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date: 11 December 2019

Role of Sex Hormones on Pain

Summary and Keywords

The modulatory influence of sex hormones on acute pain, chronic pain disorders, and pain management has been reported for over seven decades. The effect of hormones on pain is clearly evidenced by the multitude of chronic pain disorders that are more common in women, such as headache and migraine, temporomandibular joint disorder, irritable bowel syndrome, chronic pelvic pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis. Several of these pain disorders also fluctuate in pain intensity over the menstrual cycle, including headache and migraine and temporomandibular joint disorder. The sex steroid hormones (estrogen, progesterone, and testosterone) as well as some peptide hormones (prolactin, oxytocin, and vasopressin) have been linked to pain by both clinical and preclinical research. Progesterone and testosterone are widely accepted as having protective effects against pain, while the literature on estrogen reports both exacerbation and attenuation of pain. Prolactin is reported to trigger pain, while oxytocin and vasopressin have analgesic properties in both sexes. Only in the last two decades have neuroscientists begun to unravel the complex anatomical and molecular mechanisms underlying the direct effects of sex hormones and mechanisms have been reported in both the central and peripheral nervous systems. Mechanisms include directly or indirectly targeting receptors and ion channels on sensory neurons, activating pain excitatory or pain inhibitory centers in the brain, and reducing inflammatory mediators. Despite recent progress, there remains significant controversy and challenges in the field and the seemingly pleiotropic role estrogen plays on pain remains ambiguous. Current knowledge of the effects of sex hormones on pain has led to the burgeoning of gender-based medicine, and gaining further insight will lead to much needed improvement in pain management in women.

Keywords: pain, sex differences, sex hormones, estradiol, progesterone, testosterone, oxytocin, prolactin

Introduction

Pain, as defined by the International Association for the Study of Pain, is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Pain processing, or nociception, is first initiated by mechanical, chemical, or thermal activation of the sensory nerve endings of the peripheral somatosensory nervous system, termed nociceptors (Basbaum, Bautista, Scherrer, & Julius, 2009; Henry & Hargreaves, 2007; Levine, Fields, & Basbaum, 1993). Nociceptors terminate as free (unmyelinated) nerve endings in tissues where they specialize in detecting tissue damage or the threat of damage. Upon leaving the tissues a subset of these primary afferents, called Aδ‎ fibers, become myelinated for increased conduction speeds typically associated with sharp, acute pain. Myelinated Aβ‎ fibers are mechanoreceptors, and a subset are considered nociceptive and are being investigated for playing a role in the transition from acute to chronic pain. Some fibers remain unmyelinated, called C fibers, which are often associated with dull, throbbing pain.

Role of Sex Hormones on Pain

Figure 1. Illustration depicting a major ascending neural pathway carrying pain signals into the brain. Nociceptors (red) signal noxious stimuli (danger signals) to the sensory neuronal cell bodies in either the dorsal root ganglia (from limbs, torso, and viscera; example of hand is illustrated [a]) or the trigeminal ganglia (from sensory structures of the head and neck; example of tooth is illustrated [b]). The sensory neurons excite neurons in the dorsal horn of the spinal cord (blue), which then ascend through the medulla and midbrain to the thalamus (c). The thalamus serves as a sensory relay (maroon) to cortical areas (such as the somatosensory cortex as illustrated) for processing to create the perception of pain in the brain.

Created with BioRender.

These primary afferents then propagate electrical signals toward their cell bodies in the dorsal root ganglia (Figure 1a) or the trigeminal ganglia (Figure 1b) topographically located alongside the spinal cord and brain stem, respectively. The central processes of the dorsal root sensory neurons terminate in the spinal dorsal horn, delivering pain signals from the body to the spinal cord, while the trigeminal sensory neurons terminate in the medullary dorsal horn delivering pain signals from the cranial and orofacial regions to the brainstem.

Information regarding pain is relayed supraspinally to the thalamus (Figure 1c), and then to various forebrain and cortical structures for high-level processing and signal integration (Woolf, 1991). Here the experience of pain can be altered by biopsychosocial influences resulting in an individualized, unique perception of pain (Fillingim, 2017; Gatchel, Peng, Peters, Fuchs, & Turk, 2007). Furthermore, descending pain modulatory pathways from the brain to the spinal cord may then facilitate and/or inhibit the nociceptive input from the primary afferents (Heinricher, Tavares, Leith, & Lumb, 2009). While pain is a submodality of somatosensation that is necessary for survival, pain can also occur or persist in the absence of actual or threatened tissue damage. This could be due to increased responsiveness of nociceptors to stimulation following peripheral sensitization (Dray, 1995), neural wind-up leading to the development of central sensitization (Woolf, 2011; Woolf & Salter, 2000), or dysfunction of endogenous pain control systems in the central nervous system; chronic pain can be linked to psychological triggers such as stress (Feinberg et al., 2017; McLean et al., 2011; Nyland, McLean, & Averitt, 2015; Slade et al., 2007; Wei et al., 2015). Nerve injury or damage specifically leads to the development of neuropathic pain, characterized by structural and functional changes in the peripheral nerves that includes slowing of nerve conduction, degeneration of axons, loss of myelinated fibers, and demyelination of axons (Leonelli et al., 2007; Yagihashi, Mizukami, & Sugimoto, 2011).

In preclinical and clinical models of pain, increased sensitivity to noxious stimuli is termed hyperalgesia, while increased sensitivity to non-noxious stimuli is termed allodynia; changes in spontaneous pain behavior is termed nocifensive behavior (Deuis, Dvorakova, & Vetter, 2017; Sandkuhler, 2009). Importantly, the vast majority of seminal research on the neurobiology of pain has been conducted in male subjects (Mogil, 2012). In 2007, the Sex, Gender and Pain special interest group of the International Association for the Study of Pain issued a consensus paper highlighting the need for inclusion of both males and females in pain research with recommendations on how to incorporate females into study design (Greenspan et al., 2007). As females become more represented in pain research, more recent studies are shedding new light regarding the mechanisms underlying sex differences in pain and analgesia. Coinciding with the recent regulations set forth by the National Institutes of Health to include biological sex as an independent variable, there has been an upsurge of reports on sex differences in mechanisms at each level of pain processing from the primary afferents to the brain. The most remarkable finding of this collective research is that sex hormones, as well as some peptide hormones, contribute to the differential processing and experience of pain in men and women.

