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Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors
Molecular Pain volume 9, Article number: 45 (2013)
Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators.
Opioids are potent analgesics used to treat acute and chronic pain, and also notorious for their potential to cause addiction [1–4]. Gender differences in the experience of clinical and experimental pain [5–7] and the susceptibility to opioid addiction  have been reported. General observations suggest that there are more adult men than women involved in illicit drug abuse . However, this contrasts to the clinical and animal studies indicating that females are more susceptible to drug abuse problem than males . Besides the sociocultural factors, there must be true differences between the biological differences that influence drug abuse and pain perception, and estrogen has been proposed to be one of the key players [11, 12].
Sex differences in opioid analgesia and addiction
Population-based studies suggest that women are more likely to experience chronic pain syndromes and report more severe pain at a higher frequency than men [13–19]. Human studies indicate that females and males have similar thresholds for cold and ischemic pain [20, 21], while pressure pain thresholds are lower in females than males [22, 23]. Females tolerate less thermal pain (cold, heat) and pressure than males [24–26], but this is not the case for tolerance to ischemic pain, which is comparable in both genders [27, 28]. Based on a review of the available literature published between 1966 and 1998, Miaskowski and Levine suggest that opioids are better analgesics for women . A Chinese population study conducted in southern Taiwan also shows that females consume significantly less morphine via patient-controlled analgesia than males during the first three postoperative days . However, the majority of more recent studies comparing gender report that the potency and efficacy of morphine administered systemically is higher in males than in females against a variety of nociceptive modalities [31–33]. The controversy might be due to that earlier studies did not correct for the body weight differences between men and women. In addition, there are sex differences in reporting pain and seeking pain relief, and health care providers make unwarranted psychogenic attributions regarding pain in female but not male [7, 34–36].
A profile of a heroin-addiction epidemic showed that 74 percent of the addicts are males . In the United States, the past year and life time rates of heroin use are higher among men (men = 0.2% vs. women = 0.1%; 2.3% vs. 0.8%, respectively), while equivalent rates of men and women are reported to inject heroin (42.0% vs. 40.7%) . Among adolescent drug users administrated during 2002–2003 in the National Survey on Drug Use and Health, females are 3.91 times more likely to inject heroin than males . Gender differences in the clinical profiles of opioid-dependent individuals have been observed in substance use severity, craving, medical conditions, and impairment in associated areas of functioning. Craving for opioids is significantly higher among women, and women have higher drug, employment, family, medical, and psychiatric Addiction Severity Index composite scores . Among patients entering the maintenance program in Italy, there seems to be an emerging pattern of males who tend to use heroin as their opiate of choice, and are more likely to combine it with cannabis, while females are more likely to using street methadone, with adjunctive use of ketamine, benzodiazepines, hypnotic drugs and/or amphetamines . Moreover, women are at higher risk of abusing opioids through initial prescription painkiller use, and later resort to street methadone to cope with prescription pain killer addiction . Analysis from the U.S. indicates that opioid-addicted women work less and use more cocaine than their male counterparts . The use of drugs of abuse in women may be influenced by psychosocial and hormonal factors, such as psychiatric comorbidity (a higher rate of anxiety disorders) [41–44], more distressing drug-related environment, lower rate of antisocial personality traits , and estrogen-regulated neuroendocrine functions [12, 39, 46]. Sex differences in opioid analgesia and addiction in human and animals have been investigated extensively, and clinically-relevant representative studies are listed in Tables 1 and 2. Effects of opioids are inconsistent among different studies and species, which might result from different genetic backgrounds, ages of the subjects, doses of the opioids used, and assays or end points of the measurements.
Factors contributing to sex differences in drug abuse include pharmacokinetics, behavioral phenotypes for drug abuse vulnerability, sensitivity to aversive properties of drugs, puberty and adolescence, and genetic factors beyond hormones as reviewed by Wetherington . Given the ubiquitous actions and gender differences of sex hormones in the central nervous system, many investigators have attempted to relate sex differences in opioid analgesia to gonadal hormone levels [73, 80–82, 88–93, 100, 109–118]. Yet, the neurological and cellular mechanisms underlying the sexually dimorphic analgesic and addictive responsiveness to opioids remain poorly understood .
Estrogen regulation of opioid receptors
The analgesic effects and addiction liability of opioids are mediated by opioid receptors. Based on the molecular and pharmacological properties, three conventional opioid receptors – μ (MOR), δ (DOR), and κ (KOR) – have been characterized . A non-opioid branch of opioid receptors, opioid receptor-like 1 (ORL1) receptor, also known as the nociceptin/orphanin FQ peptide (NOP) receptor, has also been identified and displays pharmacological profiles distinct from those of conventional opioid receptors . Activation of opioid receptors inhibits (acute) / superactivates (chronic) adenylate cyclase (AC) activity , impedes N- and L-type Ca2+ channels, increases phospholipase C activity, activates inwardly rectifying K+ channels, and turns on mitogen-activated protein kinases (MAPK) [122, 123].
Estrogens, besides the well-established effects on female reproductive functions, exert various actions on the nervous system influencing pain sensation, mood, susceptibility to seizures, and neuroprotection against stroke damage and Alzheimer’s disease . Ovarian steroids have been found to modulate the activity of opioid receptors in healthy women and migraine sufferers , and replacement therapies through estrogens and progestagens could restore the activity of central opioid tonus in migraine patients . Estrogen has also been demonstrated to decrease the secretion of β-endorphin, an endogenous opioid peptide, from the Ishikawa cells, an endometrial carcinoma cell line, in a concentration- and time-dependent manner . The spinal KOR and DOR, but not MOR, activity is required for opioid-mediated elevations in maternal nociceptive thresholds, indicating the ability of estrogen to modulate spinal opioid antinociceptive activity .
Sexually dimorphic KOR-mediated antinociception has been demonstrated in antithetical antinociceptive/nociceptive responsiveness of female vs. males to KOR agonists-antagonists . Compared to men, women reported greater analgesic effects from the mixed MOR/KOR ligands: pentazocine, nalbuphine and butorphanol [52, 66]. In contrast, selective KOR agonists produced greater antinociceptive effects in male than female animals . An animal study demonstrated that spinal morphine antinociception in females requires concomitant activation of MOR and KOR, and the expression of MOR/KOR heterodimers is more prominent in the spinal cord in females than males . The same group further demonstrated that blockade of coexpressed ERα and GPR30, two types of estrogen receptors (detailed in the following section), substantially decreased MOR/KOR and eliminates mediation by KOR of spinal morphine antinociception, suggesting MOR/KOR could serve as a molecular target for analgesia in women  (Figure 1).
