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. Author manuscript; available in PMC: 2019 Dec 6.
Published in final edited form as: Int Rev Psychiatry. 2018 Dec 6;30(5):107–116. doi: 10.1080/09540261.2018.1514295

Systematic Review of Sex-based Differences in Opioid-based Effects

Andrew S Huhn 1, Meredith S Berry 1, Kelly E Dunn 1
PMCID: PMC6551331  NIHMSID: NIHMS1514643  PMID: 30522374

Abstract

Background:

There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex-based differences in non-analgesic opioid-based effects are poorly understood. The goal of this review is to provide a current analysis of the preclinical literature on sex-based differences in response to endogenous and exogenous opioids, including the interplay between sex hormones and opioid receptor-mediated neuronal activity and associated behaviors.

Methods:

A systematic search was performed on the following terms within PubMed between March and April of 2018: “opioid estrogen” “opioid progesterone” “opioid estradiol” “opioid testosterone”.

Results:

Preclinical research on the non-analgesic, sex-based effects of opioids is disparate, both in terms of methodology and outcomes, which prohibits a cohesive summary of the results. Themes from the preclinical literature suggest that opioid receptor binding, coupling, and density vary as a function of hormone exposure. Findings also suggest that interactions between endogenous opioid and stress systems may differ between males and females as a function of ovarian hormones.

Conclusions:

Given the current opioid-related public health crisis, there is a pressing need to increase systematic preclinical and clinical research on sex-based differences in opioid-effects and opioid use disorder.

Keywords: Opioid, sex, androgen, estrogen, treatment

1. Introduction

While the scientific literature on sex-based differences in opioid analgesia is robust, sex-based differences in other opioid-based effects have not been clearly delineated. This is particularly important in the context of current societal concerns regarding increased rates of opioid misuse and corresponding increases in the number of people diagnosed with opioid use disorder (OUD). There is specific interest in identifying whether potential physiological traits may predispose individuals to the reinforcing effects of opioids and subsequent development of OUD. Empirical evidence suggests that males and females experience opioids differently and in a manner that may predict differential abuse liability, and that these differences may be mediated by sex hormones. Thus, the goal of this review is to synergize the existing preclinical literature on differences between males and females regarding the non-analgesic properties of opioids, especially as they relate to hormone-specific physiological and behavioral responses. Evidence of sex-based, physiological and behavioral differences in response to opioids comes almost entirely from preclinical literature, and there is a pressing need to better understand this topic in human studies.

1.1. Review of gonadal hormones

This section will focus on hormones produced by the gonads, namely the androgens testosterone and dihydrotestosterone, produced in the testes, and the progestins (e.g., progesterone) and estrogens, produced in the ovaries (comprised of estrogen and estradiol in human and rodents, respectively) (Becker, 2002). Since testosterone is a precursor to estrogen and is produced in small quantities by the ovaries, males and females can be exposed to both hormone classes. Hormones receptors up- or down-regulate in response to fluctuations in circulating hormones. Though luteinizing hormone regulates the gonadal production of testosterone and estrogens gonads, this review only focuses on the primary gonadal hormones.

Hormone levels change naturally in a cyclical manner; this varies between rodents and humans. The rodent reproductive cycle is referred to as estrous and is characterized by four phases that are completed over 4–5 days. These include proestrus, when estrogen increases and ovulation (release of an egg) occurs; estrus, when estrogen levels decrease; metestrus, when estrogen is lowest; and diestrus, when estrogen increases again. The female human reproductive cycle is known as a menstrual cycle and is characterized by three phases over 28 days. These include the follicular phase, characterized by low initial levels of estrogen and progesterone and slow increases in estrogen across the phase; the ovulatory phase, when estrogen peaks, an egg is released, and progesterone begins to rise; and the luteal phase, characterized by initial high levels of estrogen that decreases and a peak and then decrease in progesterone back to the follicular phase.

1.2. Evidence of gonadal hormone and opioid system interactions

A large body of literature suggests gonadal hormones modify opioid receptor binding and density in areas of the brain that modulate reproductive behaviors (e.g., hypothalamus); these effects could also change opioid receptor availability in a manner that impacts how opioids are subjectively experienced.