Evidence of Sex Differences in Pain

Sex Differences in Clinical Pain Reports

Clinical studies on pain and analgesia are increasingly including females, and the number of studies examining sex differences in pain have increased dramatically since 1980 (Fillingim, King, Ribeiro-Dasilva, Rahim-Williams, & Riley, 2009). While it is clear that females suffer from the majority of chronic pain syndromes, studies assessing pain levels across sexes for similar ailments are more challenging to interpret (Cepeda & Carr, 2003; Sarton et al., 2000). A survey of studies examining sex differences in postoperative and/or procedural pain reported either no sex difference, greater sensitivity in females (Chia et al., 2002; De Cosmo et al., 2008; Fillingim et al., 2009; Rosseland, Solheim, & Stubhaug, 2008; Rosseland & Stubhaug, 2004), or greater sensitivity in males (Chia et al., 2002). Rarely is it reported that males display greater sensitivity. Further, many clinical studies on pain examine experimentally induced pain using noxious pressure or electrical, ischemic, and thermal stimuli, and these studies consistently report that females display lower pain thresholds and decreased tolerance to noxious stimuli in comparison to men (Berkley, 1997; Mogil & Bailey, 2010). While sex differences are not always detected or significant, the vast majority of studies indicate that women have a higher pain sensitivity than men (Mogil, 2012). In support, recent date from the Orofacial Pain: Prospective Evaluation and Risk Assessment Study reported that women were significantly more sensitive to 29 of 34 various measures of pressure, mechanical, and thermal pain (Ostrom et al., 2017).

Several “nonbiological” factors may also contribute to the finding that males and females differ in their response to pain. For example, women are more likely than men to report pain (Riley, Robinson, Wise, Myers, & Fillingim, 1998; Unruh, 1996); similarly, men who self-categorize as highly masculine tolerated more experimentally induced pain than women who self-categorized as highly feminine (Pool, Schwegler, Theodore, & Fuchs, 2007). However, fundamental sex differences have been reported in the anatomy and physiology of the human nervous system. For instance, brain imaging studies in humans report that female patients in chronic pain display more prominent sensorimotor structural and functional alterations in the brain than male chronic pain patients (Gupta et al., 2017); similarly, the endogenous opioid circuit that inhibits pain is activated to a greater degree in males compared to females (Zubieta et al., 2002). Together, these studies indicate that pain alters functional activity of sensory components of the brain in women, while concurrently engaging endogenous inhibitory systems more efficiently in men.

Gonadal hormones are also likely to contribute to sex differences in pain intensity, pain prevalence, and pain processing in the nervous system. For example, pain associated with both fibromyalgia (Korszun et al., 2000) and rheumatoid arthritis (Cairns & Gazerani, 2009) fluctuates across the menstrual cycle, and the incidence of temporomandibular joint disorder increases in postmenopausal women undergoing estrogen replacement therapy (Dao & LeResche, 2000). Further, a meta-analysis suggests that sex differences in pain emerge in children over the age of 12 when hormone cyclicity has begun (Boerner, Birnie, Caes, Schinkel, & Chambers, 2014). Hormone cyclicity has also been linked to changes at human nociceptors. Using a recently developed in vitro superfusion method to measure proinflammatory peptide release from human dental pulp from extracted teeth (Fehrenbacher, Sun, Locke, Henry, & Hargreaves, 2009). Loyd, Sun, Locke, Salas, and Hargreaves (2012) reported sex differences in inflammation-induced proinflammatory peptide release that was dependent on the phase of the menstrual cycle. Specifically, inflammatory mediator–evoked proinflammatory peptide release was highest in amenstrual females and females in the last week of menses (Loyd et al., 2012). Overall, the most apparent and dramatic sexual dimorphism has been detected in pain mechanisms and pain chronicity, while sex dependency in responses to evoked pain appear to be minor and could relate to nonbiological factors.

Support From Preclinical Models of Pain

Identification of mechanisms underlying sex differences in pain in humans is limited by reliance on self-reported pain that is likely influenced by psychosocial influences and individual perceptions. To avoid this confounding subjectivity, scientists rely on rodent models of pain. Similar to clinical studies, preclinical studies on sex differences in pain report either no sex difference or higher sensitivity in females, including neuropathic pain (LaCroix-Fralish, Tawfik, & DeLeo, 2005; Nicotra, Tuke, Grace, Rolan, & Hutchinson, 2014; Rahn, Iannitti, Donahue, & Taylor, 2014; Vacca et al., 2014), inflammatory pain (Aloisi, Albonetti, & Carli, 1994; Bradshaw, Miller, Ling, Malsnee, & Ruda, 2000; Cook & Nickerson, 2005; Green, Dahlqvist, Isenberg, Miao, & Levine, 2001; Green et al., 1999), formalin-evoked pain (Fischer, Clemente, & Tambeli, 2007; Fischer et al., 2008; Gaumond, Arsenault, & Marchand, 2002), muscle pain (Gregory, Gibson-Corley, Frey-Law, & Sluka, 2013), complex regional pain syndrome (Tajerian et al., 2015), and orofacial varicella zoster–associated pain (Stinson et al., 2017).

Sex differences in pain may be due to differences in how the primary afferents respond to noxious stimuli. Electrophysiological studies comparing male and female nociceptors report that females rats have lower cutaneous mechanical nociceptive thresholds (Hendrich et al., 2012), and female mice have more mechanically sensitive muscle afferents responsive to mechanical and thermal stimuli than muscle afferents from male mice (Ross, Queme, Lamb, Green, & Jankowski, 2018). Further, Scheff and Gold reported that while inflammatory mediators sensitized dural afferents to a similar degree, twice as many dural afferents were sensitized in afferents from female compared to male rats (Flake, Bonebreak, & Gold, 2005). It has also been reported that proinflammatory peptide release from the primary afferents is greater in female rats during persistent inflammation (Nazarian, Tenayuca, Almasarweh, Armendariz, & Are, 2014). Together these data indicate that sex differences in the peripheral to central relay of nociceptive information likely contributes to the greater chronicity of pain in women.

