Posted on Authorea 2 Oct 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160167496.62768848 | This a preprint and has not been peer reviewed. Data may be preliminary. ...HmnStudies Human 2.1.1. reward. 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All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160167496.62768848 | This a preprint and has not been peer reviewed. 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women use 2020). to example, al., likely substance NIDA, more a et 2012; also have Green al., are and Women 2020; et 2020). abuse (NIDA, Darnell Perotti, opioid & men 2003; for from Kokane than Carr, suffer criteria by to diagnostic opioids & review likely may meet prescription Cepeda more findings to to are 2009; These likely and attributed al., 2020). more pain opioids, et al., also bodily prescribed (Fillingim et general are be (Schieber more Women men to report men than likely et women than (Bawor more disorders that filled are opioids observation pain 2020), prescriptions prescription the Perotti, opioid with to & have 2011; related experience Kokane to al., be opioid 2013; et likely Ho, first 2011; (Back more & al., their opioids are in Lee et have prescription by and heroin Back to use reviews 2010; use likely to see al., heroin, more likely et 2015a; use are more (Back al., to women are 2009), likely than women sex al., more time contrast, notable et overdose are of In also Green men of period are 2018 2020). instance, risk longer There NIDA, For in a the 2016; 2020). for opioids. overdose, States Kuhn, al., heroin illicit opioid et use United vs. an (Lopresti and licit quantities, the 2000 experience of larger since to in use men likely the overdoses than more in women d 2 Posted on Authorea 2 Oct 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160167496.62768848 | This a preprint and has not been peer reviewed. Data may be preliminary. diitrdvaspapnlta pnlo eihrlrue seCat 08 aa ta. 08 onr& are Bodnar opioids 2008; when al., therapeutic apparent et a more Dahan are 2008; across Craft, differences males (see These in routes antinociceptive peripheral 2010). efficacy or greater Kest, and/or spinal in & produce than potency sensitivity Bodnar supraspinal agonists greater via 2008; nociceptive opioid by administered Craft, models, baseline evidenced (See these greater females, range In exhibit than dose males 2020). animals in (Mogil, female effects pain humans, of with models observed 2004). preclinical Beckham, that & opioid to Zacny to 2004; Similar sensitive al., more differences et are sex Studies (Fillingim men measuring measures Animal that studies pain Fillingim 2.2.2. report Laboratory all) 2004; generally not 2004). al., (but but Beckham, et some equivocal, & (Al’Absi lower on more have Zacny measures analgesia women are 2005; Similarly, pain analgesia al., laboratory 2002). opioid-induced Niesters pain et al., on in et alleviate 2020; Fillingim men Chia to Mogil, 2004; see than morphine al., but 2014; tolerances more Murphy, 2003; et pain significantly Carr, & and & require Loyd in Cepeda thresholds and 2013; analgesia 2005; several pain pain al., Ho, and opioid more et 2020), & to (Aubrun report men Mogil, Lee sensitivity women than Clinically, 2019; 2009; and Afify, 2010;). sensitivity al., & al., et pain Rasakham Nasser et 2010; Fillingim in 2014; al., Murphy, 2008; differences et analgesia/antinociception & (Craft, sex Niesters opioid Loyd 2010; humans addressed Kest, 2013; in specifically & Ho, differences have Bodnar & 2009; sex reviews Lee al., on et 2011; Fillingim published Liu-Chen, 2008; & been al., et have Dahan reviews 2008; excellent (Craft, of number A Studies Human et (Craft 2.2.1. females Analgesia/Antinociception and Opioid-Induced males and opioid-induced Pain between the equivalent in 2.2 if functionally 2002a). differences especially al., not sensitivity, sex et opioid is tolerance, Cicero acute 2008). administration opioid-induced see in al., chronic but differences al., in for 2009; sex et differences chosen al., consideration (Craft sex into dose et take shakes to Sagedhi must 2008; wet-dog regard dependence Rezazadeh, and in physical & jumping, above Nayebi with- 2005; naloxone-precipitated loss, noted severe 2001, weight As more al., greater display withdrawal et (Cicero also including Diaz species earlier rodents 1999; females, across Male and vary than spontaneous 2006). symptoms scores, undergoing symptoms Contarino, withdrawal withdrawal & rodents drawal of Papelo Male higher duration 2002a; the 2010). al., loss, although re- et Kest, weight females, (see & to greater withdrawal Bodnar compared exhibit and 2016; this symptoms dependence Koob, morphine Supporting physical & from Becker opioid-induced 2008). withdrawal 2008; for al., Craft, reported 2001). by et been al., views have et (Dahan females, (Barrett differences females functionally in chronically sex when than are than administered tolerance Similar males males are males opioid-induced in If drug of in greater a degrees functionally 2.2.2). dose comparable of is Section a demonstrate doses that dose rats (see equivalent that that at female basis meaning if and greater mg/kg and opioids, male be a opioid, of notion, an on will effects of acute females antinociceptive tolerance dose the than acute