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Contribution of Endogenous Spinal Endomorphin 2 to Intrathecal Opioid Antinociception in Rats Is Agonist Dependent and Sexually Dimorphic

Published:September 02, 2015DOI:https://doi.org/10.1016/j.jpain.2015.08.003

      Highlights

      • We studied contribution of spinal endomorphin to opioid analgesia in rats.
      • Mu-opioids enhance spinal endomorphin release in males but not in females.
      • Released endomorphin reduces the analgesia of high-efficacy mu-opioids.
      • Findings explain variable sex dependence of opioid antinociception.
      • Findings could inform the selection of opioid analgesics in humans.

      Abstract

      Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not in females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females did not result from either insufficient levels of testosterone or mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil's analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management but also helps to explain variable sex dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet.

      Perspective

      The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes.

      Key words

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      References

        • Alt A.
        • Mansour A.
        • Akil H.
        • Medzihradsky F.
        • Traynor J.R.
        • Woods J.H.
        Stimulation of guanosine-5′-O-(3-[35S]thio)triphosphate binding by endogenous opioids acting at a cloned mu receptor.
        J Pharmacol Exp Ther. 1998; 286: 282-288
        • 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
        • Barrett A.C.
        • Smith E.S.
        • Picker M.J.
        Sex-related differences in mechanical nociception and antinociception produced by mu- and kappa-opioid receptor agonists in rats.
        Eur J Pharmacol. 2002; 452: 163-173
        • Bartok R.E.
        • Craft R.M.
        Sex differences in opioid antinociception.
        J Pharmacol Exp Ther. 1997; 282: 769-778
        • Berkley K.J.
        Sex differences in pain.
        Behav Brain Sci. 1997; 20: 371-380
        • Bingefors K.
        • Isacson D.
        Epidemiology, co-morbidity, and impact on health-related quality of life of self-reported headache and musculoskeletal pain–a gender perspective.
        Eur J Pain. 2004; 8: 435-450
        • Boyer J.S.
        • Morgan M.M.
        • Craft R.M.
        Microinjection of morphine into the rostral ventromedial medulla produces greater antinociception in male compared to female rats.
        Brain Res. 1998; 796: 315-318
        • Bragdon E.E.
        • Light K.C.
        • Costello N.L.
        • Sigurdsson A.
        • Bunting S.
        • Bhalang K.
        • Maixner W.
        Group differences in pain modulation: pain-free women compared to pain-free men and to women with TMD.
        Pain. 2002; 96: 227-237
        • Cepeda M.S.
        • Carr D.B.
        Women experience more pain and require more morphine than men to achieve a similar degree of analgesia.
        Anesth Analg. 2003; 97: 1464-1468
        • Chakrabarti S.
        • Liu N.J.
        • Zadina J.E.
        • Sharma T.
        • Gintzler A.
        Pleiotropic opioid regulation of spinal endomorphin 2 release and its adaptations to opioid withdrawal are sexually dimorphic.
        J Pharmacol Exp Ther. 2012; 340: 56-63
        • Chen J.R.
        • Wang T.J.
        • Lim S.H.
        • Wang Y.J.
        • Tseng G.F.
        Testosterone modulation of dendritic spines of somatosensory cortical pyramidal neurons.
        Brain Struct Funct. 2013; 218: 1407-1417
        • Chesler E.J.
        • Wilson S.G.
        • Lariviere W.R.
        • Rodriguez-Zas S.L.
        • Mogil J.S.
        Influences of laboratory environment on behavior.
        Nat Neurosci. 2002; 5: 1101-1102
        • Cicero T.J.
        • Nock B.
        • Meyer E.R.
        Gender-related differences in the antinociceptive properties of morphine.
        J Pharmacol Exp Ther. 1996; 279: 767-773
        • Cicero T.J.
        • Nock B.
        • Meyer E.R.
        Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations.
        J Pharmacol Exp Ther. 1997; 282: 939-944
        • Cicero T.J.
        • Nock B.
        • O'Connor L.
        • Meyer E.R.
        Role of steroids in sex differences in morphine-induced analgesia: activational and organizational effects.
        J Pharmacol Exp Ther. 2002; 300: 695-701
        • Cook C.D.
        • Barrett A.C.
        • Roach E.L.
        • Bowman J.R.
        • Picker M.J.