17β-estradiol (E2), the major ligand of estrogen receptors during reproductive years, rapidly attenuates the ability of μ-opioids to hyperpolarize guinea pig hypothalamic (β-endorphin, an opioid peptide) neurons. E2 does not compete for MOR or alter the affinity of MOR, but binds to a specific receptor that activates PKA to rapidly uncouple MOR from its K+ channel . Increased PKA activity maintains cellular tolerance to MOR agonists in the hypothalamic arcuate nucleus (ARC) neurosecretory cells caused by chronic morphine treatment. Moreover, acute E2 and chronic opioid treatment attenuate MOR-mediated responses via a common PKA pathway . Based on the high density of MOR, but the lack of effects of estrogen on [35S]GTPγS binding, it is concluded that MOR interaction with its G-protein is not the target of estrogen’s actions . E2 may modulate the behavioral effects of cocaine by regulating MOR and KOR signaling in mesocorticolimbic brain structures in female rats . In addition, sex-dependent differences have been found in the intake of ethanol in the absence of β-endorphins in mice , and in the regulation of gonadal hormone, DOR binding, and MOR density in the hippocampus by prenatal exposure to morphine in rats [137, 138].
Multiple antinociceptive assays demonstrated that male rats are markedly more sensitive to morphine analgesia than females . The difference cannot be attributed to gender-linked differences in serum levels of morphine after its injection , the acute effects of steroids , the pharmacokinetics of morphine , MOR number and the binding affinity of the MOR agonists , and morphine stimulation of G protein determined using GTPase and [35S]GTPγS binding assays . It is postulated that the organizational effects of steroids during critical periods in development, which determine gender-related distinctions, may be significant in the male–female differences . Another explanation for this gender difference is that pathways downstream of MOR and G protein are more efficient in male rats than in female rats such that there is a larger receptor reserve for morphine-mediated antinociception . One mystery that remains poorly understood is that many aspects of sexually dimorphic opioid responsiveness in humans are opposite to that observed in laboratory animals .
Opioid regulation of estrogen receptors
Estrogens act on two types of receptors, nuclear estrogen receptors (ERα and ERβ) and the membrane-associated estrogen G protein-coupled receptor (GPR30, also known as GPER). ERα and ERβ modulate the long-lasting effect of estrogen by regulating gene transcription, whereas GPR30 produces more rapid effects by generation of the secondary messengers and activation of receptor tyrosine kinases .
Estrogen promotes the growth and development of breast cancer via ER. ERα is the major ER in neoplastic breast epithelium, whereas ERβ is the predominant ER in normal breast tissue [141, 142]. The MOR agonist morphine promotes tumor neovascularization in E2-dependent human breast tumor xenograft model, MCF-7 cell, in mice leading to increased tumor progression at medically relevant concentrations . In contrast, the opioid receptor antagonist naloxone inhibits MCF-7 breast cancer growth in mice [144, 145]. Naloxone modulates ERα activity directly as well as indirectly via MOR, suggesting that naloxone-like compounds can be developed as novel therapeutic molecules for breast cancer therapy . Additionally, ERβ is expressed in human vascular endothelial cells, and morphine down-regulates this receptor as determined by real-time RT-PCR . The DOR agonist SNC80 decrease anxiety- and depression-like behavior following withdrawal from chronic cocaine use in male rats , and may serve as a potential anxiolytic in females . Further research focusing on the contribution of circulating hormones and DOR agonists on cocaine withdrawal-induced anxiety in females and understanding the sex differences is needed.
The regulatory actions of opioids on estrogen receptors have been described in breast cancer, yet never been linked to the sex differences in opioid analgesia and addiction. Significance of such opioid actions in the sex difference remains elusive, and may be explored both in vitro and in vivo. The in vitro assays can be done by applying the opioids to neuronal cells expressing specific estrogen receptors to characterize the cellular responses of the estrogen receptors. The in vivo assays measuring the extent of opioid analgesia and addiction in estrogen receptor knockout mice, with females of different stages of estrous cycle and males, should be performed. Specific antagonists to the opioid receptors should be applied to characterize the interacting opioid receptors.
Interactions among opioid and estrogen receptors
MOR internalization is correlated with MOR-mediated inhibition of lordosis . MOR antagonists block receptor internalization and facilitate lordosis [149, 150]. ERα, but not ERβ, is required for estrogen-induced MOR internalization, suggesting that ERα can mediate rapid actions of estrogen . The mRNA of the ORL1 receptor, the non-canonical member of the opioid receptor family, is present in majority of ERα and/or ERβ mRNA-containing neurons, and the sex-related differences in the ORL1 gene expression in the trigeminal nucleus caudalis appear to be determined in part by estrogen levels .
GPR30, the plasma membrane ER, is expressed in pain-relevant areas of the rat central nervous system, and the expression levels are similar in the male and female [153–156]. GPR30 activation leads to hyperalgesia in rats [157, 158] and spinal nociception in mice , and is involved in mediating the rapid pronociceptive effects of E2 [155, 157, 160]. The downstream mechanisms involve cytosolic calcium increase [161, 162], ROS accumulation , and neuronal membrane depolarization . Stimulation of plasma membrane ERs is coupled to the activation of the same signaling molecules that participate in most membrane initiated signaling cascades as opioid receptors, e.g., protein kinase A, protein kinase B, protein kinase C, phospholipase C, inositol triphosphate, MAPK, ERK, tyrosine kinases, etc. [164–180] Due to the overlapping of the secondary messenger pathways, activation of GPR30 by estrogen is postulated to influence the signaling cascades of the opioid receptors, leading to the sex differences in the effects of opioids because of different GPR30 expression patterns between males and females (Figure 2).
Although opioids and estrogen can activate common signaling pathways, there is no direct evidence that signaling crosstalk among estrogen and opioid receptors contributes to the sex differences in opioid analgesia and addiction. This data gap should be filled by performing assays measuring the extent of opioid analgesia and addiction in opioid receptor knockout mice, with males and females of different stages of estrous cycle. Specific antagonists to the estrogen receptors are required to identify the interacting estrogen receptors in the behavioral assays.