Effects of Sex Steroid Hormones on Pain

Despite the decades of research reporting that males and females report different pain thresholds and intensity that fluctuates with hormonal status, the current research literature looking at underlying anatomical and molecular mechanisms remains limited in the number of published articles that examine sex or gender as an independent variable. Of this literature, all three major sex steroid hormones—estrogen, progesterone, and testosterone—have been reliably linked to pain mechanisms.

Estrogen

Recent reviews of the research literature linking pain with the menstrual cycle report conflicting findings. With experimentally induced pain, women report higher pain threshold and tolerance during the follicular phase of the menstrual cycle (when estrogen is low) (Riley et al., 1998), and that increased reactivity to pain occurs perimenstrual and during the late follicular to early luteal phase (when estrogen is rapidly fluctuating) (Martin, 2009). However, women with chronic pain report less pain during phases of the menstrual cycle associated with high estrogen (Hellstrom & Anderberg, 2003). Similar findings have been reported in rodents: pain behaviors vary across the estrous cycle (homologous in function to the human menstrual cycle but with four distinct phases: diestrus 1, diestrus 2, proestrus, estrus). In rats, estrogen levels are low during diestrus (~15–20 pg/mL), then peak and rapidly decline during proestrus and estrus (~40–60 pg/mL) (Becker et al., 2005; Fillingim & Ness, 2000; Mannino, South, Inturrisi, & Quinones-Jenab, 2005). Pain behaviors are consistently reported as highest during proestrus and estrus (Fillingim & Ness, 2000; Flake, Hermanstyne, & Gold, 2006; Gintzler, 1980; Gintzler & Bohan, 1990; Ji, Murphy, & Traub, 2003, 2007; Ji, Tang, & Traub, 2005; Kaur et al., 2018; Moloney et al., 2016; Stinson et al., 2017; Stoffel, Ulibarri, & Craft, 2003), although the opposite (Fischer et al., 2008; Kramer & Bellinger, 2009) or no effect (Vincler, Maixner, Vierck, & Light, 2001) has also been reported. Ultimately, this literature indicates that estrogen, either at high levels or when rapidly falling, is somehow altering pain processing in females (see Table 1).

There is evidence of both organizational (activity during development) and activational (acute activity during adulthood) effects of estrogen on pain in rats. Adult female rats display greater thermal and mechanical sensitivity than males and ovariectomized females (Gaumond et al., 2002; LaCroix-Fralish et al., 2005), which was reversed in pubertal and adult animals ovariectomized prior to injury (LaCroix-Fralish et al., 2005). In gonadectomized male rats, estrogen treatment increases nocifensive behaviors at the inflamed hindpaw (Aloisi & Ceccarelli, 2000); however, opposing findings have been reported in ovariectomized female rats receiving estrogen treatment. Some studies report reduced nocifensive behaviors (Fischer et al., 2008; Gaumond, Arsenault, & Marchand, 2005; Kuba et al., 2006) and higher pain thresholds (Stoffel et al., 2003), while others report that estrogen treatment triggers higher nociceptive responses (Aloisi & Ceccarelli, 2000; Evrard & Balthazart, 2004a). These opposing findings may be due to differential activity of estrogen at its receptors, ERα‎ and ERβ‎. ERα‎ agonists inhibit and ERβ‎ excite nociceptive neuronal activity in the spinomedullary horn, the brainstem site for orofacial and craniofacial afferents (Tashiro, Okamoto, & Bereiter, 2012).

There is also evidence that estradiol is altering pain thresholds by acting directly at the sensory afferents. Both ERα‎ and ERβ‎ receptors are located on sensory neurons. Sensory neurons can be classified into peptidergic (PEP1, PEP2), non-peptidergic (NP1, NP2, NP3), neurofilament-containing (NF1, NF2, NF3, NF4, NF5), and tyrosine hydroxylase-containing (TH) nociceptors, and ERα‎ and ERβ‎ receptor genes are found in all types (Usoskin et al., 2015). Estradiol can upregulate the expression of various ion channels essential to pain signaling, including the voltage-gated sodium 1.7 (Nav1.7) ion channel (Bi et al., 2017) and the transient receptor potential vanilloid 1 (TRPV1) ion channel (Yamagata et al., 2016). TRPV1 is activated by a variety of noxious stimuli including heat and the pungent ingredient in hot chili peppers, capsaicin (Caterina et al., 1997). Interestingly, it has been reported in rodent nociceptors that estradiol can either potentiate (Chen, Chang, & Wu, 2004) or inhibit (Xu, Cheng, Keast, & Osborne, 2008) capsaicin-mediated currents. In vivo, female rodents exhibit greater capsaicin-evoked nocifensive responses during proestrus (Lu, Chen, Wang, & Wu, 2009), when estrogen levels peak. Further, inflammatory mediators, such as the neurotransmitter serotonin (5HT) and bradykinin, are known to sensitize TRPV1 to lower pain thresholds. In support, 5HT-evoked pain behaviors are significantly greater and longer lasting in female rats in proestrus and estrus (Kaur et al., 2018).

Activation of peripheral nociceptors leads to calcium influx in the sensory neuron and the synaptic release of proinflammatory peptides, primarily calcitonin gene-related peptide (CGRP) and substance P, at the dorsal horn of the spinal cord. Estradiol can regulate the release of CGRP (Pota et al., 2017) and substance P (Nazarian et al., 2014). In a rat model of visceral pain, estrogen enhanced pain behaviors and signaling (Ji et al., 2003; Ji, Tang, & Traub, 2008; Murphy, Suckow, Johns, & Traub, 2009) and upregulated the spinal expression of the NR1 subunit of excitatory N-methyl-D-aspartate (NMDA) glutamate receptors (Tang, Ji, & Traub, 2008), which are important for modulating pain processing and synaptic plasticity underlying central sensitization (Bleakman, Alt, & Nisenbaum, 2006; Vyklicky et al., 2014). However, it has also been reported that estrogen can reduce intracellular calcium signals evoked by stimulation of sensory neurons with a noxious agent (Chaban, Mayer, Ennes, & Micevych, 2003). Thus, estrogen appears to be able to directly modulate both peripheral and central sensitization to play a prominent role in sex differences in pain. Further work is needed to clarify the relationship between, and mechanisms underlying, the pronociceptive versus antinociceptive effects of estrogen.