        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
        • Cooke J.P.
        • Creager M.A.
        • Osmundson P.J.
        • Shepherd J.T.
        Sex differences in control of cutaneous blood flow.
        Circulation. 1990; 82: 1607-1615
        • Coyle D.E.
        • Sehlhorst C.S.
        • Behbehani M.M.
        Intact female rats are more susceptible to the development of tactile allodynia than ovariectomized female rats following partial sciatic nerve ligation (PSNL).
        Neurosci Lett. 1996; 203: 37-40
        • Coyle D.E.
        • Sehlhorst C.S.
        • Mascari C.
        Female rats are more susceptible to the development of neuropathic pain using the partial sciatic nerve ligation (PSNL) model.
        Neurosci Lett. 1995; 186: 135-138
        • Craft R.M.
        Sex differences in opioid analgesia: “from mouse to man”.
        Clin J Pain. 2003; 19: 175-186
        • Craft R.M.
        • Tseng A.H.
        • McNiel D.M.
        • Furness M.S.
        • Rice K.C.
        Receptor-selective antagonism of opioid antinociception in female versus male rats.
        Behav Pharmacol. 2001; 12: 591-602
        • Dahlof C.
        • Linde M.
        One-year prevalence of migraine in Sweden: a population-based study in adults.
        Cephalalgia. 2001; 21: 664-671
        • de Castilhos J.
        • Hermel E.E.
        • Rasia-Filho A.A.
        • Achaval M.
        Influence of substitutive ovarian steroids in the nuclear and cell body volumes of neurons in the posterodorsal medial amygdala of adult ovariectomized female rats.
        Neurosci Lett. 2010; 469: 19-23
        • De Cosmo G.
        • Congedo E.
        • Lai C.
        • Primieri P.
        • Dottarelli A.
        • Aceto P.
        Preoperative psychologic and demographic predictors of pain perception and tramadol consumption using intravenous patient-controlled analgesia.
        Clin J Pain. 2008; 24: 399-405
        • Deleu D.
        • Khan M.A.
        • Al Shehab T.A.
        Prevalence and clinical characteristics of headache in a rural community in Oman.
        Headache. 2002; 42: 963-973
        • Dubal D.B.
        • Kashon M.L.
        • Pettigrew L.C.
        • Ren J.M.
        • Finklestein S.P.
        • Rau S.W.
        • Wise P.M.
        Estradiol protects against ischemic injury.
        J Cereb Blood Flow Metab. 1998; 18: 1253-1258
        • Emmerson P.J.
        • Clark M.J.
        • Mansour A.
        • Akil H.
        • Woods J.H.
        • Medzihradsky F.
        Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor.
        J Pharmacol Exp Ther. 1996; 278: 1121-1127
        • Fillingim R.B.
        • Gear R.W.
        Sex differences in opioid analgesia: clinical and experimental findings.
        Eur J Pain. 2004; 8: 413-425
        • Fillingim R.B.
        • King C.D.
        • Ribeiro-Dasilva M.C.
        • Rahim-Williams B.
        • Riley 3rd, J.L.
        Sex, gender, and pain: a review of recent clinical and experimental findings.
        J Pain. 2009; 10: 447-485
        • Fillingim R.B.
        • Maixner W.
        • Kincaid S.
        • Silva S.
        Sex differences in temporal summation but not sensory-discriminative processing of thermal pain.
        Pain. 1998; 75: 121-127
        • Fillingim R.B.
        • Ness T.J.
        • Glover T.L.
        • Campbell C.M.
        • Hastie B.A.
        • Price D.D.
        • Staud R.
        Morphine responses and experimental pain: sex differences in side effects and cardiovascular responses but not analgesia.
        J Pain. 2005; 6: 116-124
        • Gagliese L.
        • Gauthier L.R.
        • Macpherson A.K.
        • Jovellanos M.
        • Chan V.W.
        Correlates of postoperative pain and intravenous patient-controlled analgesia use in younger and older surgical patients.
        Pain Med. 2008; 9: 299-314
        • Gerdle B.
        • Bjork J.
        • Henriksson C.
        • Bengtsson A.
        Prevalence of current and chronic pain and their influences upon work and healthcare-seeking: a population study.
        J Rheumatol. 2004; 31: 1399-1406
        • Gintzler A.R.
        • Xu H.