Although numerous reports have addressed gender differences of opioid receptor agonists, very few directly examined the mechanism. It has been proposed that differences in opioid receptor levels, distribution and efficiency of signaling and neural circuitry modulated by opioid receptor activation cause the sexual dimorphism . However, direct evidence of the interactions among estrogen and opioid receptors is lacking. Animals deficient of estrogen receptors ERα, ERβ, or GPR30 lack the estrogen-regulated opioid effects, and hence display distinct analgesic and addictive responses to morphine. Functional interactions between estrogens and opioids should be investigated to provide the insight into gender differences in analgesia and addiction at both cellular and physiological levels. Male sex hormone such as testosterone may also play a role in opioid analgesia and addiction, as anabolic androgenic steroids have been shown to alter opioid receptor expression in SH-SY5Y human neuroblastoma cells . This review focuses on estrogen receptors, but does not exclude the possibility that androgen receptors could cross-talk with opioid receptors and thereby contribute to the sex differences of opioid effects. Organismal factors must be considered when interpreting the data, since just as a male is not a female, a mouse is not a small rat, and a primate is not a human. Developmental stages, drug doses, routes of drug administration, types of assays employed, and genetic backgrounds should be considered and matched in future randomized clinical studies to define the sex differences in opioid analgesia and addiction.
Estrogen receptor α
Estrogen receptor β
Estrogen G protein-coupled receptor
Mitogen-activated protein kinases
Nociceptin/orphanin FQ peptide
Opioid receptor-like 1 receptor.
Coluzzi F, Pappagallo M, National Initiative on Pain C: Opioid therapy for chronic noncancer pain: practice guidelines for initiation and maintenance of therapy. Minerva Anestesiol 2005, 71: 425–433.
Ballantyne JC: Opioid analgesia: perspectives on right use and utility. Pain Physician 2007, 10: 479–491.
Whistler JL: Examining the role of mu opioid receptor endocytosis in the beneficial and side-effects of prolonged opioid use: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend 2012, 121: 189–204. 10.1016/j.drugalcdep.2011.10.031
Portenoy RK: Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 1996, 11: 203–217.
Paulson PE, Minoshima S, Morrow TJ, Casey KL: Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 1998, 76: 223–229. 10.1016/S0304-3959(98)00048-7
Manson JE: Pain: sex differences and implications for treatment. Metabolism 2010, 59(Suppl 1):S16-S20.
Unruh AM: Gender variations in clinical pain experience. Pain 1996, 65: 123–167. 10.1016/0304-3959(95)00214-6
Back SE, Payne RL, Wahlquist AH, Carter RE, Stroud Z, Haynes L, Hillhouse M, Brady KT, Ling W: Comparative profiles of men and women with opioid dependence: results from a national multisite effectiveness trial. Am J Drug Alcohol Abuse 2011, 37: 313–323. 10.3109/00952990.2011.596982
SAMHSA: Results from the 2011 National Survey on Drug Use and Health: Mental Health Findings. Rockville, MD: NSDUH Series H-45, HHS Publication No. (SMA) 12–4725; 2011. USA: Substance Abuse and Mental Health Services Administration
Lynch WJ, Roth ME, Carroll ME: Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology (Berl) 2002, 164: 121–137. 10.1007/s00213-002-1183-2
Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP: Sex and estrogen influence drug abuse. Trends Pharmacol Sci 2004, 25: 273–279. 10.1016/j.tips.2004.03.011
Hughes ZA, Liu F, Marquis K, Muniz L, Pangalos MN, Ring RH, Whiteside GT, Brandon NJ: Estrogen receptor neurobiology and its potential for translation into broad spectrum therapeutics for CNS disorders. Curr Mol Pharmacol 2009, 2: 215–236.
Andersson HI, Ejlertsson G, Leden I, Rosenberg C: Chronic pain in a geographically defined general population: studies of differences in age, gender, social class, and pain localization. Clin J Pain 1993, 9: 174–182. 10.1097/00002508-199309000-00004
Blyth FM, March LM, Brnabic AJ, Jorm LR, Williamson M, Cousins MJ: Chronic pain in Australia: a prevalence study. Pain 2001, 89: 127–134. 10.1016/S0304-3959(00)00355-9
Buskila D, Abramov G, Biton A, Neumann L: The prevalence of pain complaints in a general population in Israel and its implications for utilization of health services. J Rheumatol 2000, 27: 1521–1525.
Eriksen J, Jensen MK, Sjogren P, Ekholm O, Rasmussen NK: Epidemiology of chronic non-malignant pain in Denmark. Pain 2003, 106: 221–228. 10.1016/S0304-3959(03)00225-2
Moulin DE, Clark AJ, Speechley M, Morley-Forster PK: Chronic pain in Canada–prevalence, treatment, impact and the role of opioid analgesia. Pain Res Manag 2002, 7: 179–184.
Tsang A, Von Korff M, Lee S, Alonso J, Karam E, Angermeyer MC, Borges GL, Bromet EJ, Demytteneare K, de Girolamo G, et al.: Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J Pain 2008, 9: 883–891. 10.1016/j.jpain.2008.05.005
Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd: Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009, 10: 447–485.
Zimmer C, Basler HD, Vedder H, Lautenbacher S: Sex differences in cortisol response to noxious stress. Clin J Pain 2003, 19: 233–239. 10.1097/00002508-200307000-00006
Riley JL 3rd, Robinson ME, Wise EA, Myers CD, Fillingim RB: Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain 1998, 74: 181–187. 10.1016/S0304-3959(97)00199-1
Garcia E, Godoy-Izquierdo D, Godoy JF, Perez M, Lopez-Chicheri I: Gender differences in pressure pain threshold in a repeated measures assessment. Psychol Health Med 2007, 12: 567–579. 10.1080/13548500701203433
Chesterton LS, Barlas P, Foster NE, Baxter GD, Wright CC: Gender differences in pressure pain threshold in healthy humans. Pain 2003, 101: 259–266. 10.1016/S0304-3959(02)00330-5
Fillingim RB, Maixner W, Kincaid S, Silva S: Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain 1998, 75: 121–127. 10.1016/S0304-3959(97)00214-5
Nishino T, Isono S, Ishikawa T, Shinozuka N: Sex differences in the effect of dyspnea on thermal pain threshold in young healthy subjects. Anesthesiology 2008, 109: 1100–1106. 10.1097/ALN.0b013e31818d8f43
Raak R, Wahren LK: Stress coping strategies in thermal pain sensitive and insensitive healthy subjects. Int J Nurs Pract 2001, 7: 162–168. 10.1046/j.1440-172X.2001.00258.x
Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G, Choiniere M: A systematic literature review of 10 years of research on sex/gender and experimental pain perception - part 1: are there really differences between women and men? Pain 2012, 153: 602–618. 10.1016/j.pain.2011.11.025
Edwards RR, Haythornthwaite JA, Sullivan MJ, Fillingim RB: Catastrophizing as a mediator of sex differences in pain: differential effects for daily pain versus laboratory-induced pain. Pain 2004, 111: 335–341. 10.1016/j.pain.2004.07.012
Miaskowski C, Levine JD: Does opioid analgesia show a gender preference for females? Pain Forum 1999, 8: 34–44. 10.1016/S1082-3174(99)70044-9
Chia YY, Chow LH, Hung CC, Liu K, Ger LP, Wang PN: Gender and pain upon movement are associated with the requirements for postoperative patient-controlled iv analgesia: a prospective survey of 2,298 Chinese patients. Can J Anaesth 2002, 49: 249–255. 10.1007/BF03020523
Dahan A, Kest B, Waxman AR, Sarton E: Sex-specific responses to opiates: animal and human studies. Anesth Analg 2008, 107: 83–95. 10.1213/ane.0b013e31816a66a4
Cepeda MS, Carr DB: Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg 2003, 97: 1464–1468.