1.2.1. Hormone regulation of opioid receptor binding

In vitro analyses have reported the glucocorticoid/progesterone antagonist RU486 inhibits opioid binding to the mu opioid receptor (MOR) (Maggi et al., 1996), and that estrogen increases MOR coupling within the dorsal striatum (Acosta-Martinez & Etgen, 2002). Preclinical in vivo evaluations provide substantial evidence that gonadal hormones produce location-specific changes in opioid receptors. The density (but not affinity) of MORs in the hypothalamus varies as a function of estrous phase and time of day in female rats (Maggi et al., 1993). In addition, the presence or absence of estrogen and/or progesterone can directly influence MOR receptor density in the rostral forebrain (Joshi, Billiar, & Miller, 1993) and hypothalamus (Weiland & Wise, 1990) and decrease binding in specific hypothalamic regions (Brown, Pasi, & Etgen, 1996) in a cyclical manner (Mateo, Hijazi, & Hammer Jr, 1992). Estrogen exposure increases MOR mRNA levels within specific hypothalamic regions (Quiñones-Jenab, Jenab, Ogawa, Inturrisi, & Pfaff, 1997) and stimulates endogenous opioid release within limbic and hypothalamic systems(Eckersell, Popper, & Micevych, 1998; Tejwani, Vaswani, & Barbacci, 1985).

Recent evidence also suggests gonadal hormones may alter opioid gene expression. Specifically, mRNA expression of genes coding the MOR and kappa opioid receptors (ORPM1 and OPRK1, respectively) may be estrogen-dependent, though this finding did not extend to the gene that codes for the delta opioid receptor (OPRD1) (Cruz et al., 2015). Chronic morphine treatment also increases both ORPM1 and MOR protein expression in the striatum of female rats whose ovaries have been removed (Teodorov, Camarini, Bernardi, & Felicio, 2014). Notably, chronic morphine and methadone treatment do not influence central nervous system uptake of estradiol (Sheridan, 1978) or androgen-receptor binding (Sheridan & Buchanan, 1980), suggesting that hormonal effects on the opioid system are related to changes in opioid receptor density rather than changes in hormone-receptor binding.

1.2.2. Hormonal regulation of opioid-induced physiological changes

Gonadal hormones may also influence opioid pharmacokinetics, which may also produce systematic sex-based differences in opioid abuse liability. In vitro pretreatment of estradiol to rat livers reduces the clearance rate of the opioid meperidine and related metabolites by 45%, but not the barbiturate pentobarbital, suggesting this effect is opioid-specific (Knodell, Allen, & Kyner, 1982). Yet a within-subject study that administered the fast-acting opioid alfentanil to adult women on days their estrogen and progesterone levels peaked reported no differences in pharmacokinetic clearance rates during those two peak hormone days relative to a control day, suggesting that potential hormone-mediated changes in opioid clearance may not be associated with differences in liver enzyme P450 3A4 activity in humans (Kharasch et al., 1997).

Additional evidence suggests estrogen can influence physiological outcomes in a manner relevant for opioid tolerance and withdrawal. For instance, estrogen attenuates naloxone-precipitated increases in skin temperature in rats physically-dependent on morphine (Katovich & O’Meara, 1987). There is also evidence of sex-based differences in respiratory control. One study that compared double-blind morphine to placebo in healthy men and women reported significantly larger decreases in carbon dioxide and hypoxic sensitivity in women compared to men (Dahan, Sarton, Teppema, & Olievier, 1998). A second study reported differences in fentanyl-induced decreases in respiratory depression in pregnant versus non-pregnant women, which the authors attributed to increased progesterone levels during pregnancy (Cao et al., 2017). Finally, postmenopausal women receiving double-blinded estrogen replacement versus placebo for 3 months reported significantly greater increases in systolic blood pressure following acute stress within women receiving estrogen relative to those receiving placebo; this could be blocked by the opioid antagonist naltrexone (Allen, McCubbin, Loveless, & Helfer, 2014).

1.3. Summary

Given neuronal and physiological evidence that gonadal hormones interact with the opioid system in a way that could produce clinically-different outcomes across sexes, there is value in evaluating the degree to which gonadal hormones or participant sex may influence important aspects of OUD. This review systematically summarizes preclinical studies that directly compared and/or evaluated the effects of sex hormones on opioid-related outcomes. The overarching goal is to demonstrate preliminary evidence of consistent sex-based differences in response to opioids and identify areas for which future research is warranted.