given then to males a sensitivity the in to in to sensitive greater differences sensitive more sex functionally more to is are part, dose Males in given relative due, opioids. males be may of in 2001). tolerance development effects al., tolerance opioid-induced tolerance et which in of (South differences to rate females but Sex extent testosterone-treated the 2007; the and reduces al., in males castration et For differences intact Mousavi and hormones. sex both 2001; gonadal 2007), abolishes to by al., al., part, females et 1984; in et and Barrett George, mediated, (Mousavi 1999; are males & develops differences al., both Kasson sex et 2005; These of (Craft Wala, gonadectomy females. extent & than instance, greater 2004) (Holtman al., a rate et to faster Holtman and see a 2001) at al., differences tolerance sex et Furthermore, kappa develop consistent South which rats of in Male effects areas tests. additional rate-suppressing observed. two substitution are are the dependence in to physical observed and females tolerance not Opioid-induced than are 1998b). males differences al., sex in et agonists, potent (Craft mu agonists more with seen are that agonists unlike kappa and females, 3 Posted on Authorea 2 Oct 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160167496.62768848 | This a preprint and has not been peer reviewed. 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All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160167496.62768848 | This a preprint and has not been peer reviewed. Data may be preliminary. et eetr nC3prmdlclso h ipcmu,btti ffc sas eedn nteestrous the on dependent also is effect this of but sex concentrations cases, hippocampus, greater these the exhibit of Females of cycle. both cells et estrous In pyramidal (Williams the 2002). 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All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160167496.62768848 | This a preprint and has not been peer reviewed. Data may be preliminary. h podatgns ateoebok h enocn ffcso etseoei natml ases(Peters hamsters male intact with in positive shell pretreatment testosterone the accumbens that Importantly, of given nucleus 1999). effects activity, reinforcing al., the et opioid the et into blocks endogenous Arnedo (King naltrexone injections by area 1994; antagonist mediated preoptic site-specific opioid al., are medial the or or testosterone et 1996) 1997) of (Alexander al., al., place effects et reinforcing injections et Packard conditioned 2002; Caladrone systemic a al., see its either et produces of (Frye but following Testosterone doses 2002; rodents high) 2006). 2000, male not al., Wood, (but intact self-administer & low in also circulating (DiMeo and preference will that (DHT), estradiol suggesting hamsters dihydrotestosterone metabolite, 2004), testosterone, Male antiandrogenic Wood, of self-administration. & metabolite intact testosterone (DiMeo androgenic in to the hamsters testosterone sensitivity male of intake increase intraventricular castrated infusions increases intraventricular androgens in replacement of Testosterone and testosterone infusions 2004). 2004) intravenous exogenous Wood, by al., & of maintained (Peters et hamsters reliably (Wood female be and rats can male male Intact choice poking two-bottle intact nose models. a Similarly, in in preclinical vehicle 2001). testosterone than Wood, in testosterone & oral effects (Johnson of rewarding amounts test greater conditioned self-administer reliably and hamsters reinforcing male positive produces 1999). liability Testosterone al., abuse men. et the in Kindlundh true enhance 1996; with particularly mutually al., Animals be may concurrently et 3.1.2 may AAS McBride and 2010; this and 2009; to and Rane, (G˚arevik al., agonists another, & abuse prior et opioid one Skarberg AAS that occurs of 2009a; 2014; to suggest also al., al., susceptibility findings et use et increases such addiction Ranjan Collectively, Kanayama Opioid also opioid 1999; of use 2005; 2003). al., risk et opioid Currier, al., the Wines that & increases et suggesting (Trenton abuse Kanayama abuse, AAS use 2018; that AAS et AAS conclude al., admission Kanayama to of between et investigators 2009; relationship history leading (Kanayama al., a 2014), prior et reported al., to a Skarberg have et precursor studies 2003; and Ranjan a several al., treatment often Indeed, et is opioid 2009b). abuse (Kanayama al., for AAS opioids et humans, particularly Kanayama females In 2009a; to drugs, 2008). compared al., Wood, other (AAS) 2018; of steroids al., abuse anabolic et androgenic the Kanayama abuse 2010; and al., use et to (Kanayama likely more significantly are Males Humans 3.1.1 Outcomes Abuse-Related Chang, of Effects 3.1 phase Harris, Opioid-Related the 2007; of account al., into Control et available. take Androgenic Drake are should 3. 