Aubrun F, Salvi N, Coriat P, Riou B: Sex- and age-related differences in morphine requirements for postoperative pain relief. Anesthesiology 2005, 103: 156–160. 10.1097/00000542-200507000-00023
Colameco S, Becker LA, Simpson M: Sex bias in the assessment of patient complaints. J Fam Pract 1983, 16: 1117–1121.
Bernstein B, Kane R: Physicians’ attitudes toward female patients. Med Care 1981, 19: 600–608. 10.1097/00005650-198106000-00004
Calderone KL: The Influence of Gender on the Frequency of Pain and Sedative Medication Administered to Postoperative-Patients. Sex Roles 1990, 23: 713–725. 10.1007/BF00289259
DuPont RL: Profile of a heroin-addiction epidemic. N Engl J Med 1971, 285: 320–324. 10.1056/NEJM197108052850605
Wu LT, Howard MO: Is inhalant use a risk factor for heroin and injection drug use among adolescents in the United States? Addict Behav 2007, 32: 265–281. 10.1016/j.addbeh.2006.03.043
Maremmani I, Stefania C, Pacini M, Maremmani AG, Carlini M, Golia F, Deltito J, Dell’Osso L: Differential substance abuse patterns distribute according to gender in heroin addicts. J Psychoactive Drugs 2010, 42: 89–95. 10.1080/02791072.2010.10399789
Kelly SM, Schwartz RP, O’Grady KE, Mitchell SG, Reisinger HS, Peterson JA, Agar MH, Brown BS: Gender Differences Among In- and Out-of-Treatment Opioid-Addicted Individuals. Am J Drug Alcohol Abuse 2009, 35: 38–42. 10.1080/00952990802342915
De Wilde J, Soyez V, Broekaert E, Rosseel Y, Kaplan C, Larsson J: Problem severity profiles of substance abusing women in European Therapeutic Communities: influence of psychiatric problems. J Subst Abuse Treat 2004, 26: 243–251. 10.1016/j.jsat.2004.01.006
Zimmermann G, Pin MA, Krenz S, Bouchat A, Favrat B, Besson J, Zullino DF: Prevalence of social phobia in a clinical sample of drug dependent patients. J Affect Disord 2004, 83: 83–87. 10.1016/j.jad.2004.05.003
Kecskes I, Rihmer Z, Kiss K, Sarai T, Szabo A, Kiss GH: Gender differences in panic disorder symptoms and illicit drug use among young people in Hungary. Eur Psychiatry 2002, 17: 29–32.
Grilo CM, Martino S, Walker ML, Becker DF, Edell WS, McGlashan TH: Psychiatric comorbidity differences in male and female adult psychiatric inpatients with substance use disorders. Compr Psychiatry 1997, 38: 155–159. 10.1016/S0010-440X(97)90068-7
Landheim AS, Bakken K, Vaglum P: Gender differences in the prevalence of symptom disorders and personality disorders among poly-substance abusers and pure alcoholics. Substance abusers treated in two counties in Norway. Eur Addict Res 2003, 9: 8–17. 10.1159/000067732
Anker JJ, Carroll ME: Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Top Behav Neurosci 2011, 8: 73–96.
McQuay HJ, Bullingham RE, Paterson GM, Moore RA: Clinical effects of buprenorphine during and after operation. Br J Anaesth 1980, 52: 1013–1019. 10.1093/bja/52.10.1013
Watson PJ, McQuay HJ, Bullingham RE, Allen MC, Moore RA: Single-dose comparison of buprenorphine 0.3 and 0.6 mg i.v. given after operation: clinical effects and plasma concentration. Br J Anaesth 1982, 54: 37–43. 10.1093/bja/54.1.37
Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA: Sublingual buprenorphine used postoperatively: clinical observations and preliminary pharmacokinetic analysis. Br J Clin Pharmacol 1981, 12: 117–122.
Miller PL, Ernst AA: Sex differences in analgesia: a randomized trial of mu versus kappa opioid agonists. South Med J 2004, 97: 35–41. 10.1097/01.SMJ.0000085743.68121.A9
Sibille KT, Kindler LL, Glover TL, Gonzalez RD, Staud R, Riley JL 3rd, Fillingim RB: Individual differences in morphine and butorphanol analgesia: a laboratory pain study. Pain Med 2011, 12: 1076–1085. 10.1111/j.1526-4637.2011.01157.x
Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 1996, 2: 1248–1250. 10.1038/nm1196-1248
Zacny JP, Beckman NJ: The effects of a cold-water stimulus on butorphanol effects in males and females. Pharmacol Biochem Behav 2004, 78: 653–659. 10.1016/j.pbb.2004.01.021
Gourlay GK, Kowalski SR, Plummer JL, Cousins MJ, Armstrong PJ: Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain. Anesth Analg 1988, 67: 329–337.
Chang KY, Dai CY, Ger LP, Fu MJ, Wong KC, Chan KH, Tsou MY: Determinants of patient-controlled epidural analgesia requirements: a prospective analysis of 1753 patients. Clin J Pain 2006, 22: 751–756. 10.1097/01.ajp.0000210924.56654.03
Tamsen A, Bondesson U, Dahlstrom B, Hartvig P: Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone. Clin Pharmacokinet 1982, 7: 252–265. 10.2165/00003088-198207030-00005
Mercadante S, Casuccio A, Agnello A, Barresi L: Methadone response in advanced cancer patients with pain followed at home. J Pain Symptom Manage 1999, 18: 188–192. 10.1016/S0885-3924(99)00048-2
Bennett R, Batenhorst R, Graves DA, Foster TS, Griffen WO, Wright BD: Variation in postoperative analgesic requirements in the morbidly obese following gastric bypass surgery. Pharmacotherapy 1982, 2: 50–53.
Dahlstrom B, Tamsen A, Paalzow L, Hartvig P: Patient-controlled analgesic therapy, Part IV: pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet 1982, 7: 266–279. 10.2165/00003088-198207030-00006
Bahar M, Rosen M, Vickers MD: Self-administered nalbuphine, morphine and pethidine. Comparison, by intravenous route, following cholecystectomy. Anaesthesia 1985, 40: 529–532.