2. Methods

2.1. General search strategy

This literature review is based upon automated and manual searches for peer-reviewed publications describing sex-based differences in opioid response, excluding papers focused on pain or analgesia outcomes. Systematic searches were conducted within the PubMed electronic database during March and April of 2018, consistent with the guidelines for systematic reviews outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher, Liberati, Tetzlaff, Altman, & Prisma Group, 2009) and using systematic search vocabulary as key words in the title and abstract. The following search terms were used: “opioid estrogen” “opioid progesterone” “opioid estradiol” “opioid testosterone”.

2.2. Inclusion/Exclusion criteria

For studies to qualify for inclusion, the published manuscripts were required to have: (1) included a study abstract, (2) been published in English, (3) been a primary peer reviewed article, (4) been published between the years of 1990 – 2018, (5) focused on outcome measures (e.g., neurological, hormonal, or behavioral) resulting from naturally occurring sex-differences in opioid or gonadal hormone systems, acute or chronic opioid administration, acute or chronic opioid peptide administration, or the effects of gonadal hormonal manipulation on aspects of the opioid system (6) been conducted in non-human primate, or rodent species, and (7) reported data that directly compared outcomes as a function of sex.

Manuscripts were excluded if: (1) the primary outcome measures were pain, analgesia, antinociception, outcomes exclusively focused on the preoptic area that did not serve the primary goals of this review, or reproductive behavior, (2) hormonal measurement and/or manipulation did not include the primary gonadal hormones estrogen/estradiol, progesterone, and/or testosterone (e.g., studies focusing exclusively on luteinizing hormone were excluded), or (3) only described results for one sex.

All three authors reviewed the titles and abstracts of studies to determine initial relevance. In cases where the title and abstract did not provide sufficient information to determine relevance, the authors reviewed the article and evaluated inclusion/exclusion criteria. To ensure accurate representation of the originally presented forms of opioid administration and use, as well as various outcome measures, the original terms and concepts employed by the primary study authors remain intact and were retained for the purpose of this review (Berry & Johnson, 2018; Heerde, Hemphill, & Scholes-Balog, 2018).

3. Results

3.1. Summary

The initial search yielded 1361 manuscripts. Fifteen published manuscripts that met all inclusion/exclusion criteria and were synthesized in the Results section.

3.2. Sex-based Differences in Preclinical Research

Converging physiological and neuronal evidence indicates that gonadal hormones and the opioid system interact in a way that produces sex-specific differences in opioid effects. Preclinical studies of this topic vary widely with regard to methodology, analyses, and outcome measures and include sex-based comparisons of opioid receptor expression; neuronal responses to the opioid antagonists naloxone and naltrexone, or the opioid agonist morphine; response to opioid neuropeptide treatment and gonadal hormone interactions; and behavioral responses to morphine. Many of the studies examined hormones by removing the gonads (known as castration) and/or administering exogenous hormones to developing or adult animals. Teste removal is formally known as orchidectomy and ovarian removal is formally known as ovariectomy.

3.2.1. Sex-based Differences in Opioid Receptor Expression

Several studies have evaluated sex-based differences in opioid receptor density in the central nervous system. The first compared MOR-binding characteristics across four groups of rats: normal male, normal female, males that were orchidectomized 2 days after birth, and females that received testosterone 2 days after birth (Limonta, Dondi, Maggi, & Piva, 1991). MOR-receptor density was significantly increased in normal females compared to the other groups of rats at day 26 and also increased between day 26 and 60 within the orchidectomized males. No changes in normal males or androgenized females were observed during the course of the study. The authors concluded that hypothalamic-MOR density was sexually dimorphic and may be linked to the presence or absence of androgens such as testosterone at the time of birth.

Females may differ in opioid receptor gene expression based on hormone fluctuations during the menstrual cycle. Research on this topic has demonstrated that there was co-localization of opioid receptor-like 1 receptor (ORL1) and estrogen receptor mRNA in neurons of the spinal trigeminal nucleus caudalis in rats such that both males and females expressed ORL1 receptor mRNA in the majority of estrogen receptor (α and/or β) mRNA-containing neurons (Flores, Shughrue, Petersen, & Mokha, 2003). Though the ORL1–receptor gene was abundantly expressed in males and females during the proestrus phase of the estrus cycle, it was significantly higher in the rostral trigeminal nucleus caudalis and the junction of the caudalis and interpolaris sub-nuclei when females were in the diestrus phase.