2011; sensitivity data these opioid those al., in when that et differences cycle Williams evidence 2000; sex estrous 2008; Given al., of Murphy, the et fashion. determinations & Bradshaw 2004), Wang, cyclic (e.g., Drake, Loyd, a the consequences In & 2003; functional of in sexes. al., have course differences both concentrations et the sex receptor in Flores over and eliminating hormones significantly peptide vary then gonadal fluctuate in receptors and by variations receptors opioid creating regulation and and dynamic cycle, peptides of under estrous peptides endogenous concentrations are Importantly, of opioid stage. proteins concentrations in developmental females, and differences and regarding peptides age that known various across reveal vary is these section and Less region 2004). this neuroanatomical al., in across et described both Harris forebrain. in studies 2007; the increasing al., The within and et with receptors (Drake proestrus cycle, kappa estrus during estrous in cord during the (Kren, differences on spinal medulla males sex dependent the and of to highly within cord compared concentrations are increasing spinal differences midbrain) females higher the These necessarily in significantly 2007). not density al., have (but receptor et kappa hindbrain rats Drake and 2008; female Welch, cord & that spinal Haller, suggest the in data memory 2016). receptors available and kappa al., learning the et in (Mazid limited, differences stressors sex Although delta of for alter types implications stress different has chronic to which and response fashion, acute dimorphic further, in sexually matters a Complicating in proestrus. receptors during apparent only and cycle 6 Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. 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Data may be preliminary. steeidct htadoescnitrc ihfcossc sseis podrcpo utp,and subtype, receptor opioid species, such as Findings such the 2005). factors reduces al., testosterone with processes. et antinociceptive and (Stoffel interact opioid-mediated 2016), rats can influence al., male to androgens et gonadectomized assay that Tsutsui behavioral in effects 2003; indicate agonist decreases antinociceptive al., these delta androgen-induced the et as a of (Philipova reduce of rats reports not DHT effects male isolated does and antinociceptive intact by also nandrolone in treatment complicated example, Testosterone morphine also For 1998). of ovariectomy is following al., antinociception. picture monkeys et opioid-mediated female The monkeys (Cook in in 2002). male opioids sheep Mello, in mixed-action in or & morphine kappa, agonist (Negus of mu, kappa effects effects a antinociceptive 2003), antinociceptive (C´el´erier or the al., the mice alter 2001) testosterone receptor et alter male by al., androgen not in or et the does morphine 1999) to (Negus treatment of Bodnar, exposure testosterone effects & chronic Krzanowska chronic antinociceptive nor 1989; and the acute al., influences neither 1996; et Similarly, al., nandrolone, Kepler et 2011). agonist, (Cicero in 1993; al., castration al., studies by et multiple et altered (Peckham not Islam instance, replacement are For 2002b; several morphine sensitivity. al., are of opioid effects et antinociception antinociceptive on Cicero opioid-mediated the testosterone manipulation that in androgen report increases androgens rats of finasteride of male effect Finally, role no the 2007). reporting of Ahmadiani, 2006). follow- studies & understanding rats al., (Verdi across clear male Moreover, et morphine observed a adult of Sumner 2005). Complicating are in effects al., 2005; effects antinociceptive agonists et the these 2003, kappa decreases Stoffel enhances and and al., castration 2002; and mu rats, al., et instance, concentrations both et adult (Stoffel For Terner of in castration 2015; effects agonists rats. ing al., antinociceptive kappa et adult the (Bai and increases in assays mu testosterone reported behavioral previously of and been described range strains antinociception have wide different et opioid effects Krzanowska a in 2002b, Similar to differences al., sex sensitivity et 2.2.2). of (Cicero magnitude neonatal Section adulthood in the (See in treatment reducing testosterone morphine thereby addition, androgens of nocicep- 2002), In that effects inflammation-related al., 2002). suggest antinociceptive and al., thermal data the et both of increases Krzanowska in 2006; abundance females Fuchs, rats an & male but (Borzan adult decreases assays in 2020), castration tive morphine neonatal Afify; of et instance, & effects For Craft antinociceptive Nasser by conditions. the and reviews many under (see 2008; antinociception equivocal opioid-mediated al. somewhat increase et are Dahan antinociception opioid-induced 2004; on al., androgens 2019). thresholds of nociceptive al., effects on et The swimming testosterone (Sharma Finally, of administration. opioids effects testosterone 2005). endogenous by the 2004, by enhanced that Frye, mediated is suggesting & is effect effect, (Edinger this this rats and blocks male rats, naloxone Importantly, castrated castrated that in in evidence thresholds stimuli intrahippocampal also nociceptive thermal is increases that to There given response 2004). mediated, of in 3 al., centrally olds effects or et DHT, are the testosterone, (Aloisi thresholds that of dependent nociceptive administration suggesting sex in females, not stimuli increases & are in mechanical androgen-induced (Borzan processes licking to testosterone nociceptive formalin-induced with response on reduces treated in androgens also rats thresholds Testosterone castrated nociceptive 2006). to Mulgaonker, lower Fuchs, relative & have Pednekar inflammation 2006; rats carrageenan-induced Fuchs, male following & electrical (Borzan castrated and replacement thermal Moreover, testosterone to response given 1994). nociceptive in rats in thresholds involved castrated nociceptive are lower than have activity stimuli adults androgenic as and but castrated testosterone rats 2006), Male that processes. al., evidence ample et yield are Daniell populations. studies There 2011; Preclinical heterogenous 2009). al., and sizes Zylicz, et sample Studies & Aloisi small Animal Roantree 2015; by 3.2.2. 