Burns JW, Hodsman NB, McLintock TT, Gillies GW, Kenny GN, McArdle CS: The influence of patient characteristics on the requirements for postoperative analgesia. A reassessment using patient-controlled analgesia. Anaesthesia 1989, 44: 2–6. 10.1111/j.1365-2044.1989.tb11086.x
De Kock M, Scholtes JL: Postoperative P.C.A. in abdominal surgery. Analysis of 200 consecutive patients. Acta Anaesthesiol Belg 1991, 42: 85–91.
Tsui SL, Tong WN, Irwin M, Ng KF, Lo JR, Chan WS, Yang J: The efficacy, applicability and side-effects of postoperative intravenous patient-controlled morphine analgesia: an audit of 1233 Chinese patients. Anaesth Intensive Care 1996, 24: 658–664.
Sidebotham D, Dijkhuizen MR, Schug SA: The safety and utilization of patient-controlled analgesia. J Pain Symptom Manage 1997, 14: 202–209. 10.1016/S0885-3924(97)00182-6
Lehmann KA, Tenbuhs B: Patient-controlled analgesia with nalbuphine, a new narcotic agonist–antagonist, for the treatment of postoperative pain. Eur J Clin Pharmacol 1986, 31: 267–276. 10.1007/BF00981122
Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain 1999, 83: 339–345. 10.1016/S0304-3959(99)00119-0
Fillingim RB, Hastie BA, Ness TJ, Glover TL, Campbell CM, Staud R: Sex-related psychological predictors of baseline pain perception and analgesic responses to pentazocine. Biol Psychol 2005, 69: 97–112. 10.1016/j.biopsycho.2004.11.008
Fillingim RB, Ness TJ, Glover TL, Campbell CM, Price DD, Staud R: Experimental pain models reveal no sex differences in pentazocine analgesia in humans. Anesthesiology 2004, 100: 1263–1270. 10.1097/00000542-200405000-00031
Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, et al.: The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A 2003, 100: 4867–4872. 10.1073/pnas.0730053100
Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD: Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 1996, 205: 207–209. 10.1016/0304-3940(96)12402-2
Tamsen A, Hartvig P, Fagerlund C, Dahlstrom B: Patient-controlled analgesic therapy. Part I: Pharmacokinetics of pethidine in the per- and postoperative periods. Clin Pharmacokinet 1982, 7: 149–163. 10.2165/00003088-198207020-00004
Bartok RE, Craft RM: Sex differences in opioid antinociception. J Pharmacol Exp Ther 1997, 282: 769–778.
Terner JM, Barrett AC, Grossell E, Picker MJ: Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats. Psychopharmacology (Berl) 2002, 163: 183–193. 10.1007/s00213-002-1143-x
Cook CD, Barrett AC, Roach EL, Bowman JR, Picker MJ: Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the mu opioid receptor. Psychopharmacology (Berl) 2000, 150: 430–442. 10.1007/s002130000453
Barrett AC, Cook CD, Terner JM, Craft RM, Picker MJ: Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids. Psychopharmacology (Berl) 2001, 158: 154–164. 10.1007/s002130100821
Holtman JR Jr, Sloan JW, Jing X, Wala EP: Modification of morphine analgesia and tolerance by flumazenil in male and female rats. Eur J Pharmacol 2003, 470: 149–156. 10.1016/S0014-2999(03)01782-5
Lomas LM, Barrett AC, Terner JM, Lysle DT, Picker MJ: Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats. Psychopharmacology (Berl) 2007, 191: 273–285. 10.1007/s00213-006-0663-1
Thornton SR, Smith FL: Characterization of neonatal rat fentanyl tolerance and dependence. J Pharmacol Exp Ther 1997, 281: 514–521.
Rodriguez M, Carlos MA, Ortega I, Suarez E, Calvo R, Lukas JC: Sex specificity in methadone analgesia in the rat: a population pharmacokinetic and pharmacodynamic approach. Pharm Res 2002, 19: 858–867. 10.1023/A:1016117218760
Baamonde AI, Hidalgo A, Andres-Trelles F: Sex-related differences in the effects of morphine and stress on visceral pain. Neuropharmacology 1989, 28: 967–970. 10.1016/0028-3908(89)90197-4
Cicero TJ, Nock B, Meyer ER: Gender-related differences in the antinociceptive properties of morphine. J Pharmacol Exp Ther 1996, 279: 767–773.
Cicero TJ, Nock B, O’Connor L, Meyer ER: Role of steroids in sex differences in morphine-induced analgesia: activational and organizational effects. J Pharmacol Exp Ther 2002, 300: 695–701. 10.1124/jpet.300.2.695
Cicero TJ, Nock B, Meyer ER: Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther 1997, 282: 939–944.
Badillo-Martinez D, Kirchgessner AL, Butler PD, Bodnar RJ: Monosodium glutamate and analgesia induced by morphine. Test-specific effects. Neuropharmacology 1984, 23: 1141–1149. 10.1016/0028-3908(84)90231-4
Craft RM, Stratmann JA, Bartok RE, Walpole TI, King SJ: Sex differences in development of morphine tolerance and dependence in the rat. Psychopharmacology (Berl) 1999, 143: 1–7. 10.1007/s002130050911
Craft RM, Lee DA: NMDA antagonist modulation of morphine antinociception in female vs. male rats. Pharmacol Biochem Behav 2005, 80: 639–649. 10.1016/j.pbb.2005.02.003
South SM, Wright AW, Lau M, Mather LE, Smith MT: Sex-related differences in antinociception and tolerance development following chronic intravenous infusion of morphine in the rat: modulatory role of testosterone via morphine clearance. J Pharmacol Exp Ther 2001, 297: 446–457.