Progesterone

Progesterone is the other major female sex steroid hormone that plays a role in pain modulation. Like estrogen, the main source of progesterone in women are the ovaries, except during pregnancy when the placenta becomes the main source (Schumacher et al., 2001; Tuckey, 2005). Progesterone can also be synthesized and released by the adrenal glands (Schumacher et al., 2004), neurons, and glia (Jung-Testas et al., 1999; Schumacher et al., 2001) and is reduced to the metabolites 5α‎-pregnane-3,20-dione (5α‎-dihydroprogesterone; DHP) and 5α‎-pregnan-3α‎-ol-20-one (3α‎5α‎-tetrahydroprogesterone or allopregnanolone), both of which can also have physiological effects on the nervous system. Women who use hormonal contraceptives that involve the continuous release of progestin, a clinically used form of progesterone, experience higher pain thresholds (Maximo et al., 2015). In women with fibromyalgia, pain is reported as less severe when blood levels of progesterone are high (Schertzinger, Wesson-Sides, Parkitny, & Younger, 2018), and women with temporomandibular joint disorder experience attenuation in pain symptoms during pregnancy when progesterone levels are high (LeResche et al., 2005). Furthermore, women who received an injection of a progesterone derivative had longer-lasting pain relief compared to those that received corticosteroid injection (Ginanneschi et al., 2012).

In support, the preclinical literature has consistently reported a neuroprotective, anti-inflammatory, and antinociceptive role of progesterone and its metabolites (Bourque et al., 2016; Garay et al., 2012; Garcia-Ovejero et al., 2014; Hong, Liu, Zhang, Wu, & Hou, 2018; Hong et al., 2016; Irwin, Solinsky, & Brinton, 2014; Ji et al., 2005; Kasturi & Stein, 2009) (see Table 2). Progesterone treatment reduces the inflammatory regulators interleukin 1 beta (IL-1β‎), tumor necrosis factor alpha (TNF-α‎), transforming growth factor beta 1 (TGF-β‎1), nuclear factor kappa B p65 (NFκ‎B p65), and glial fibrillary acidic protein (GFAP) (Giatti et al., 2012; Pan, Liu, Yang, & Cao, 2007), and treatment with progesterone, DHP, or allopregnanolone reduces pain behaviors in rodents (Afrazi & Esmaeili-Mahani, 2014; Kuba et al., 2006; Leonelli et al., 2007; Ren, Wei, Dubner, Murphy, & Hoffman, 2000; Svensson, Persson, Fitzsimmons, & Yaksh, 2013). Progesterone treatment can also reduce chronic pain and inflammation (Xue et al., 2017), and allopregnanolone can reduce glial activation associated with neuropathic pain (Huang et al., 2016).

Progesterone or allopregnanolone treatment can also reduce mechanical and cold allodynia following spinal cord injury (Coronel, Labombarda, De Nicola, & Gonzalez, 2014; Coronel, Labombarda, Roig, et al., 2011; Coronel, Labombarda, Villar, De Nicola, & Gonzalez, 2011; Coronel, Raggio, et al., 2016; Coronel, Sanchez Granel, et al., 2016; Huang et al., 2016; Meyer, Patte-Mensah, Taleb, & Mensah-Nyagan, 2011; Meyer, Venard, Schaeffer, Patte-Mensah, & Mensah-Nyagan, 2008). Treatment with progesterone or DHP also reverses the thermal hyperalgesia induced by spinal cord injury (Kim et al., 2012; Roglio et al., 2008). Similarly, DHP or allopregnanolone treatment attenuates mechanical allodynia and hyperalgesia induced by neuropathy triggered by chemotherapy-induced nerve damage (Meyer, Patte-Mensah, Taleb, & Mensah-Nyagan, 2010; Meyer et al., 2011).

In animal models of neuropathy, chronic treatment with progesterone, DHP, or allopregnanolone increases nerve conduction velocity and mRNA levels of myelin proteins (Leonelli et al., 2007). Two major myelin proteins are involved in myelin formation or demyelination in the peripheral nervous system, protein zero (P0) and peripheral myelin protein 22 (PMP22) (Quarles, 2002). An increase in pain occurs when these proteins are either overexpressed or downregulated leading to demyelination. Charcot-Marie-Tooth disease is an inherited PMP22-related neuropathy where overexpression of PMP22 results in demyelination (Nishimoto et al., 2016; van Paassen et al., 2014), and progesterone treatment appears to improve this neuropathy (Kim et al., 2012; Roglio et al., 2009; Sereda, Meyer zu Horste, Suter, Uzma, & Nave, 2003). Similarly, spinal cord injury–induced downregulation of P0 and PMP22 is reversed with progesterone or DHP treatment (Roglio et al., 2008).

Progesterone has also been shown to modulate various proteins involved in the development and maintenance of pain. NMDA receptors are upregulated in injured nerves and play a vital role in the development and maintenance of neuropathic pain (Coronel, Labombarda, Villar, et al., 2011; Kim et al., 2019; Labombarda, Coronel, Villar, Nicola, & Gonzalez, 2008; Ultenius, Linderoth, Meyerson, & Wallin, 2006). Interestingly, administration of progesterone to rats with an injury to the sciatic nerve prevents the upregulation of spinal NMDA receptor subunits (Coronel, Labombarda, Roig, et al., 2011; Coronel, Labombarda, Villar, et al., 2011), which may reduce central sensitization and pain. Progesterone can also act as an antagonist at the sigma 1 receptor (Sig-1R) to reduce pain (Romero, Merlos, & Vela, 2016). It is unclear how pain inhibition is occurring, but it was recently reported that progesterone antagonism of Sig-1R resulted in downregulation of TRPV1 expression and capsaicin-evoked currents in sensory neurons (Ortiz-Renteria et al., 2018). Overall, there is strong evidence that progesterone is protective against nerve injury, inflammation, and pain.