2017; al., to limited al., et relative is Basaria et literature therapy (e.g., (Raheem that replacement of findings population testosterone much these control of to a initiation typically exceptions to the hypogonadism several and upon with men baseline analgesics instance, own For opioid opioid use. their of for of intake frequency need or their the dose decreases reduce in generally reductions treatment for testosterone allowing sensitivity, α- nrsaeil( H eaoie nrae oietv thresh- nociceptive increases metabolite) DHT (a androstanediol 8 Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. ay n h eritreit oeo h iutr Hn ta. 92 ergi ta. 92.Confirming 1982). al., et Petraglia 1982; al., et (Hong pituitary pitui- the anterior pituitary, of In whole lobe examined. plasma, neurointermediate region in the beta-endorphin the beta-endorphin and increases tary, decreases on consistently castration activity depend androgenic instance, pituitary, concentrations For and concentrations. beta-endorphin plasma in on particularly androgens regions, many of literature. effects existing qualitative the from The evident effects are These patterns 2008). Wood, general Beta-endorphin 2015; some al., 3.4.1.1 peptides but et opioid Mhillaj loci, of 2012; neuroanatomical Hallberg, concentrations across & the vary Nyberg influence see often review, androgens (for exogenous receptors opioid of and administration and castration Both Peptides Opioid 3.4.1 Receptors and Peptides 2019). dopamine Opioid al., (Vel´asquez morphine-induced 3.4 et adulthood rats receptors, testos- in opioid female of preference mu or dose place of male conditioned bolus expression either morphine-induced responses single the in or opioid-mediated a alter effects, on that not locomotor given androgens does morphine-induced effects, of 1 the release, developmental day effects antagonize than postnatal the functionally rather on can of activational terone androgens Some to that Chronic conditions. attributed suggesting 2000). some be 2000), al., under can al., et opioids et Harlan mu (Harlan 2001; of putamen al, effects caudate et the increase morphine-induced D’Souza acutely in decreases (e.g., agonists on significantly regions opioid androgens brain mu exogenous multiple rats, with in male treatment expression intact gene In JunB 2008). al., and et Endoge- (Ahanagar antinociception. treatment opioid-induced testosterone in differences GIRK sex in for decreases of GIRK responsible effector increase partly post-synaptic androgens least primary at nous the are without are 2006). and (GIRKs) or al., opioids channels (with mu et potassium castration (Craft rectifying and inwardly activity 2014), protein-coupled locomotor Wood, G morphine-induced & activity alter Cooper locomotor not 2003; (C´el´erier does morphine-induced al., mice replacement) alter et and testosterone not rats mice do male male both androgens intact Moreover, intact in exogenous in 2004). Woods, hypothermia contrast, morphine-induced & In increases (Peters these nandrolone 2003). naltrexone and (C´el´erier exposure of antagonist, hamsters, al., administration receptor Repeated male et chronic opioid AAS 2006). in and the from activity Wood, acute by lethality locomotor 2004; blocked and and Woods, be 2004), temperature, can & Woods, effects body (Peters & respiration, heroin (Peters decreases and weeks testosterone two morphine to as of resulting little that as mortality resembles in overdoses significant depression produces autonomic examined. testosterone severe endpoints intracerebroventricular from disparate effects. of the opioid-mediated across self-administration unconditioned consistency 2015b; Chronic influence little al., been report androgens et has Bawor research studies exogenous less available 2019; comparatively and few al., contrast, endogenous The In et 2019). AminiLari both long-term Ho, by 1999; on in reviews al., hypogonadism conducted et (see relevant Yilmaz agonists 2016; clinically Wosnitzer, mu to & recreational O’Rourke leading and males, medicinal identify in of activity 2011). Opioids users to androgenic al., of failing decreases et Effects Peckham use studies Unconditioned 1986; Opioid Indeed, on al., Androgens et identify 2002). to Kepler of al., fail Terner 1996; Effects often al., 2005; et and 3.3. et common 2003, administration Krzanoskwa less Cicero al., testosterone much 2002b; (e.g., are et neonatal mechanism sensitivity al., Stoffel via opioid alternative in 2015; females et an differences of al., sex Cicero masculinization et of mechanisms 2005; by (Bai neonatal androgenic or al., by adult males, eliminated or et of completely 2002) (Cataldo castration or al., 2002) partially et al., are Krzanoskwa antinociception. sex females et 2002b; opioid-induced and linking al., of