Kepler KL, Kest B, Kiefel JM, Cooper ML, Bodnar RJ: Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol Biochem Behav 1989, 34: 119–127. 10.1016/0091-3057(89)90363-8
Krzanowska EK, Bodnar RJ: Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res 1999, 821: 224–230. 10.1016/S0006-8993(98)01364-X
Islam AK, Cooper ML, Bodnar RJ: Interactions among aging, gender, and gonadectomy effects upon morphine antinociception in rats. Physiol Behav 1993, 54: 45–53. 10.1016/0031-9384(93)90042-E
Kasson BG, George R: Endocrine influences on the actions of morphine: IV. Effects of sex and strain. Life Sci 1984, 34: 1627–1634. 10.1016/0024-3205(84)90633-7
Krzanowska EK, Ogawa S, Pfaff DW, Bodnar RJ: Reversal of sex differences in morphine analgesia elicited from the ventrolateral periaqueductal gray in rats by neonatal hormone manipulations. Brain Res 2002, 929: 1–9. 10.1016/S0006-8993(01)03350-9
Mousavi Z, Shafaghi B, Kobarfard F, Jorjani M: Sex differences and role of gonadal hormones on glutamate level in the nucleus accumbens in morphine tolerant rats: a microdialysis study. Eur J Pharmacol 2007, 554: 145–149. 10.1016/j.ejphar.2006.10.010
Terner JM, Barrett AC, Lomas LM, Negus SS, Picker MJ: Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains. Pain 2006, 122: 90–101. 10.1016/j.pain.2006.01.019
Liu NJ, von Gizycki H, Gintzler AR: Sexually dimorphic recruitment of spinal opioid analgesic pathways by the spinal application of morphine. J Pharmacol Exp Ther 2007, 322: 654–660. 10.1124/jpet.107.123620
Lomas LM, Picker MJ: Behavioral assessment of temporal summation in the rat: sensitivity to sex, opioids and modulation by NMDA receptor antagonists. Psychopharmacology (Berl) 2005, 180: 84–94. 10.1007/s00213-005-2153-2
Kavaliers M, Innes DG: Developmental changes in opiate-induced analgesia in deer mice: sex and population differences. Brain Res 1990, 516: 326–331. 10.1016/0006-8993(90)90936-6
Kavaliers M, Innes D: Sex differences in the effects of neuropeptide FF and IgG from neuropeptide FF on morphine- and stress-induced analgesia. Peptides 1992, 13: 603–607. 10.1016/0196-9781(92)90096-L
Kavaliers M, Innes DG: Sex differences in the effects of Tyr-MIF-1 on morphine- and stress-induced analgesia. Peptides 1992, 13: 1295–1297. 10.1016/0196-9781(92)90038-5
Candido J, Lutfy K, Billings B, Sierra V, Duttaroy A, Inturrisi CE, Yoburn BC: Effect of adrenal and sex hormones on opioid analgesia and opioid receptor regulation. Pharmacol Biochem Behav 1992, 42: 685–692. 10.1016/0091-3057(92)90015-8
Kest B, Wilson SG, Mogil JS: Sex differences in supraspinal morphine analgesia are dependent on genotype. J Pharmacol Exp Ther 1999, 289: 1370–1375.
Grisel JE, Mogil JS, Belknap JK, Grandy DK: Orphanin FQ acts as a supraspinal, but not a spinal, anti-opioid peptide. Neuroreport 1996, 7: 2125–2129. 10.1097/00001756-199609020-00012
Craft RM, Bernal SA: Sex differences in opioid antinociception: kappa and ‘mixed action’ agonists. Drug Alcohol Depend 2001, 63: 215–228. 10.1016/S0376-8716(00)00209-X
Terner JM, Lomas LM, Smith ES, Barrett AC, Picker MJ: Pharmacogenetic analysis of sex differences in opioid antinociception in rats. Pain 2003, 106: 381–391. 10.1016/j.pain.2003.08.008
Lynch WJ, Carroll ME: Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl) 1999, 144: 77–82. 10.1007/s002130050979
Carroll ME, Morgan AD, Lynch WJ, Campbell UC, Dess NK: Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology (Berl) 2002, 161: 304–313. 10.1007/s00213-002-1030-5
Cicero TJ, Aylward SC, Meyer ER: Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav 2003, 74: 541–549. 10.1016/S0091-3057(02)01039-0
Wetherington CL: Sex differences and gonadal hormone influences in drug addiction and sexual behavior: progress and possibilities. Horm Behav 2010, 58: 2–7. 10.1016/j.yhbeh.2010.03.004
Kepler KL, Standifer KM, Paul D, Kest B, Pasternak GW, Bodnar RJ: Gender effects and central opioid analgesia. Pain 1991, 45: 87–94. 10.1016/0304-3959(91)90168-W
Ali BH, Sharif SI, Elkadi A: Sex differences and the effect of gonadectomy on morphine-induced antinociception and dependence in rats and mice. Clin Exp Pharmacol Physiol 1995, 22: 342–344. 10.1111/j.1440-1681.1995.tb02012.x
Ratka A, Simpkins JW: Effects of estradiol and progesterone on the sensitivity to pain and on morphine-induced antinociception in female rats. Horm Behav 1991, 25: 217–228. 10.1016/0018-506X(91)90052-J
Chatterjee TK, Das S, Banerjee P, Ghosh JJ: Possible physiological role of adrenal and gonadal steroids in morphine analgesia. Eur J Pharmacol 1982, 77: 119–123. 10.1016/0014-2999(82)90005-X
Kasson BG, George R: Endocrine influences on the actions of morphine. I. Alteration of target gland hormones. J Pharmacol Exp Ther 1983, 224: 273–281.
Banerjee P, Chatterjee TK, Ghosh JJ: Ovarian steroids and modulation of morphine-induced analgesia and catalepsy in female rats. Eur J Pharmacol 1983, 96: 291–294. 10.1016/0014-2999(83)90319-9
Borzan J, Fuchs PN: Organizational and activational effects of testosterone on carrageenan-induced inflammatory pain and morphine analgesia. Neuroscience 2006, 143: 885–893. 10.1016/j.neuroscience.2006.08.034
Stoffel EC, Ulibarri CM, Craft RM: Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats. Pain 2003, 103: 285–302. 10.1016/s0304-3959(02)00457-8
Dawson-Basoa ME, Gintzler AR: Estrogen and progesterone activate spinal kappa-opiate receptor analgesic mechanisms. Pain 1996, 64: 608–615. 10.1016/0304-3959(96)87175-2
Claiborne J, Nag S, Mokha SS: Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male. J Neurosci 2006, 26: 13048–13053. 10.1523/JNEUROSCI.4783-06.2006
Kieffer BL, Evans CJ: Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology 2009, 56(Suppl 1):205–212.
Zaveri NT: The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications. Curr Top Med Chem 2011, 11: 1151–1156. 10.2174/156802611795371341
Pierre S, Eschenhagen T, Geisslinger G, Scholich K: Capturing adenylyl cyclases as potential drug targets. Nat Rev Drug Discov 2009, 8: 321–335. 10.1038/nrd2827
Christie MJ: Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol 2008, 154: 384–396.
Law PY, Wong YH, Loh HH: Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 2000, 40: 389–430. 10.1146/annurev.pharmtox.40.1.389
McEwen BS: Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 2001, 91: 2785–2801.