        Different G proteins mediate the opioid inhibition or enhancement of evoked [5-methionine]enkephalin release.
        Proc Natl Acad Sci U S A. 1991; 88: 4741-4745
        • Gonzales J.M.
        Anesthetic barbiturates enhance Gs alpha-dependent cyclic AMP production in S49 mouse lymphoma cells.
        J Neurochem. 1995; 64: 2559-2566
        • Gupta D.S.
        • vonGizycki H.
        • Gintzler A.R.
        Sex-/ovarian steroid-dependent release of endomorphin 2 from spinal cord.
        J Pharmacol Exp Ther. 2007; 321: 635-641
        • Guyton A.
        • Hall J.E.
        Guyton and Hall Textbook of Medical Physiology.
        12th ed. Saunders, Philadelphia, PA2010
        • Hirasawa M.
        • Hasegawa J.
        • Nishiyama J.
        • Suzuki T.
        Utilization of PCIA (patient-controlled intravenous analgesia) for postoperative analgesia of spine fusion.
        Tokai J Exp Clin Med. 2003; 28: 17-20
        • Hosohata K.
        • Burkey T.H.
        • Alfaro-Lopez J.
        • Varga E.
        • Hruby V.J.
        • Roeske W.R.
        • Yamamura H.I.
        Endomorphin-1 and endomorphin-2 are partial agonists at the human mu-opioid receptor.
        Eur J Pharmacol. 1998; 346: 111-114
        • Humar M.
        • Andriopoulos N.
        • Pischke S.E.
        • Loop T.
        • Schmidt R.
        • Hoetzel A.
        • Roesslein M.
        • Pahl H.L.
        • Geiger K.K.
        • Pannen B.H.
        Inhibition of activator protein 1 by barbiturates is mediated by differential effects on mitogen-activated protein kinases and the small G proteins ras and rac-1.
        J Pharmacol Exp Ther. 2004; 311: 1232-1240
        • Ihlebaek C.
        • Hansson T.H.
        • Laerum E.
        • Brage S.
        • Eriksen H.R.
        • Holm S.H.
        • Svendsrod R.
        • Indahl A.
        Prevalence of low back pain and sickness absence: a “borderline” study in Norway and Sweden.
        Scand J Public Health. 2006; 34: 555-558
        • Ji Y.
        • Murphy A.Z.
        • Traub R.J.
        Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated.
        Am J Physiol Regul Integr Comp Physiol. 2006; 291: R307-R314
        • Jinks C.
        • Jordan K.
        • Croft P.
        Measuring the population impact of knee pain and disability with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
        Pain. 2002; 100: 55-64
        • Joels C.S.
        • Mostafa G.
        • Matthews B.D.
        • Kercher K.W.
        • Sing R.F.
        • Norton H.J.
        • Heniford B.T.
        Factors affecting intravenous analgesic requirements after colectomy.
        J Am Coll Surg. 2003; 197: 780-785
        • Kaiko R.F.
        • Wallenstein S.L.
        • Rogers A.G.
        • Houde R.W.
        Sources of variation in analgesic responses in cancer patients with chronic pain receiving morphine.
        Pain. 1983; 15: 191-200
        • Kayser V.
        • Berkley K.J.
        • Keita H.
        • Gautron M.
        • Guilbaud G.
        Estrous and sex variations in vocalization thresholds to hindpaw and tail pressure stimulation in the rat.
        Brain Res. 1996; 742: 352-354
        • King C.D.
        • Wong F.
        • Currie T.
        • Mauderli A.P.
        • Fillingim R.B.
        • Riley 3rd, J.L.
        Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder.
        Pain. 2009; 143: 172-178
        • Krzanowska E.K.
        • Bodnar R.J.
        Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats.
        Brain Res. 1999; 821: 224-230
        • Krzanowska E.K.
        • Ogawa S.
        • Pfaff D.W.
        • Bodnar R.J.
        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
        • Lee Y.C.
        • Wang H.P.
        • Chiu H.M.
        • Lin C.P.
        • Huang S.P.
        • Lai Y.P.
        • Wu M.S.
        • Chen M.F.
        • Lin J.T.
        Factors determining post-colonoscopy abdominal pain: prospective study of screening colonoscopy in 1000 subjects.
        J Gastroenterol Hepatol. 2006; 21: 1575-1580
        • Li Z.
        • Duckles S.P.