Testosterone

Testosterone, the primary male sex steroid hormone, has also been solidly linked to antinociceptive effects. In women with fibromyalgia, testosterone levels are significantly lower than controls (Dessein et al., 1999), and pain is reported as less severe when blood levels of testosterone are highest (Schertzinger et al., 2018). Testosterone has also been evaluated as a potential therapeutic for pain. Men with chronic angina that received testosterone by transdermal patch for 12 weeks experienced significant improvements in pain perception (English, Steeds, Jones, Diver, & Channer, 2000), and testosterone replacement therapy in men with chronic pain improves the quality and intensity of pain (Aloisi et al., 2011).

Preclinical research supports the antinociceptive effects of testosterone (see Table 1). Gonadectomy in male rats increases formalin-evoked nocifensive behaviors in the rat hindpaw, which is reversed by testosterone replacement (Gaumond et al., 2002). Testosterone treatment in gonadectomized male or ovariectomized female rats reduces heat pain threshold (Stoffel et al., 2003), mechanical allodynia, and thermal hyperalgesia (Gaumond et al., 2005). Testosterone also reduces thermal hyperalgesia in male sparrows (Hau, Dominguez, & Evrard, 2004). In addition, supraphysiological levels of testosterone are reported to reduce pain behaviors at the rat temporomandibular joint (Fischer et al., 2007). While it is not yet clear how testosterone is providing antinociceptive effects, testosterone may be reducing pain via regulating the expression and activity of ion channels and receptors involved in endogenous pain inhibition, such as TRPV1 ion channels (Bai, Zhang, & Zhou, 2018), cannabinoid receptors (Lee, Asgar, Zhang, Chung, & Ro, 2013), alpha(2)-adrenoceptors (Nag & Mokha, 2009), and mu opioid receptors (MOR; Claiborne, Nag, & Mokha, 2006; Lee et al., 2016).

Table 1. Evidence of the Effects of Sex Steroid Hormones on Pain in Rodents

Steroid Hormones

Manipulation

Report

Citation

Estradiol

In vitro exposure to rat sensory neuron cultures

In vivo estradiol treatment in ovariectomized rats

In vivo estradiol treatment in gonadectomized male rats

Potentiated capsaicin-mediated currents

Dose-dependent release of CGRP

Increased release of substance P

Upregulated Nav1.7 expression

Estradiol reduced nociceptive neural activity in sensory neurons

Increased sensitivity to noxious visceral stimuli

Increased visceral pain-induced NMDA receptor activity in the lumbar spinal cord

Reduced nocifensive behavior in the rat hindpaw

Dose-dependent upregulation of TRPV1 mRNA

Reduced nocifensive behaviors at the temporomandibular joint

Raised threshold to noxious heat

ERα‎ agonist reduced and ERβ‎ excited nociceptive neural activity in the brainstem

Increased nocifensive behaviors at the inflamed hindpaw

Reduced formalin-evoked nocifensive behavior in the rat hindpaw

Chen et al., 2004

Pota et al., 2017

Nazarian et al., 2014

Bi et al., 2017

Chaban et al., 2003

Ji et al., 2003

Tang et al., 2008

Kuba et al., 2006, Gaumond et al., 2005

Yamagata et al., 2016

Fischer et al., 2008; Xue et al., 2017

Stoffel et al., 2003

Tashiro et al., 2012

Aloisi & Ceccarelli, 2000

Gaumond et al., 2005

Progesterone

In vitro exposure to mouse sensory neuron cultures

In vivo progesterone treatment in ovariectomized rats

In vivo progesterone treatment in male rats

Decreased TRPV1 protein levels

Attenuated inflammatory thermal hyperalgesia

Reduced inflammatory nocifensive behavior

Reduced nocifensive behaviors at the temporomandibular joint

Prevented allodynia after spinal cord injury

Attenuated trigeminal neuropathic pain

Raised threshold to noxious thermal heat

Prevented nerve injury-induced upregulation of NMDA receptors

Ortiz-Renteria, et al., 2018

Ren et al., 2000

Fischer et al., 2008

Kuba et al., 2006

Coronel et al., 2011, 2014

Kim et al., 2012

Leonelli et al., 2007

Coronel et al., 2011

Testosterone

In vivo testosterone treatment in male rats

In vivo testosterone treatment in female rats

Reduced formalin-evoked nocifensive behaviors in the rat hindpaw

Reduced neuropathic thermal hyperalgesia and mechanical allodynia

Reduced nocifensive behaviors in the inflamed temporomandibular joint

Reduced formalin-evoked nocifensive behaviors in the rat hindpaw

Reduced neuropathic thermal hyperalgesia and mechanical allodynia

Raised threshold to noxious heat

Gaumond et al., 2005

LaCroix-Fralish et al., 2005

Fischer, et al., 2007

Gaumond et al., 2005

LaCroix-Fralish et al., 2005

Stoffel et al., 2003

Effects of Peptide Hormones on Pain

Prolactin

Prolactin, a peptide hormone synthesized in the pituitary gland, brain, uterus, and mammary glands, has distinct biological functions ranging from reproduction to lactation to homeostasis (Freeman, Kanyicska, Lerant, & Nagy, 2000). Prolactin has also been implicated in pain and inflammation (see Table 2). For example, inflammation, incisions, and headache attacks in migraine patients all induce prolactin release (Bosco et al., 2008; Patil, Green, Henry, & Akopian, et al., 2013; Scotland et al., 2011). Blockade of peripheral prolactin receptor (PR) reduces inflammatory thermal hyperalgesia (Scotland et al., 2011), while in PR knock-out mice, postoperative thermal hyperalgesia is reduced in females and allodynia is reduced in males and females (Patil, Ruparel, Henry, & Akopian, 2013).