Genazzani AR, Petraglia F, Volpe A, Facchinetti F: Estrogen changes as a critical factor in modulation of central opioid tonus: possible correlations with post-menopausal migraine. Cephalalgia 1985, 5(Suppl 2):212–214.
Gravanis A, Makrigiannakis A, Stournaras C, Margioris AN: Interaction between steroid hormones and endometrial opioids. Ann N Y Acad Sci 1994, 734: 245–256. 10.1111/j.1749-6632.1994.tb21754.x
Dawson-Basoa M, Gintzler AR: Involvement of spinal cord delta opiate receptors in the antinociception of gestation and its hormonal simulation. Brain Res 1997, 757: 37–42. 10.1016/S0006-8993(97)00092-9
Gintzler AR, Liu NJ: Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors. Front Neuroendocrinol 2012, 33: 412–424. 10.1016/j.yfrne.2012.09.004
Rasakham K, Liu-Chen LY: Sex differences in kappa opioid pharmacology. Life Sci 2011, 88: 2–16. 10.1016/j.lfs.2010.10.007
Chakrabarti S, Liu NJ, Gintzler AR: Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proc Natl Acad Sci U S A 2010, 107: 20115–20119. 10.1073/pnas.1009923107
Liu NJ, Chakrabarti S, Schnell S, Wessendorf M, Gintzler AR: Spinal synthesis of estrogen and concomitant signaling by membrane estrogen receptors regulate spinal kappa- and mu-opioid receptor heterodimerization and female-specific spinal morphine antinociception. J Neurosci 2011, 31: 11836–11845. 10.1523/JNEUROSCI.1901-11.2011
Lagrange AH, Ronnekleiv OK, Kelly MJ: Modulation of G protein-coupled receptors by an estrogen receptor that activates protein kinase A. Mol Pharmacol 1997, 51: 605–612.
Wagner EJ, Ronnekleiv OK, Kelly MJ: Protein kinase A maintains cellular tolerance to mu opioid receptor agonists in hypothalamic neurosecretory cells with chronic morphine treatment: convergence on a common pathway with estrogen in modulating mu opioid receptor/effector coupling. J Pharmacol Exp Ther 1998, 285: 1266–1273.
Cunningham MJ, Fang Y, Selley DE, Kelly MJ: mu-Opioid agonist-stimulated [35S]GTPgammaS binding in guinea pig hypothalamus: effects of estrogen. Brain Res 1998, 791: 341–346. 10.1016/S0006-8993(98)00201-7
Segarra AC, Agosto-Rivera JL, Febo M, Lugo-Escobar N, Menendez-Delmestre R, Puig-Ramos A, Torres-Diaz YM: Estradiol: a key biological substrate mediating the response to cocaine in female rats. Horm Behav 2010, 58: 33–43. 10.1016/j.yhbeh.2009.12.003
Racz I, Schurmann B, Karpushova A, Reuter M, Cichon S, Montag C, Furst R, Schutz C, Franke PE, Strohmaier J, et al.: The opioid peptides enkephalin and beta-endorphin in alcohol dependence. Biol Psychiatry 2008, 64: 989–997. 10.1016/j.biopsych.2008.05.008
Vathy I, Rimanoczy A, Slamberova R: Prenatal exposure to morphine differentially alters gonadal hormone regulation of delta-opioid receptor binding in male and female rats. Brain Res Bull 2000, 53: 793–800. 10.1016/S0361-9230(00)00409-3
Slamberova R, Rimanoczy A, Bar N, Schindler CJ, Vathy I: Density of mu-opioid receptors in the hippocampus of adult male and female rats is altered by prenatal morphine exposure and gonadal hormone treatment. Hippocampus 2003, 13: 461–471. 10.1002/hipo.10076
Peckham EM, Barkley LM, Divin MF, Cicero TJ, Traynor JR: Comparison of the antinociceptive effect of acute morphine in female and male Sprague–Dawley rats using the long-lasting mu-antagonist methocinnamox. Brain Res 2005, 1058: 137–147. 10.1016/j.brainres.2005.07.060
Prossnitz ER, Arterburn JB, Sklar LA: GPR30: A G protein-coupled receptor for estrogen. Mol Cell Endocrinol 2007, 265–266: 138–142.
Hall JM, Couse JF, Korach KS: The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 2001, 276: 36869–36872. 10.1074/jbc.R100029200
Khan SA, Rogers MA, Obando JA, Tamsen A: Estrogen receptor expression of benign breast epithelium and its association with breast cancer. Cancer Res 1994, 54: 993–997.
Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002, 62: 4491–4498.
Tegeder I, Grosch S, Schmidtko A, Haussler A, Schmidt H, Niederberger E, Scholich K, Geisslinger G: G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res 2003, 63: 1846–1852.
Farooqui M, Geng ZH, Stephenson EJ, Zaveri N, Yee D, Gupta K: Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells. Mol Cancer Ther 2006, 5: 611–620. 10.1158/1535-7163.MCT-05-0016
Cadet P, Mantione K, Bilfinger TV, Stefano GB: Morphine down regulates human vascular tissue estrogen receptor expression determined by real-time RT-PCR. Neuro Endocrinol Lett 2002, 23: 95–100.
Perrine SA, Sheikh IS, Nwaneshiudu CA, Schroeder JA, Unterwald EM: Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat. Neuropharmacology 2008, 54: 355–364. 10.1016/j.neuropharm.2007.10.007
Ambrose-Lanci LM, Sterling RC, Van Bockstaele EJ: Cocaine withdrawal-induced anxiety in females: impact of circulating estrogen and potential use of delta-opioid receptor agonists for treatment. J Neurosci Res 2010, 88: 816–824.
Sinchak K, Micevych PE: Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior. J Neurosci 2001, 21: 5723–5729.
Eckersell CB, Popper P, Micevych PE: Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. J Neurosci 1998, 18: 3967–3976.
Micevych PE, Rissman EF, Gustafsson JA, Sinchak K: Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor internalization. J Neurosci Res 2003, 71: 802–810. 10.1002/jnr.10526
Flores CA, Shughrue P, Petersen SL, Mokha SS: Sex-related differences in the distribution of opioid receptor-like 1 receptor mRNA and colocalization with estrogen receptor mRNA in neurons of the spinal trigeminal nucleus caudalis in the rat. Neuroscience 2003, 118: 769–778. 10.1016/S0306-4522(02)01000-X
Dun SL, Brailoiu GC, Gao X, Brailoiu E, Arterburn JB, Prossnitz ER, Oprea TI, Dun NJ: Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia. J Neurosci Res 2009, 87: 1610–1619. 10.1002/jnr.21980
Hazell GG, Yao ST, Roper JA, Prossnitz ER, O’Carroll AM, Lolait SJ: Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J Endocrinol 2009, 202: 223–236. 10.1677/JOE-09-0066
Liverman CS, Brown JW, Sandhir R, McCarson KE, Berman NE: Role of the oestrogen receptors GPR30 and ERalpha in peripheral sensitization: relevance to trigeminal pain disorders in women. Cephalalgia 2009, 29: 729–741. 10.1111/j.1468-2982.2008.01789.x
Takanami K, Sakamoto H, Matsuda K, Hosokawa K, Nishi M, Prossnitz ER, Kawata M: Expression of G protein-coupled receptor 30 in the spinal somatosensory system. Brain Res 2010, 1310: 17–28.