        Influence of gender on vascular reactivity in the rat.
        J Pharmacol Exp Ther. 1994; 268: 1426-1431
        • Li Z.
        • Krause D.N.
        • Doolen S.
        • Duckles S.P.
        Ovariectomy eliminates sex differences in rat tail artery response to adrenergic nerve stimulation.
        Am J Physiol. 1997; 272: H1819-H1825
        • Liem M.S.
        • van Duyn E.B.
        • van der Graaf Y.
        • van Vroonhoven T.J.
        • Coala Trial G
        Recurrences after conventional anterior and laparoscopic inguinal hernia repair: a randomized comparison.
        Ann Surg. 2003; 237: 136-141
        • Lipton R.B.
        • Stewart W.F.
        • Diamond S.
        • Diamond M.L.
        • Reed M.
        Prevalence and burden of migraine in the United States: data from the American Migraine Study II.
        Headache. 2001; 41: 646-657
        • Liu N.J.
        • Gintzler A.R.
        Prolonged ovarian sex steroid treatment of male rats produces antinociception: identification of sex-based divergent analgesic mechanisms.
        Pain. 2000; 85: 273-281
        • Liu N.J.
        • Gintzler A.R.
        Spinal endomorphin 2 antinociception and the mechanisms that produce it are both sex- and stage of estrus cycle-dependent in rats.
        J Pain. 2013; 14: 1522-1530
        • Liu N.J.
        • Schnell S.
        • Wessendorf M.W.
        • Gintzler A.R.
        Sex, pain and opioids: inter-dependent influences of sex and pain modality on dynorphin-mediated antinociception in rats.
        J Pharmacol Exp Ther. 2013; 344: 522-530
        • Liu N.J.
        • Schnell S.A.
        • Schulz S.
        • Wessendorf M.W.
        • Gintzler A.R.
        Regulation of spinal dynorphin 1-17 release by endogenous pituitary adenylyl cyclase-activating polypeptide in the male rat: relevance of excitation via disinhibition.
        J Pharmacol Exp Ther. 2011; 336: 328-335
        • Liu N.J.
        • von Gizycki H.
        • Gintzler A.R.
        Sexually dimorphic recruitment of spinal opioid analgesic pathways by the spinal application of morphine.
        J Pharmacol Exp Ther. 2007; 322: 654-660
        • Loyd D.R.
        • Morgan M.M.
        • Murphy A.Z.
        Morphine preferentially activates the periaqueductal gray-rostral ventromedial medullary pathway in the male rat: a potential mechanism for sex differences in antinociception.
        Neuroscience. 2007; 147: 456-468
        • Loyd D.R.
        • Murphy A.Z.
        The neuroanatomy of sexual dimorphism in opioid analgesia.
        Exp Neurol. 2014; 259: 57-63
        • Madia P.A.
        • Navani D.M.
        • Yoburn B.C.
        [(35)S]GTPgammaS binding and opioid tolerance and efficacy in mouse spinal cord.
        Pharmacol Biochem Behav. 2012; 101: 155-165
        • Marks H.E.
        • Hobbs S.H.
        Changes in stimulus reactivity following gonadectomy in male and female rats of different ages.
        Physiol Behav. 1972; 8: 1113-1119
        • Martin-Schild S.
        • Gerall A.A.
        • Kastin A.J.
        • Zadina J.E.
        Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent.
        J Comp Neurol. 1999; 405: 450-471
        • Meyer P.J.
        • Fossum E.N.
        • Ingram S.L.
        • Morgan M.M.
        Analgesic tolerance to microinjection of the micro-opioid agonist DAMGO into the ventrolateral periaqueductal gray.
        Neuropharmacology. 2007; 52: 1580-1585
        • Mogil J.S.
        • Chanda M.L.
        The case for the inclusion of female subjects in basic science studies of pain.
        Pain. 2005; 117: 1-5
        • Mogil J.S.
        • Sternberg W.F.
        • Kest B.
        • Marek P.
        • Liebeskind J.C.
        Sex differences in the antagonism of swim stress-induced analgesia: effects of gonadectomy and estrogen replacement.
        Pain. 1993; 53: 17-25
        • Moguilewsky M.
        • Bouton M.M.
        How the study of the biological activities of antiandrogens can be oriented towards the clinic.
        J Steroid Biochem. 1988; 31: 699-710
        • Nayebi A.R.