Prolactin reportedly increases nociceptive responses by acting on TRP ion channels, acid-sensing ion channels, or different prolactin receptor isoforms (Belugin et al., 2013; Diogenes et al., 2006; Liu et al., 2016; Patil, Green, et al., 2013; Patil, Ruparel, et al., 2013; Scotland et al., 2011). Prolactin treatment in female rats significantly potentiates capsaicin-induced nocifensive behaviors, but only in the presence of estradiol (Diogenes et al., 2006). Prolactin also appears to act in a sex-dependent manner such that prolactin sensitizes TRP channels in sensory neurons of female but not male rats (Patil, Ruparel, et al., 2013). The sex difference observed for prolactin in female versus male rats may be due to the level of estradiol in females, as estradiol appears to regulate prolactin expression (Diogenes et al., 2006; Dussor, Boyd, & Akopian, 2018). Overall, prolactin has nociceptive properties that are mediated differently in both sexes and inhibition of the prolactin system may provide therapeutic advantages when treating pain disorders.

Oxytocin

Synthesized in the hypothalamus, oxytocin is another peptide hormone that has central and peripheral actions on pain (see Table 2). In contrast to prolactin, oxytocin reduces pain due to capsaicin in male rodents (Nersesyan et al., 2017), inflammation in male and female rodents (Eliava et al., 2016; Engle, Ness, & Robbins, 2012; Gonzalez-Hernandez et al., 2017; Reeta et al., 2006), and nerve damage in male and female rodents (Han & Yu, 2009; Kubo et al., 2017; Petersson, Eklund, & Uvnas-Moberg, 2005; Russo et al., 2012; Schorscher-Petcu et al., 2010). Inflammation also upregulates oxytocin receptor expression in sensory neurons in male rodents (Tzabazis et al., 2016). Similar to progesterone, oxytocin levels increase during pregnancy and breastfeeding, which is thought to contribute to the reduced recurrence of migraine following pregnancy and postpartum in migraineurs (Hoshiyama et al., 2012). In support, oxytocin administration elicits analgesia in men and women with tension-type headache (Wang et al., 2013) and migraine (Tzabazis et al., 2017). Several mechanisms have been proposed to account for oxytocin-induced analgesia. Oxytocin inhibits neuronal firing of Aδ‎ and C fibers or lamina II interneurons in the male rodent spinal cord (Breton, Poisbeau, & Darbon, 2009; Breton et al., 2008; Gonzalez-Hernandez et al., 2017; Juif & Poisbeau, 2013; Paloyelis et al., 2016), reduces capsaicin-evoked CGRP release (Tzabazis et al., 2016), and inhibits acid-sensing ion channels (Qiu et al., 2014). Oxytocin-induced analgesia may also involve activation of κ‎- and δ‎-opioid receptors (Gu & Yu, 2007; Reeta et al., 2006), as site-specific administration of oxytocin into opioid-dense brain areas, including the periaqueductal grey, amygdala, and nucleus accumbens, inhibits pain in male rodents (Gu & Yu, 2007; Han & Yu, 2009; Yang et al., 2011). Together these studies support the possibility that the oxytocin system may be a beneficial target when treating pain in both men and women.

Vasopressin

Vasopressin is synthesized in the hypothalamus and released into the blood by the posterior pituitary to modulate blood pressure and water resorption by the kidneys. Vasopressin can also act in the brain to modulate social behavior and pair bonding (Johnson & Young, 2015; Lim, Murphy, & Young, 2004). Like oxytocin, vasopressin appears to play a protective role against pain in both sexes. Intranasal arginine vasopressin relieves headache (Yang et al., 2012) and orthopedic pain after surgery (Yang, Ma, Yang, Zhu, & Wang, 2019) in men and women. In men, pain sensitivity has been linked to mutations in the gene encoding vasopressin (Mogil et al., 2011), and intranasal vasopressin raises mechanical pain thresholds in men (Pohl et al., 1996), but not at levels low enough to not disrupt normal water retention (Kemppainen, Pertovaara, Huopaniemi, Hamalainen, & Gronblad, 1987). Preclinical studies support the analgesic effects of vasopressin, but only with actions in the brain (see Table 2). Intraventricular, but not intrathecal or intravenous, injection of vasopressin increases pain thresholds, and reducing vasopressin levels decreases pain thresholds in male rodents (Berntson & Berson, 1980; Bodnar, Nilaver, Wallace, Badillo-Martinez, & Zimmerman, 1984; Kordower & Bodnar, 1984; Yang, Song, Liu, & Lin, 2006). Site-specific injection of vasopressin into the periaqueductal gray or nucleus raphe magnus also raises pain thresholds in male rodents, an effect thought to be mediated by increasing endogenous opioid levels (Yang, Chen, et al., 2006; Yang et al., 2007). Interestingly, oxytocin is similar in structure to vasopression (Chini & Manning, 2007) and can evoke analgesia by binding the vasopressin-1a receptor (Garcia-Boll, Martinez-Lorenzana, Condes-Lara, & Gonzalez-Hernandez, 2018; Han et al., 2018; Kubo et al., 2017). In support, oxytocin administration in oxytocin receptor knock-out male and female mice still produces analgesia via the vasopressin 1a-receptor (Schorscher-Petcu et al., 2010). Overall, these lines of evidence indicate that both oxytocin and vasopressin, potentially via intranasal administration, may provide an alternative method of analgesia in both men and women.

Table 2. Evidence of the Effects of Peptide Hormones on Pain in Rodents

Peptide Hormones

Manipulation

Finding

Citation

Prolactin

In vitro exposure to rat sensory neuron cultures

In vivo prolactin treatment in female rats

In vivo prolactin receptor antagonist treatment

Female mice with prolactin receptor knock-out

Male mice with prolactin receptor knock-out

Enhanced capsaicin-evoked currents, calcium influx, and CGRP release

Potentiated capsaicin-induced nocifensive behaviors in the presence of estradiol

Dose-dependent reduction in inflammatory hyperalgesia

Reduced post-operative thermal hyperalgesia and mechanical allodynia

Loss of post-operative mechanical allodynia

Diogenes et al., 2006

Diogenes et al., 2006;

Belugin et al., 2013

Scotland et al., 2011

Patil, Green, et al., 2013

Patil, Ruparel, et al., 2013

Oxytocin

In vitro exposure to cell cultures

In vivo injection in male and female rodents

In vivo intranasal administration in male and female rodents

Evoked release of oxytocin from hypothalamic nuclei

Enhanced capsaicin-evoked currents and calcium influx

Dose-dependently reduces capsaicin evoked CGRP release

Inhibited acid-sensing ion channels and acidosis-evoked membrane excitability

Attenuated capsaicin-evoked nocifensive behaviors

Attenuated inflammatory nocifensive behaviors

Attenuated inflammatory thermal and mechanical hyperalgesia and Inhibited visceromotor reflexes associated with visceral pain behaviors