Three additional studies used immunoreactivity to examine sex-based differences in opioid receptor or peptide density as a function of sex. Quantitative immunoperoxidase light microscopy evaluation of delta opioid receptor expression in hippocampal sections of adult male and normal cycling female rats revealed that, relative to males, females exhibited reduced delta opioid receptor immunoreactivity in the granule cell layer of the dentate gyrus, suggesting lower receptor density (Williams, Torres-Reveron, Chapleau, & Milner, 2011). Females in proestrus (high estrogen) displayed the lowest level of delta opioid receptor immunoreactivity in the CA1 pyramidal cell layer of all groups. Immunoreactivity has also been used to analyze hippocampal sections of adult male and proestrus female rats, to assess whether corticotropin-releasing factor (CRF) receptors were colocalized with delta-opioid receptors in pyramidal cell dendrites (Williams, Akama, Knudsen, McEwen, & Milner, 2011). Results showed that females in proestrus and males expressed similar levels of CRF receptor immunoreactivity per dendrite, though proestrus females also expressed increased dual-labeled dendritic profiles and membrane density of CRF and delta-opioid receptor immunoreactivity relative to males. This suggests that interactions between the opioid and stress systems may differ between males and females as a function of ovarian hormones. Finally, a quantitative immunocytochemistry study reported that, relative to males, female brains demonstrated higher levels of dynorphin and enkephalin immunoreactivity in the CA3a in CA3b sections of the hippocampus, respectively (Van Kempen et al., 2013).

3.2.2. Sex-based Differences in Neuronal Response to Naloxone, Naltrexone, or Morphine

Several preclinical studies have examined whether sex underlies different responses to opioid antagonists and agonists. One study reported limited evidence of sex-based differences in basal transmission and long-term potentiation (LTP) outcomes within male and female rat hippocampal slices following administration of the fast-acting opioid antagonist naloxone (Harte-Hargrove, Varga-Wesson, Duffy, Milner, & Scharfman, 2015), but did note that naloxone enhanced mossy fiber transmission in females during proestrus but not males. A study on hyperinsulinemia (excess insulin relative to glucose) reported that pretreating concanavalin A-injected rats with the opioid antagonists naloxone or naltrexone blocked the hyperinsulinemia produced by lectin in males and females, suggesting that concanacalin A may increase the levels of circulating insulin in rats in a manner that is opioid-dependent and hormonally-regulated (Francisco-DoPrado, Zambelli, Melo-Lima, & Ribeiro-DaSilva, 1998).

Sex hormones may also influence opioid-based effects in the neural reward system. One study used microdialysis to measure glutamate levels and collect cerebrospinal fluid dialysates from the left nucleus accumbens core to demonstrate that normal males developed tolerance to chronic morphine administration more quickly than normal females, though differences abated when rats were castrated (Mousavi, Shafaghi, Kobarfard, & Jorjani, 2007). In addition, while significantly higher glutamate levels were initially observed in the nucleus accumbens of female morphine-tolerant rats, levels decreased following females overiectomization, though orchidectomization did not alter glutamate levels in males.

Finally, while increases in estrogen receptor α and β and expression of the androgen receptor are evident in females treated with morphine, morphine administration has been associated with decreases in estrogen receptor α and β mRNA expression, but not androgen receptor levels, among males (Vodo et al., 2013).

3.2.3. Sex-based Differences in Response to Opioid Neuropeptide Treatment and Hormone Interactions

Three studies examined the degree to which sex is associated with differences in opioid neuropeptide treatment outcomes and interactions. The first compared three groups of 26-day old rats to determine whether endogenous opioids affected sex hormone expression. During the study, female rats were injected with estradiol and then progesterone 48 hours later, and male rats were orchidectomized (Shishkina, Babichev, & Pankov, 1991). Animals were sacrificed on Day 28 and serum levels of sex hormones were determined. A second cohort of male and female rats received injections of the opioid peptide β-endorphin during the first five postnatal days, and were sacrificed at 90 days (females were sacrificed on proestrus at 18:00). Radioimmunoassay was used to determine estradiol and testosterone concentrations. While β-endorphin injections did not change the concentration of estradiol receptors in the hypothalamus of female rats, they did reduce the level of E2 receptors in males. β-endorphin injections did not affect serum concentrations of testosterone or estradiol in either male or female rats (Shishkina et al., 1991).