males studies et between modulation within (Cicero differences androgenic correspondence sex strong to instance, a antinociception For is opioid-induced there in findings, differences contradictory seemingly these Despite 2 xrsinfloigcsrto;hwvr hs ffcscno ervre yexogenous by reversed be cannot effects these however, castration; following expression 2 eeepeso ntebanadsia odi aert seiecdby evidenced as rats male in cord spinal and brain the in expression gene 9 c-fos n uBgn expressi- gene JunB and c-fos Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. es o xml,crncnnrln diitainsgicnl erae C ocnrtosi regions andro- in by concentrations control DCE regulatory the decreases under of significantly are cleavage administration concentrations nandrolone via DCE chronic and enkephalins example, 1992), into modulations For al., gens. androgen-induced dynorphins et by transforms (Silberring part, DCE peptide in dynorphin (DCE). explained, enzyme be dynorphin-converting may 2008). in dynorphin al., in et Triemstra Birgner modulations (cf., 2009; Androgen-induced mixed al., is theoreti- et possibility should Silva this dynorphin 2007; for in al., evidence nucleus however, reductions moti- et concentrations; the in androgen-induced dopamine in accumbens involved accumbal and activity nucleus structure increase 2013), dopaminergic cally critical The Carlezon, inhibits a 2000b). & Dynorphin is (Muschamp addiction. al., and and accumbens et dynorphin area reinforcement, tegmental (Johansson decreases drug ventral significantly rats behavior, the vated nandrolone intact from with in afferents treatment accumbens concen- dopaminergic dynorphin receives Chronic nucleus in regions. the increase brain in androgen-induced chronic concentrations other the by to in reversed exception seen fully an trations is and accumbens 1986) nucleus 1989). al., the al., Interestingly, et et reversed the (Fullerton (Molineaux partially DHT in be testosterone can with concentrations decreases with treatment dynorphin these in (7-day) treatment and decreases PAG 1989), (2-day) al., castration and subchronic et Similarly, Fullerton striatum, by 1986; 2000a). al., hypothalamus, al., et (Molineaux the et with pituitary anterior treatment (Johansson in chronic rats concentrations instance, male For dynorphin regions. intact brain increases most significantly in dynorphin nandrolone of concentrations increase males 1983). Androgens intact Hong, in & (Yoshikawa 1983). testosterone pituitary with Hong, anterior treatment Dynorphin & the (Yoshikawa chronic 3.4.1.3. 1983). in that castration concentrations Hong, observation following leu-enkephalin the & pituitary and Yoshikawa is anterior met- findings 1982; decreases the greater these al, in concentrations have to increases et leu-enkephalin exception castration also testosterone) and One (Hong and not rats (but met- rats, females male DHT, both female in metabolite, Intact intact of testosterone observed conditions 2000b). than the those of all) pituitary 2000a; administration not anterior to Chronic al., (but the concentrations et some in these under Johansson leu-enkephalin reduces and and (cf., concentra- 2000a) met- area met-enkephalin al., of gray increases et concentrations nandrolone (Johansson periaqueductal with striatum the treatment and many in chronic hypothalamus in peptides the rats, enkephalin in male of tions intact concentrations increase In androgens regions. beta-endorphin, brain on effects their to Similar beta-endorphin of concentrations increase Enkephalins androgens 3.4.1.2. that tissue. rule and latter plasma general these 1994). collectively, both the taken al., When in to ef- 1986). et (Wardlaw, exceptions this testosterone (Menard and represent with hypothalamus, nucleus treatment findings basal chronic te- arcuate by medial reversed the and rostral is in decanoate, fect concentrations the nandrolone beta-endorphin within increases instance, undecylenate, castration For beta-endorphin Moreover, boldenone conditions. decreases androgens, limited, cypionate, exogenous albeit stosterone the some, with under and treatment beta-endorphin reinforcement in chronic of opioid Finally, in concentrations 2000). implicated decrease al., heavily Androgens region et 2015). a (Harlan Margolis, 1997), in rats & al., concentrations et (Fields male beta-endorphin (Johansson addiction increases intact area significantly in tegmental nandrolone ventral with thalamus the treatment of chronic rats, midline male the intact boldeno- 17b-cypionate in AAS, testosterone the beta-endorphin and with not decanoate, increases also treatment but nandrolone rats androgen 1-de-hydro-17a-methyltestosterone, male manner, chronic intact undecylenate, dose-dependent to instance, ne a androgens For exogenous in concentrations. of 2009). testosterone beta-endorphin administration al., with Chronic increases et treatment DHT. (Pluchino chronic metabolite, testosterone rats by plasma, the (Pe- intact reversed in by testosterone to are concentrations relative with effects beta-endorphin hypothalamus treatment latter lower and chronic The exhibit lobe, following rats neurointermediate reversed gonadectomized pituitary, Similarly, partially anterior 1982). are al., effects et these traglia androgens, for role a 10 Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. eetr n 2 nrgncdcessi eetrdniyaeosre ntepeec fa nrgnre- androgen an of androgen presence express the not in does observed that are line re- density cell observation delta receptor a the expressing in in by observed decreases naturally evidenced are androgenic as lines density (2) receptors receptor cell and androgen in hybrid receptors decreases of in androgenic independent (1) expression are that delta mRNA effects decreases these receptor treatment Interestingly, Nandrolone delta ceptors. cells. and neuronal in binding 2017). expression al., receptor receptor et opioid (Lee delta rats decrease Androgens male intact dose-dependently in prevents and agonist Receptors flutamide, opioid ganglia Delta mu antagonist, trigeminal 3.4.2.2. a the receptor of in (Zhang androgen effects testosterone mRNA antihyperalgesic the with the receptor with treatment blocks mu treatment chronic of following subchronic upregulation restored Similarly, inflammation-induced is ganglion conditions. 2014). upregulation sensory limited) al., the (albeit and in et mRNA some nerve, receptors under receptor trigeminal mu density of mu the receptor upregulation of opioid on inflammation-induced mu prevents androgens increase castration of in androgens instance, that For effects beta-endorphin noted direct of be the must possible concentrations as It out increased such rule by synthesis. & areas not part, protein Smith in does or in 1986; expression density this explained, al., however, receptor be et regions; those mu Hnatowich can these to in 1992; hypothalamus similar by al., decreases and density part, et midbrain androgenic-induced receptor in (Bergasa Consequently, opioid explained, administration in 2003). concentrations be Yancey, decreases agonist the may chronic compensatory in areas following produce Increases these observed peptides et receptors). concentrations. of opioid mu Piva beta-endorphin some hypothalamic endogenous see endogenous on in of but androgens in density 1991; of al., increases receptor effects et null mu androgen-induced (Limonta of in examples rats decreases for female Androgen-induced 1990 of developmental al., hypothalamus slows et Takayma the recep- administration and mu testosterone in in 1987 increases neonatal density manipulations al., and Castration receptor proandrogenic rats, 1991). mu male either al., in of by et increases hypothalamus (Limonta eliminated the males are in in density differences manipulations tor sex antiandrogenic these by or and females rats, female intact than as n iia ffcsaeosre ntednaegrso atae aspeaal xoe omorphine to exposed prenatally castrated rats vehicle-treated castrated to of relative gyrus hippocampus dentate the the of in regions observed CA3 are ( and effects CA1 concentra- similar lower the and have in rats, rats receptors castrated mu (Takaya- testosterone-treated density, testosterone of receptor with tions opioid treatment mu chronic in by increases blocked decreases Castration see is androgenic midbrain. but effect 1990, and this al., thalamus and et areas, the ma Androgens by these in 2008). blocked in concentrations density fully Spampinato, protein receptor is & receptor mu effect (Guarino opioid this antagonist mu and receptor neuroblas- decrease treatment, human androgenic also In nandrolone an regions. following with brain decreases treatment multiple mRNA simultaneous across receptor cells mu neuronal cells, in toma receptors opioid receptor mu and decrease peptide Androgens In both region. on brain greater effects Receptors androgenic and with Mu compare subtype ligands 3.4.2.1. to across using data inferences. sufficient differ functional studies are draw that Later there to receptors cases, 1985). concentrations all opioid Fishman, testosterone not on with but & treatment effects some by Han reversed androgenic is 1979; reported effect this &Fishman, specificity and Han rats, male (TP; intact to propionate [ relative ligand, brain whole opioid in nonselective receptors the using studies Early exhibits treatment. Receptors which androgen Opioid si- 2007), following 3.4.2. treatment al., concentrations et nandrolone dynorphin (Magnusson contrast, in accumbens In the decrease nucleus significant 2007). including the a al., treatment, in concentrations et androgen DCE (Magnusson following increases PAG concentrations gnificantly and dynorphin hypothalamus in putamen, increase caudate an exhibit typically that lmeo´ ta. 03.Fnly natml asehbtlwrm eetrdniyi h hypothalamus the in density receptor mu lower exhibit rats male intact Finally, 2003). al., Slamberov´a et ˇ lmeo´ ta. 02fropsn ffcsi ueircliuu) ute supporting Further colliculus). superior in effects opposing for 2002 Slamberov´a al., et ˇ 3 11 ]ateoe eotdta atainicessopioid increases castration that reported H]naltrexone, Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. e r oelkl ouehri n te lii pod,weeswmnaemr ieyt s pres- use to likely more are women whereas opioids, illicit other and heroin use to likely more are Disorders Men Use analgesia. by Opioid opioid augmented enhance for be and Implications could sensitivity dose treatment 4.2. measuring pain subsequent opioid diminished tests decrease and endogenous detected, simultaneously determinations and blood is of to dose hypogonadism simple