        • Ahmadiani A.
        Involvement of the spinal serotonergic system in analgesia produced by castration.
        Pharmacol Biochem Behav. 1999; 64: 467-471
        • Nelson N.R.
        • Bird I.M.
        • Behan M.
        Testosterone restores respiratory long term facilitation in old male rats by an aromatase-dependent mechanism.
        J Physiol. 2011; 589: 409-421
        • Neri R.
        • Florance K.
        • Koziol P.
        • Van Cleave S.
        A biological profile of a nonsteroidal antiandrogen, SCH 13521 (4′-nitro-3′-trifluoromethylisobutyranilide).
        Endocrinology. 1972; 91: 427-437
        • Nielsen C.S.
        • Stubhaug A.
        • Price D.D.
        • Vassend O.
        • Czajkowski N.
        • Harris J.R.
        Individual differences in pain sensitivity: genetic and environmental contributions.
        Pain. 2008; 136: 21-29
        • Peckham E.M.
        • Barkley L.M.
        • Divin M.F.
        • Cicero T.J.
        • Traynor J.R.
        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
        • Peckham E.M.
        • Traynor J.R.
        Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats.
        J Pharmacol Exp Ther. 2006; 316: 1195-1201
        • Peng X.
        • Knapp B.I.
        • Bidlack J.M.
        • Neumeyer J.L.
        Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors.
        J Med Chem. 2007; 50: 2254-2258
        • Phoenix C.H.
        • Goy R.W.
        • Gerall A.A.
        • Young W.C.
        Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig.
        Endocrinology. 1959; 65: 369-382
        • Ritter M.A.
        • Wing J.T.
        • Berend M.E.
        • Davis K.E.
        • Meding J.B.
        The clinical effect of gender on outcome of total knee arthroplasty.
        J Arthroplasty. 2008; 23: 331-336
        • Robinson-White A.
        Mechanisms of action of anesthetics on inositol phospholipid hydrolysis in vascular endothelial cells and rat basophilic leukemia cells in tissue culture.
        Adv Exp Med Biol. 1991; 301: 271-287
        • Rollman G.B.
        • Lautenbacher S.
        Sex differences in musculoskeletal pain.
        Clin J Pain. 2001; 17: 20-24
        • Rosseland L.A.
        • Solheim N.
        • Stubhaug A.
        Pain and disability 1 year after knee arthroscopic procedures.
        Acta Anaesthesiol Scand. 2008; 52: 332-337
        • Sarton E.
        • Olofsen E.
        • Romberg R.
        • den Hartigh J.
        • Kest B.
        • Nieuwenhuijs D.
        • Burm A.
        • Teppema L.
        • Dahan A.
        Sex differences in morphine analgesia: an experimental study in healthy volunteers.
        Anesthesiology. 2000; 93 (discussion 1246A): 1245-1254
        • Soignier R.D.
        • Vaccarino A.L.
        • Brennan A.M.
        • Kastin A.J.
        • Zadina J.E.
        Analgesic effects of endomorphin-1 and endomorphin-2 in the formalin test in mice.
        Life Sci. 2000; 67: 907-912
        • Stevens C.W.
        • Lacey C.B.
        • Miller K.E.
        • Elde R.P.
        • Seybold V.S.
        Biochemical characterization and regional quantification of mu, delta and kappa opioid binding sites in rat spinal cord.
        Brain Res. 1991; 550: 77-85
        • Sufrin G.
        • Coffey D.S.
        Flutamide. Mechanism of action of a new nonsteroidal antiandrogen.
        Invest Urol. 1976; 13: 429-434
        • Tague S.E.
        • Smith P.G.
        Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: modulation by ovarian hormones.
        J Chem Neuroanat. 2011; 41: 1-12
        • Takeshima T.
        • Ishizaki K.
        • Fukuhara Y.
        • Ijiri T.
        • Kusumi M.
        • Wakutani Y.
        • Mori M.
        • Kawashima M.
        • Kowa H.
        • Adachi Y.
        • Urakami K.
        • Nakashima K.
        Population-based door-to-door survey of migraine in Japan: the Daisen study.
        Headache. 2004; 44: 8-19
        • Thomas E.
        • Silman A.J.
        • Croft P.R.
        • Papageorgiou A.C.
        • Jayson M.I.
        • Macfarlane G.J.