Higher threshold to noxious electrical stimulation

Reduced mechanical allodynia in a rat model of trigeminal neuralgia

Increased threshold to noxious heat

Injection into the amygdala attenuated thermal and mechanical hyperalgesia

Attenuated allodynia and nocifensive behaviors evoked by traumatic brain injury

Attenuated nocifensive behaviors in rodent models of inflammatory and neuropathic orofacial pain

Attenuated inflammatory thermal hyperalgesia and mechanical allodynia

Nersesyan et al., 2017

Tzabazis et al., 2016

Qiu et al., 2014

Nersesyan et al., 2017

Reeta et al., 2006; Gonzalez-Hernandez et al., 2017

Russo et al., 2012;

Schorscher-Petcu et al., 2010

Engle et al., 2012

Yang et al., 2007

Kubo et al., 2017

Petersson et al., 2005

Han & Yu, 2009

Meidahl et al., 2018

Tzabazis et al., 2017

Eliava et al., 2016

Vasopressin

In vivo injection in male and/or female rodent

Vasopressin receptor 1a gene knockout mice

Intracerebroventricular injection elevated nociceptive thresholds

Vasopressin antisera reduced nociceptive thresholds

Injection into the periaqueductal gray or nucleus raphe magnus raised pain thresholds

Increased enkephalin and endorphin release in the periaqueductal gray

Greater inflammatory nocifensive behaviors

Korodower & Bodnar, 1984; Bertson & Benson, 1980; Yang, Song, et al., 2006

Bodnar et al., 1984

Yang, Chen, et al., 2006; Yang, Song, et al., 2006

Yang et al., 2007

Mogil et al., 2011

Effects of Sex Steroid Hormones on Opioid Analgesia

In addition to sex differences in pain, sex differences in pain management with opioids, such as morphine, have also been reported. This is important to consider because opioids are the most common form of pain management for chronic pain states and women experience greater prevalence of many chronic pain states. Thus, it becomes important for women’s health to continue to uncover the mechanisms underlying both sexually dimorphic pain and opioid analgesia. When considering these studies, it is important to recognize that opioid receptor specificity, route and dose of drug administration, type of analgesiometric test employed, and species and strain of animal tested have been shown to influence the pharmacodynamics of opioid analgesia (Mogil, 2012). Sex differences in morphine analgesia are not likely due to dimorphisms in the pharmacokinetics of morphine in humans (Sarton et al., 2000) or rodents (Cicero, Nock, & Meyer, 1997) as no sex differences in morphine elimination rates or levels have been reported (Cicero, Nock, & Meyer, 1996; Cicero et al., 1997). There is strong evidence that there is an inherent sexual dimorphism in how opioids act at the nervous to alleviate pain.

Clinical Evidence of Sex Differences in Opioid Analgesia

Clinical research on sex differences in opioid analgesia remain controversial, with reports of greater analgesia reported in men and women or no sex difference (Cepeda & Carr, 2003; Fillingim et al., 2005; Gordon et al., 1995; Sarton et al., 2000). In one study, females reportedly required 30% more morphine to reach the same level of analgesia as males (Cepeda & Carr, 2003). In contrast, Sarton et al. reported greater morphine analgesia in females (Sarton et al., 2000), while other studies reported no sex difference (Fillingim et al., 2005; Gordon et al., 1995). On the other hand, retrospective studies have reported that men typically consume more morphine than women for postsurgical pain relief (Chia et al., 2002; Miaskowski, Gear, & Levine, 2000). However, since women experience greater negative side effects associated with morphine, including nausea, headache, and dysphoria, consumption is not a reliable indicator of analgesia (Fillingim et al., 2005). Of further interest, women transition to addiction quicker than men, which has been attributed to the effects of estrogen on the mesolimbic dopamine system (Bobzean, Dennis, & Perrotti, 2014; Bobzean, DeNobrega, & Perrotti, 2014). One complicating factor is that many of these studies were conducted in an experimental pain setting in which healthy volunteers subjectively rated pain before and after morphine administration. Future studies using assays that more closely mimic the conditions for which morphine is prescribed may help clarify the impact of sex on morphine analgesia.

Preclinical Evidence of Sex Differences in Opioid Analgesia

Sex differences in morphine potency were first reported in rodents in the late 1980s, and results from preclinical animal models examining the impact of sex on opioid analgesia are more consistent than clinical reports. Studies utilizing orofacial, somatosensory, or visceral pain assays typically report that morphine produces a significantly greater degree of analgesia in male rodents compared to females (Craft, 2003; Craft, Mogil, & Aloisi, 2004; Ji, Murphy, & Traub, 2006; Loyd, Wang, & Murphy, 2008; Wang, Traub, & Murphy, 2006). In both persistent inflammatory pain (Wang et al., 2006) and visceral pain (Ji et al., 2006) models, the median effective dose (ED50) for systemic morphine is twofold higher in females than in males.

Examining the brain anatomical pathways that contribute to pain and analgesia have provided evidence of an anatomical substrate for sex differences in analgesia. In 1969, a novel field of research emerged when it was first reported that electrical stimulation of a midbrain structure, the periaqueductal gray (PAG), produced profound analgesia in the male rat (Reynolds, 1969). This report launched an extensive effort to characterize the descending neural pathway responsible for analgesia that is known as the endogenous descending pain inhibitory circuit. This circuit consists of descending projections from the PAG to the rostroventromedial medulla (RVM), which projects bilaterally via the dorsolateral funiculus to the dorsal horn of the spinal cord (Figure 2). Electrical or chemical stimulation of this descending pathway produces potent analgesia that is blocked by central or systemic administration of opioid receptor antagonists (Basbaum & Fields, 1984). The PAG–RVM pathway is sexually dimorphic in both its anatomical organization and its functional activation by pain and morphine (Loyd, Morgan, & Murphy, 2007; Loyd, Morgan, & Murphy, 2008; Loyd & Murphy, 2006, 2009), suggesting a greater initiation of descending pain control in males.