disorders treatment levels initial where by androgen pain guide low cases diagnosed could chronic in Regardless, levels be Moreover, both Testosterone 2018). quickly adjustments. testosterone. to Nieschlag, can total contributor & Hypogonadism and Vorona free analgesics. unrecognized (Christou 2011; opioid an hypogonadism to Hallak, and be sensitivity & fertility may for Souza with activity women, clinically de problems androgenic In 2017; Although to women. androgens leading al., receptors. and exogenous activity, men, men et androgen in androgenic both whereas of effects, for endogenous activation anti-feminizing drawbacks suppress and indirect limiting masculinizing clinically produce or androgens have instance, direct would opioid of by practice effectiveness this increased the intriguing, that blockade be is androgenic analgesia could opioid by enhancement analgesics minimized androgen-induced males. of be in implication can activity obvious females. androgenic One differences in greater sex stimulation to that androgenic (at underappreciated part, additional suggest or but in doses sizeable Some due, males data lower A are in 2.2.1). clinical need analgesia. differences typically and of (Section sex levels and preclinical these disorders comparable that analgesics Indeed, obtain pain suggests opioid to evidence from weight) to of body suffer sensitive body of more to function are a likely as men more are least that women are indicates that and indicate also strongly pain evidence studies to epidemiological sensitive and areas. clinical, more these preclinical, in from making evidence The Converging decision Analgesia practice. future amplify health Opioid guide to public might for androgens or that Implications of clinical possibilities ability 4.1. in several The considered to disorder. sufficiently in point use apparent been above opioid are not reviewed for differences has data risk sex differences the significant these above, and minimize) reviewed analgesia (or number As opioid a health. has to behaviors public sensitivity opioid-mediated and both in personal differences for sex implications to contribute of populations. may androgens human that in observation Implications drug AAS The accumbens Health of and effects nucleus Public behavior abuse-related and the motivated and Clinical in positive-reinforcing in 4. signaling the involved for opioid modulates critically part, kappa negatively is in in account, dynorphin which could decreases 3.4.1), accumbens, androgen-induced (Section nucleus Consequently, above the addiction. noted in receptor opioid As release kappa and compensatory is treatment. dopamine concentrations exception as androgenic dynorphin notable both part, these following in One of in decreases density concentrations. most exhibits explained, In dynorphin which slices). be endogenous accumbens, brain nucleus can in hypothalamic the increases density on castration androgen-induced receptor et of to kappa effects (Magnusson responses in the endopiriform for decreases dorsal brain 2015 and androgen-induced al., most putamen et regions, nandrolone Ruka caudate in chronic see the contrast, also receptors In in 2009, 2009). density al., opioid al., receptor et kappa kappa (Magnusson terminalis increases decreases amygdaloid stria treatment central and hypothalamus, nandrolone shell, pallidus, accumbens globus with nucleus investigation. lateral the single nucleus, treatment in a observed from chronic decreases derived significant is rats, with receptors kappa regions, on male androgens of intact effects the In about known is what in of Much increases androgenic by Receptors induced in Kappa down-regulation decreases 3.4.2.3. receptor androgen-induced by admi- receptors, part, by mu concentrations. in in completely to enkephalin reversed explained, density Similar endogenous is be receptor 1990). effect may opioid al., this receptors delta et and delta (Takayama increases hypothalamus, testosterone castration and is of instance, density midbrain, nistration for receptor thalamus, opioid rats, bulb, delta olfactory In in the regions. decreases brain Androgen-induced across 2000). al., widespread et (Pasquariello antagonist ceptor 12 Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. nbt ae n eae odtrietecnrbto fadoest e ieecsi pod reward opioids in differences sex to androgens of contribution and the conducted physiological determine be to both to need females including start will and devel- to reinforcement, studies and males positioned for Preclinical opioid AAS both perfectly risk abuse. between in is in the AAS link androgens research of on clear Preclinical characteristic of androgens a concentrations absent. role of supraphysiological indicate is effects the relationship data equivocal, reinforcement, the examining causal epidemiological are regarding a and the systematically data of conclusions reward Although preclinical evidence draw opioid available abuse, disorder. to on opioid The use difficult androgens substance is literature. a of it laboratory oping time effects human this the and at regarding clinical and information the are of problematic in opioids minimizing dearth particularly thus if a reduced, Even liability. is be abuse could analgesia. There andro- and opioid opioid indeed, tolerance of