A second study explored whether sex hormones influenced the expression of endogenous opioids. More specifically, in situ hybridization was utilized to examine whether gonadal hormone administration modified the number of proenkephalin and prodynorphin mRNA-containing neurons in the anteroventral periventricular nucleus (AVPv) of both developing and adult male and female rats (Simerly, 1991). Data suggested testosterone produced divergent effects in developing females; indeed, testosterone-treated females expressed more proenkephalin but fewer prodynorphin mRNA-containing neurons in the AVPv, relative to untreated females. Within the adult cohort, male rats expressed twice the amount of proenkephalin mRNA containing neurons in the AVPv than female mature rats at baseline. Administering estradiol significantly increased prodynorphin mRNA levels in adult ovariectomized female rats, but no changes in prodynorphin or proenkephalin mRNA expression were observed in male rats that had been orchidectomized or administered testosterone.

A final study examined the contribution of hormones to differences in the basal firing rate and responsiveness of neurons in the pyramidal cell layer of the hippocampus upon administration of the opioid peptides leu-enkephalin and dynorphin (Osada, Nishihara, & Kimura, 1991). Male rats were found to have higher baseline pyramidal cell firing rates than females, and results did not vary following castration (Osada et al., 1991). Further, the neurons of castrated male but not female rats were more responsive to the opioid peptide leu-enkephalin, but not dynorphin, whereas castrated females experienced significantly greater inhibition following leu-enkephalin administration when compared to male rats.

3.2.4. Sex Differences in Behavioral Effects of Morphine

Three studies have examined the effects of morphine on behavioral outcomes as a function of sex. Locomotor suppression is a well-established behavioral outcome of opioid administration, and variability in locomotor suppression may have implications for abuse liability (e.g. motivation to seek drug) and/or negative side effects (e.g. lethargy). Relative to saline, morphine has been shown to initially suppress locomotor activity more profoundly in males than females but to ultimately increase locomotor activity at a similar rate for both sexes (Craft, Clark, Hart, & Pinckney, 2006). In a follow-up experiment, morphine also did not alter locomotor response in male rats that were orchidectomized, independent of whether they were treated with testosterone, but did reduce locomotor activity among ovariectomized females that were treated with estradiol (Craft et al., 2006).

A second study injected rats with either morphine or saline for 3-day intervals prior to a morphine-sensitization locomotor test (Stewart & Rodaros, 1999). Results showed that male and female rats that had been injected with morphine exhibited more morphine-induced increases in locomotor activity during the sensitization test than saline rats. Intact males also exhibited a progressive increase in morphine-induced locomotor activity, whereas orchidectomized males did not show increases, regardless of whether testosterone was administered. However, female rats that were overiectomized and received estradiol exhibited progressive increases in morphine-induced locomotor activity, whereas ovariectomized females that did not receive estradiol showed no differences, relative to a saline group.

A final study found that low doses of morphine increased feeding behavior among male but not female rats, but that higher doses of morphine increased feeding behavior among female but not male rats (Bodnar, Hadjimarkou, Krzanowska, Silva, & Stein, 2003). Neonatal castration was also observed to further enhance the impact of low-dose morphine on feeding behavior of males, whereas that behavior was reduced among intact females. Morphine-induced feeding behavior increased at higher doses when testosterone was administered to neonatal females.

4. Discussion

This review was premised upon substantial neuronal evidence that the gonadal hormone and endogenous opioid systems have meaningful interactions that may impact how males and females experience opioids. This includes data suggesting that opioid receptor binding (Maggi et al., 1996), coupling (Acosta-Martinez & Etgen, 2002), and density (Maggi et al., 1993) varies as a function of hormone exposure. Substantial differences in preclinical studies exist with regard to the manipulation of gonadal hormones, comparison groups, experimental models used, opioids examined, and primary outcomes evaluated, which makes it difficult to draw uniform conclusions. In addition, many of the reviewed studies were conducted in small sample sizes and utilized different rodent models; as a result the generalizability of outcomes and ability to synthesize results are limited.