Kuhn J, Dina OA, Goswami C, Suckow V, Levine JD, Hucho T: GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat. Eur J Neurosci 2008, 27: 1700–1709. 10.1111/j.1460-9568.2008.06131.x
Lu CL, Hsieh JC, Dun NJ, Oprea TI, Wang PS, Luo JC, Lin HC, Chang FY, Lee SD: Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats. Gastroenterology 2009, 137: 1040–1050. 10.1053/j.gastro.2009.03.047
Deliu E, Brailoiu GC, Arterburn JB, Oprea TI, Benamar K, Dun NJ, Brailoiu E: Mechanisms of G protein-coupled estrogen receptor-mediated spinal nociception. J Pain 2012, 13: 742–754. 10.1016/j.jpain.2012.05.011
Fehrenbacher JC, Loverme J, Clarke W, Hargreaves KM, Piomelli D, Taylor BK: Rapid pain modulation with nuclear receptor ligands. Brain Res Rev 2009, 60: 114–124. 10.1016/j.brainresrev.2008.12.019
Ariazi EA, Brailoiu E, Yerrum S, Shupp HA, Slifker MJ, Cunliffe HE, Black MA, Donato AL, Arterburn JB, Oprea TI, et al.: The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res 2010, 70: 1184–1194. 10.1158/0008-5472.CAN-09-3068
Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER: A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 2005, 307: 1625–1630. 10.1126/science.1106943
Kim HY, Lee KY, Lu Y, Wang J, Cui L, Kim SJ, Chung JM, Chung K: Mitochondrial Ca(2+) uptake is essential for synaptic plasticity in pain. J Neurosci 2011, 31: 12982–12991. 10.1523/JNEUROSCI.3093-11.2011
Aronica SM, Kraus WL, Katzenellenbogen BS: Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci U S A 1994, 91: 8517–8521. 10.1073/pnas.91.18.8517
Bi R, Broutman G, Foy MR, Thompson RF, Baudry M: The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci U S A 2000, 97: 3602–3607. 10.1073/pnas.97.7.3602
Cardona-Gomez GP, Mendez P, Garcia-Segura LM: 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 2002, 107: 80–88. 10.1016/S0169-328X(02)00449-7
Gu Q, Moss RL: 17 beta-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade. J Neurosci 1996, 16: 3620–3629.
Lieberherr M, Grosse B, Kachkache M, Balsan S: Cell signaling and estrogens in female rat osteoblasts: a possible involvement of unconventional nonnuclear receptors. J Bone Miner Res 1993, 8: 1365–1376.
Marino M, Pallottini V, Trentalance A: Estrogens cause rapid activation of IP3-PKC-alpha signal transduction pathway in HEPG2 cells. Biochem Biophys Res Commun 1998, 245: 254–258. 10.1006/bbrc.1998.8413
Mendoza C, Soler A, Tesarik J: Nongenomic steroid action: independent targeting of a plasma membrane calcium channel and a tyrosine kinase. Biochem Biophys Res Commun 1995, 210: 518–523. 10.1006/bbrc.1995.1690
Minami T, Oomura Y, Nabekura J, Fukuda A: 17 beta-estradiol depolarization of hypothalamic neurons is mediated by cyclic AMP. Brain Res 1990, 519: 301–307. 10.1016/0006-8993(90)90092-P
Mobbs CV, Kaplitt M, Kow LM, Pfaff DW: PLC-alpha: a common mediator of the action of estrogen and other hormones? Mol Cell Endocrinol 1991, 80: C187-C191. 10.1016/0303-7207(91)90136-G
Nabekura J, Oomura Y, Minami T, Mizuno Y, Fukuda A: Mechanism of the rapid effect of 17 beta-estradiol on medial amygdala neurons. Science 1986, 233: 226–228. 10.1126/science.3726531
Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Ronnekleiv OK, Kelly MJ: Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J Neurosci 2003, 23: 9529–9540.
Razandi M, Pedram A, Greene GL, Levin ER: Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 1999, 13: 307–319. 10.1210/me.13.2.307
Singh M, Setalo G Jr, Guan X, Warren M, Toran-Allerand CD: Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 1999, 19: 1179–1188.
Szego CM, Davis JS: Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proc Natl Acad Sci U S A 1967, 58: 1711–1718. 10.1073/pnas.58.4.1711
Toran-Allerand CD, Singh M, Setalo G Jr: Novel mechanisms of estrogen action in the brain: new players in an old story. Front Neuroendocrinol 1999, 20: 97–121. 10.1006/frne.1999.0177
Watters JJ, Campbell JS, Cunningham MJ, Krebs EG, Dorsa DM: Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology 1997, 138: 4030–4033. 10.1210/en.138.9.4030
Zhou Y, Watters JJ, Dorsa DM: Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain. Endocrinology 1996, 137: 2163–2166. 10.1210/en.137.5.2163
Cornil CA, Ball GF, Balthazart J: Functional significance of the rapid regulation of brain estrogen action: where do the estrogens come from? Brain Res 2006, 1126: 2–26. 10.1016/j.brainres.2006.07.098
Guarino G, Spampinato S: Nandrolone decreases mu opioid receptor expression in SH-SY5Y human neuroblastoma cells. Neuroreport 2008, 19: 1131–1135. 10.1097/WNR.0b013e328305639d
Financial support for the preparation of this manuscript was provided by the National Health Research Institutes (PD-102-PP-16 and NHRI-102A1-PDCO-1312141) and China Medical University Hospital (DMR-101-123 and DMR-102-029).
Only the authors listed are responsible for the content and preparation of this manuscript. The authors declare no conflict of interest.
CW-SL drafted the manuscript and reviewed the literature. I-KH designed the review topic and helped write the manuscript. Both authors read the approved the final manuscript.
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Lee, C.WS., Ho, IK. Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors. Mol Pain 9, 45 (2013). https://doi.org/10.1186/1744-8069-9-45
- Sex differences
- Opioid analgesia
- Opioid addiction
- Opioid receptors
- Estrogen receptors