Role of Sex Hormones on Pain

Figure 2. A schematic of the descending inhibitory pathway for pain modulation illustrating the projections from the caudal ventrolateral column of the midbrain periaqueductal gray to the rostral ventromedial medulla in the brainstem and the dorsal horn of the spinal cord at the level of incoming stimulation from sensory neurons of the dorsal root ganglia. Also indicated are local GABAergic interneurons (green) and PAG-RVM output neurons (black). Mu opioid receptors (blue) expressed on local GABAergic interneurons and PAG-RVM output neurons are also indicated.

Morphine primarily binds MOR, which are densely localized on projection neurons and GABAergic neurons in the PAG (Figure 2), and there is evidence of sex differences in PAG MOR expression (Loyd, Wang, & Murphy, 2008). Lesions of PAG MOR in males completely attenuates morphine analgesia, suggesting that sex differences in MOR expression are necessary and sufficient for the dimorphic effects of morphine (Krzanowska & Bodnar, 1999; Loyd, Wang, & Murphy, 2008). Sex differences in the initiation of MOR second messenger signaling cascades have also been reported (Burstein et al., 2013; Craft, Tseng, McNiel, Furness, & Rice, 2001; Mitrovic et al., 2003; Schwindinger, Borrell, Waldman, & Robishaw, 2009). Morphine produces analgesia via presynaptic inhibition of voltage-gated calcium channels and, in part, via postsynaptic inhibition of G protein-coupled inwardly rectifying potassium channels (GIRKs). Sex differences in signal transduction of pain and morphine by GIRK have been reported such that male mice lacking the GIRK2 channel subunit exhibit reduced pain thresholds and morphine analgesia levels similar to wild-type females (Mitrovic et al., 2003).

Effects of Estrogen and Testosterone on Opioid Analgesia

Sex differences in gonadal hormone concentrations appear to play a primary role in contributing to sex differences in analgesia (Stoffel et al., 2003). Circulating levels of estradiol across the rat estrous cycle influence morphine analgesia with greater potency reported during diestrus, when circulating estradiol is lowest (Craft et al., 2004; Vincler et al., 2001). Male rats feminized at birth demonstrate reduced morphine potency in adulthood, while masculinized female rats demonstrate greater morphine potency (Krzanowska & Bodnar, 1999).

The PAG contains the largest population of both estrogen (ERα‎) and androgen (AR) receptor containing neurons outside of the hypothalamus (Murphy & Hoffman, 1999, 2001) and the ventrolateral PAG neurons projecting to the RVM in the descending pain modulatory pathway specifically express both steroid hormone receptors (Loyd & Murphy, 2008). This PAG region also contains the highest density of MOR and suggests a direct mechanism whereby changes in endogenous gonadal steroid levels could modulate morphine analgesia. In support, microinjection of morphine directly into the PAG produces significantly lower analgesia during the estrus stage in female rats, while there was no significant difference in morphine potency between females in diestrus compared to males (Bernal, Morgan, & Craft, 2007; Loyd, Wang, & Murphy, 2008).

Estradiol has been shown to uncouple the MOR from G protein-gated inwardly rectifying potassium channels (Kelly, Qiu, & Ronnekleiv, 2003), resulting in an attenuation of morphine-induced hyperpolarization. Estradiol has also been shown to induce MOR internalization (Eckersell, Popper, & Micevych, 1998), thereby reducing available opioid binding sites on the cell membrane. Interestingly, ERα‎ is required for estradiol-induced MOR internalization (Micevych, Rissman, Gustafsson, & Sinchak, 2003), supporting the hypothesis that colocalization of MOR and ERα‎ in the PAG-RVM output neurons provides a unique mechanism through which estrogens may differentially affect morphine potency in male and female rats (Gintzler & Liu, 2012).

In addition to the PAG, numerous studies suggest that sex differences in the anatomical, physiological, and biochemical organization of the spinal cord also contribute to the dimorphic effects of opioids. The dorsal horn of the spinal cord is densely populated with estrogen receptors ERα‎ and ERβ‎ (Liu, von Gizycki, & Gintzler, 2007; Papka et al., 2001), and MOR and sex differences in analgesia can be elicited following intrathecal administration of opioids. For instance, endomorphin, the predominant endogenous opioid ligand in the spinal cord, is more effective at producing spinal antinociception in male rats (Liu & Gintzler, 2013), an effect that is hormone dependent. During diestrus, when circulating estrogens are low, spinal antinociception to endomorphin was minimal. In contrast, during proestrus, when circulating estrogens are high, spinal endomorphin antinociception was robust and comparable in magnitude to that noted in males. Intrathecal injection of morphine in females, but not males, requires concomitant activation of mu and kappa opioid receptors (Liu et al., 2007). Kappa opioid receptors can form heterodimers with MOR in the spinal cord, and the levels of heterodimers are approximately fourfold greater in the spinal cord of proestrus female versus male rats (Chakrabarti, Liu, & Gintzler, 2010), which contributes to the sexually dimorphic effects of intrathecal morphine. This sexual dimorphism is limited to postsynaptic heterodimers in the spinal cord as presynaptic mu and kappa opioid receptors are expressed in different neuronal groups in sensory neurons (Usoskin et al., 2015). Overall, it is important to recognize that sex differences in both endogenous and exogenous pain inhibition are contributing factors to sex hormone modulation of pain.

Conclusion

Current clinical and preclinical research provide strong evidence of various modulatory roles of sex steroid hormones and peptide hormones on cellular, molecular, and genetic mechanisms underlying pain and its inhibition. Overall, these studies indicate that testosterone, progesterone, oxytocin, and vasopressin each provide some level of protection against pain, while oxytocin is involved in initiating pain. The role of estrogen on pain is vastly more variable and complex and it is of particular importance for future research to unravel the central and peripheral mechanisms by which estrogen acts to modulate pain in both sexes. Ultimately, these studies highlight the need for deeper insight into the role of sex hormones on pain mechanisms to explain why there is a greater prevalence of pain conditions in women and to identify novel targets for pain management.

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