Despite these aforementioned challenges, several notable trends emerged. First, every study identified at least one sex-based differences in the measures assessed, which provides compelling evidence that sex may underlie differences in physiological responses to opioids in a way that could impact the onset and persistence of OUD in humans. Second, several of the studies reviewed here reported naturally occurring sex-based differences in opioid receptor expression, as well as sex-based differences in neuronal response to morphine (as well as naloxone, naltrexone, and opioid neuropeptide treatments). For example, MOR-receptor density was significantly increased in intact (i.e., non-ovariectomized) females compared to intact (i.e., non-orchidectomized) males (Limonta et al., 1991), suggesting that naturally occurring differences in male and female MOR-receptor densities are sexually dimorphic and directly influenced by gonadal hormone production. In response to morphine treatment, increases in estrogen receptor α and β and expression of the androgen receptor are evident in females; however, the same result was not observed in males (Vodo et al., 2013). Ultimately, while these studies begin to lay the foundation for naturally occurring and opioid-induced sex-based differences in the opioid and hormonal systems, they also highlight the fact that more research to systematically evaluate the influence of gonadal hormone interactions with the opioid system is warranted. Such research would have substantial implications for persons with OUD.

A minority (N=3) of the studies that met eligibility criteria evaluated sex-based differences using behavioral outcome measures. Two of these studies investigated locomotor activity and reported that males and female rats exhibited differential locomotion over time in response to morphine treatment (Craft et al., 2006; Stewart and Rodaros, 1999). This may have implications for abuse potential of opioids, as increased locomotor function during opioid effects could be indicative of tolerance and/or motivation to seek opioids. In addition, sex-based differences in the non-analgesic side effects of opioids (e.g. lethargy) could also have implications for humans as individuals experiencing fewer side effects might be more prone to continue opioid use over a longer period of time, and individuals using despite side effects might be at increased risk for development of OUD. Another study that investigated feeding behavior found that low doses of morphine increased feeding behavior among male but not female rats, but the opposite was true at higher doses (Bodnar et al., 2003), demonstrating the dose dependence of behavioral effects. This could also inform the human experience. Specifially, many individuals with OUD experience weight loss during problematic use and subsequent weight gain in OUD treatment; this phenomenon may be exacerbated in women and future preclinical and clinical research on this topic warranted (Fenn, Laurent, & Sigmon, 2015). The limited number of studies that systematically examined sex-based differences opioid effects with behavioral assays highlights the need for additional systematic preclinical behavioral research.

Another notable trend in the literature reviewed here is the evidence of sex-based differences in the interaction between stress and endogenous opioid systems. For example, Williams et al. (2011), showed that females in proestrus and males expressed similar levels of CRF and receptor immunoreactivity per dendrite, though proestrus females also expressed increased dual-labeled dendritic profiles and membrane density of CRF receptor immunoreactivity relative to males. These data suggest that interactions between the opioid and stress systems may differ between males and females and that sex-based differences in delta opioid receptor activation may underlie those effects. These results have implications for sex-based differences in clinical outcomes, especially in stress reactivity in persons with OUD or chronic pain.

4.1. Future Directions

The National Institutes of Health (NIH) now requires preclinical and human research to evaluate key biological variables, including sex. Preclinical research that is prospectively designed to evaluate the role of sex hormones in opioid effects – especially as they relate to the onset of OUD – is needed to inform clinical research on this topic. In addition, women and men respond to OUD treatment differently, and preclinical research that informs the underlying mechanisms of treatment-specific responses (e.g. response to opioid withdrawal, or long-term opioid agonist treatment) would be incredibly valuable in designing clinical research to improve medication strategies for persons with OUD.

4.2. Conclusion

In conclusion, the data reviewed here suggest gonadal hormone interactions with the opioid system are likely to produce meaningful sex-based differences in the subjective experience of opioids, which may translate to differences in behavior and/or treatment response. The limited numbers of preclinical studies that have examined sex-based differences in these domains provide preliminary evidence they exist, though the direction of effects varies and is inconsistent. Prospectively designed, empirical evaluations are critically lacking and sorely needed. The recent mandate by the NIH to evaluate the contribution of biological mechanisms, such as sex, is timely and supports this line of research. Understanding the breadth and magnitude of sex-specific effects in non-analgesic responses to opioids will help to inform studies in humans to examine whether sex hormones may confer differential abuse liability profiles for men and women who are exposed to opioids, and could ultimately advance the understanding of how problematic opioid use onsets in humans, as well as inform novel medication development for OUD.

Table 1.

