex and ovarian hormones on temporomandibular joint nociception in rats
J. Pain
Critical re-examination of the distribution of aromatase-immunoreactive cells in the quail forebrain using antibodies raised against human placental aromatase and against the recombinant quail, mouse or human enzyme
J. Chem. Neuroanat.
The role of sex hormones on formalin-induced nociceptive responses
Brain Res.
The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain
Pain
Action of naloxone on gender-dependent analgesic and antianalgesic effects of nalbuphine in humans
J. Pain
Changes in visceral pain reactivity as a function of estrous cycle in female rats with artificial ureteral calculosis
Brain Res.
Pain threshold variations in somatic wall tissues as a function of menstrual cycle, segmental site and tissue depth in non-dysmenorrheic women, dysmenorrheic women and men
Pain
Cloning of a complete cDNA encoding human aromatase: immunochemical identification and sequence analysis
Biochem. Biophys. Res. Commun.
The visceromotor response to colorectal distention fluctuates with the estrous cycle in rats
Neuroscience
Modulation of hypothalamic mu-opioid receptor density by estrogen: a quantitative autoradiographic study of the female C57BL/6J mouse
Brain Res. Bull.
Dynorphin increases in the dorsal spinal cord in rats with a painful peripheral neuropathy
Peptides
Estrous and sex variations in vocalization thresholds to hindpaw and tail pressure stimulation in the rat
Brain Res.
Differential sensitivity of preoptic-septal neurons to microelectrophoresed estrogen during the estrous cycle
Brain Res.
Reversal of sex differences in morphine analgesia elicited from the ventrolateral periaqueductal gray in rats by neonatal hormone manipulations
Brain Res.
Androgens regulate aromatase cytochrome P450 messenger ribonucleic acid in rat brain
Endocrinology
Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain
Endocrinology
Estrogen modulation of mu-opioid receptor-stimulated [35S]-GTP-gamma-S binding in female rat brain visualized by in vitro autoradiography
Neuroendocrinology
Distribution of uridine diphosphate-glucuronosyltransferase (UGT) expression and activity in cynomolgus monkey tissues: evidence for differential expression of steroid-conjugating UGT enzymes in steroid target tissues
Endocrinology
Role of gonadal hormones in formalin-induced pain responses of male rats: modulation by estradiol and naloxone administration
Neuroscience
Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
Eur. J. Neurosci.
Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription
Proc. Natl. Acad. Sci. USA
Oestradiol increases phosphorylation of a dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32) in female rat brain
J. Neuroendocrinol.
Rapid and reversible inhibition of brain aromatase activity
J. Neuroendocrinol.
Calcium-dependent phosphorylation processes control brain aromatase in quail
Eur. J. Neurosci.
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