        Predicting who develops chronic low back pain in primary care: a prospective study.
        BMJ. 1999; 318: 1662-1667
        • Thornton S.R.
        • Smith F.L.
        Characterization of neonatal rat fentanyl tolerance and dependence.
        J Pharmacol Exp Ther. 1997; 281: 514-521
        • Tsang A.
        • Von Korff M.
        • Lee S.
        • Alonso J.
        • Karam E.
        • Angermeyer M.C.
        • Borges G.L.
        • Bromet E.J.
        • Demytteneare K.
        • de Girolamo G.
        • de Graaf R.
        • Gureje O.
        • Lepine J.P.
        • Haro J.M.
        • Levinson D.
        • Oakley Browne M.A.
        • Posada-Villa J.
        • Seedat S.
        • Watanabe M.
        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
        • Unruh A.M.
        Gender variations in clinical pain experience.
        Pain. 1996; 65: 123-167
        • Verzillo V.
        • Madia P.A.
        • Liu N.J.
        • Chakrabarti S.
        • Gintzler A.R.
        Mu-opioid receptor splice variants: sex-dependent regulation by chronic morphine.
        J Neurochem. 2014; 130: 790-796
        • Vierck C.J.
        • Acosta-Rua A.J.
        • Rossi H.L.
        • Neubert J.K.
        Sex differences in thermal pain sensitivity and sympathetic reactivity for 2 strains of rat.
        J Pain. 2008; 9: 739-749
        • Von Korff M.
        • Crane P.
        • Lane M.
        • Miglioretti D.L.
        • Simon G.
        • Saunders K.
        • Stang P.
        • Brandenburg N.
        • Kessler R.
        Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication.
        Pain. 2005; 113: 331-339
        • Walker J.S.
        • Carmody J.J.
        Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen.
        Anesth Analg. 1998; 86: 1257-1262
        • Wang L.
        • Gintzler A.R.
        Bimodal opioid regulation of cAMP formation: implications for positive and negative coupling of opiate receptors to adenylyl cyclase.
        J Neurochem. 1994; 63: 1726-1730
        • Wang X.
        • Traub R.J.
        • Murphy A.Z.
        Persistent pain model reveals sex difference in morphine potency.
        Am J Physiol Regul Integr Comp Physiol. 2006; 291: R300-R306
        • Wijnhoven H.A.
        • de Vet H.C.
        • Picavet H.S.
        Prevalence of musculoskeletal disorders is systematically higher in women than in men.
        Clin J Pain. 2006; 22: 717-724
        • Xu H.
        • Gintzler A.R.
        Opioid enhancement of evoked [Met5]enkephalin release requires activation of cholinergic receptors: possible involvement of intracellular calcium.
        Proc Natl Acad Sci U S A. 1992; 89: 1978-1982
        • Xu H.
        • Smolens I.
        • Gintzler A.R.
        Opioids can enhance and inhibit the electrically evoked release of methionine-enkephalin.
        Brain Res. 1989; 504: 36-42
        • Yunus M.B.
        Gender differences in fibromyalgia and other related syndromes.
        J Gend Specif Med. 2002; 5: 42-47
        • Zabka A.G.
        • Mitchell G.S.
        • Behan M.
        Conversion from testosterone to oestradiol is required to modulate respiratory long-term facilitation in male rats.
        J Physiol. 2006; 576: 903-912
        • Zadina J.E.
        • Hackler L.
        • Ge L.J.
        • Kastin A.J.
        A potent and selective endogenous agonist for the mu-opiate receptor.
        Nature. 1997; 386 ([see comments]): 499-502
        • Zhu J.
        • Xue J.C.
        • Law P.Y.
        • Claude P.A.
        • Luo L.Y.
        • Yin J.
        • Chen C.
        • Liu-Chen L.Y.
        The region in the mu opioid receptor conferring selectivity for sufentanil over the delta receptor is different from that over the kappa receptor.
        FEBS Lett. 1996; 384: 198-202
        • Zubieta J.K.
        • Smith Y.R.
        • Bueller J.A.
        • Xu Y.
        • Kilbourn M.R.
        • Jewett D.M.
        • Meyer C.R.
        • Koeppe R.A.
        • Stohler C.S.
        mu-opioid receptor-mediated antinociceptive responses differ in men and women.
        J Neurosci. 2002; 22: 5100-5107