Articles on Sex-based Differences in Opioid Effects

Author names Year Sample size Article Type Primary Outcome Measure Drug Type Primary Results
Bodnar et al. 2003 6–11 rats per group (further details not reported) Experimental Food Intake Morphine Morphine-induced feeding increased in male, but not female rats at low doses, and female, but not male rats at higher doses.
Craft et al. 2006 16–18 female rats; 16–22 male rats (numbers reported were pooled across conditions) Experimental Locomotor Activity Morphine Morphine relative to saline initially suppressed locomotor activity (an effect most pronounced in males) and later increased locomotor activity for both sexes.
Flores et al. 2003 6 rats per each female/male group Experimental Distribution of opioid receptor-like 1 receptor mRNA and co-localization with estrogen receptor mRNA in neurons N/A ORL1 –receptor gene abundantly expressed in males/proestrus females; but significantly higher in the rostral trigeminal nucleus caudalis and the junction of the caudalis and interpolaris Vc/Vi of diestrus females
Francisco-DoPrado et al. 1998 6 rats per each female/male group Experimental Hyperinsulimenia production Naloxone and naltrexone Pretreating concanavalin A-injected rats with naloxone or naltrexone, blocked the hyperinsulinemia produced by the lectin in males as well as females
Harte-Hargrove et al. 2015 73 female rats; 32 male rats Experimental Basal transmission, long-term potentiation, mossy fiber transmission Naloxone Opioid antagonist naloxone enhanced mossy fiber transmission in females during proestrus, however, no effect was observed in males
Limonta et al. 1991 Minimum of 8 rats per group (further details not reported) Experimental MOR-Receptor density Testosterone Increase in the number of MOR-receptors was observed in normal females compared to the other groups of rats at day 26; also increased in males between day 26 and 60
Mousavi et al. 2007 Saline and sham females/males (n=4 per group); Intact and gonadectomized females/males (n=8 per group) Experimental Glutamate levels in nucleus accumbens Morphine Higher glutamate levels in the nucleus accumbens of female morphine tolerant rats; overiectomy decreased the glutamate level; orchidectomy did not change glutamate levels in males
Osada et al. 1991 23 female rats; 22 male rats Experimental Hippocampal neuron firing rate, responsiveness to opioid peptides Opioid neuropeptide Male rats higher baseline pyramidal cell firing rates than females; neurons of castrated male but not female rats were more responsive to the opioid peptide leu-enkephalin, but not dynorphin
Shishkina et al. 1991 Intact + β-endorphin females and males (n=9 per group); Gonadectomized + β-endorphin (7–8 per group) Experimental Gonadal hormone levels, concentration of E2 receptors Opioid neuropeptide β-endorphin injections did not change the concentration of estradiol receptors of female rats; reduced the level of estradiol receptors in males. Did not affect serum concentrations of testosterone or estradiol in either male or female rats.
Simerly 1991 4 rats per each female/male group Experimental Proenkephalin and prodynorphin mRNA-containing neurons Testosterone Adult male rats expressed twice the amount of proenkephalin mRNA containing neurons in the AVPv than female mature rats at baseline.
Stewart & Rodaros 1999 120 female rats; 48 male rats Experimental Locomotor activity Morphine Intact males (but not orchidectomized males) exhibited progressive increase in morphine-induced locomotor activity; Overiectomized estradiol treated female rats (although not without estradiol) exhibited progressive increases in morphine-induced locomotor activity
Van Kempen et al. 2013 Group 1: 24 female and male mice; Group 2: 38 female and male mice Experimental Dynorphin and enkephalin immunoreactivity N/A Females had higher levels of dynorphin immunoreactivity in CA3a and enkephalin immunoreactivity in CA3b relative to males
Vodo et al. 2013 4 rats per each female/male group Experimental Estrogen receptor, androgen receptor, TRPV1 gene expression Morphine Morphine increased estrogen receptor α and estrogen receptor β, as well as the androgen receptor and TRPV1 mRNA expression in the ovary, but not in male teste.
Williams et al. 2011 Minimum of 4 rats per each female/male group Experimental Corticotropin-releasing factor, receptor immunoreactivity, density N/A Proestrus females expressed increased dual-labeled dendritic profiles and membrane density of corticotropin-releasing factor receptor immunoreactivity relative to males
Williams et al. 2011 Minimum of 5 rats per each female/male group Experimental Delta opioid receptor immunoreactivity, density N/A Females in proestrus (high estrogen) displayed the lowest level of delta opioid receptor immunoreactivity in the CA1 pyramidal cell layer of all groups.
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Footnotes

Conflicts of Interest: None

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