for pain as analgesics; dose need such androgen-augmented the opioid effects the that with of side suggest negate augmentation trials data may androgenic clinical available to analgesics the begin necessary, limited nonopioid hypogonadism. pa- to be of borderline data dosing not augmentation or sufficient optimal need genic undiagnosed now trials and with Such are tolerance, men opioid there in pain therapies. increase management populations, levels, and pain these testosterone sensitivity maximize pain In of to decrease evaluation needed androgens Clinical are that rameters suggesting 3.2). literature a as of (Section cycle body analgesia estrous sizable the a same include model these is must on There working differences hormones a sex ovarian in explore create of differences explicitly role to sex that complex to variable. the data to studies the biological that degree Future enough androgens by of suggest complicated not females. the contribution further strongly in are The and is proteins data there observations. receptors available stage, but empirical and the developmental of peptides specific, activational All number opioid or region or limited and age specific. the developmental age explain region across predominately to are are differ are androgens androgens 2.4 androgens androgens of is of (Sections of effects of There effects proteins effects central effects these and research. the the in the peptides further whether which differences whether opioid for unclear sex nature, endogenous is ripe reported in It to is both contribute that of 3.4). androgens area concentrations and that central an and is modulate receptors, behavior androgens opioid opioid-mediated that on evidence androgens ample for of candidates role them avoided. The making be 2010), must al., effects Directions et feminizing Future Mella or 5. 2016; masculinizing al., potential Finasteride where et male- testosterone. trials Hirshburg (i.e., clinical of 2014; future levels alopecia Charrette, normal androgenic & with (Gupta and men tioning prostate) impact 5 5 enlarged exclusively a other or (i.e., is and primarily to hyperplasia finasteride sensitive that prostatic is example, baldness) seeking For treat pattern opioid feasible. to or because intake be used men- problematic opioid might inhibitor be if As interventions problematic also Regardless, to some disorders. would men. lead manipulations, antagonists use cisgender would receptor in androgenic opioid receptors Androgen effects of individuals. androgen feminizing treatment of produce at determined majority they the agonists be the indirect in to in or remains aid effects direct It side to of opioids. manipulated are a and administration who is be AAS above, males, opioids both tioned can adult of misuse activity young simultaneously misuse interventions and androgenic and the early adolescent AAS whether that an utilize be similarly, misuse would should suggesting and to interventions programs likely opioids, abuse, these prevention mostly opioid of illicit drug-abuse for target 3.1.1), and obvious factor (Section An licit risk abuse appropriately. notable a AAS both nonetheless is for drugs. of is AAS factor of It abuse of risk classes misuse androgens. the pharmacological the of two with that role the correlated Given between the highly relationship at unknown is looking in there still AAS data and hormones but examined, clinical of gonadal underappreciated extensively and abuse of been preclinical not role the has both many The disorders that of to use role. paucity opioid due prominent and a likely are most use is observations more opioid the much in These playing differences are use. likely sex women drug mediating factors Moreover, their psychosocial 2.1.1). from with (Section consequences disorder factors, psychosocial use negative opioid experience an to develop and opioids α- euts niiosd o rdc eiiigeet n aelmtdeet nsxa func- sexual on effects limited have and effects feminizing produce not do inhibitors reductase 13 α- reductase Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. hrp n podtprn o podidcdhpgnds mn ainswt hoi ocne pain: noncancer replacement chronic Hormone with (2019). patients W. among J. hypogonadism review. Busse, opioid-induced systematic & affects for L., a Testosterone Wang, tapering R., (2004). opioid Couban, (2011). and C. S., therapy G. Massafra, Craigie, P., & Pari, Manjoo, rats. M., & M., female A. AminiLari, and Padova, male De . in . P., . differently Fiorenzani, responses S., I., formalin-induced Ceccarelli, Mameli, M., G., patients. A. Sindaco, pain Aloisi, chronic A., male Suman, hypogonadic Endocrinology M., and morphine-induced Biology Carlucci, M. in therapy I., Meriggiola, men. replacement & Ceccarelli, and Hormone A., women M., Bertaccini, transsexual A. in I., Aloisi, pain Ceccarelli, changes R., administration Stefani, hormone A., in S60-S67. Cross-sex Costantino, properties V., affective (2007). rewarding Bachiocco, C. motivation. has sexual M., Testosterone of A. basis (1994). Aloisi, morphine biological M. on the Hines, gender for & implications and G., housing rats: M. of male Packard, effect M., The G. (1978). Alexander, F. P. Hadaway, & rats. B., in R. self-administration (2004). Coambs, gene E. K., blockade. J. GIRK2 B. Grant, opioid Alexander, & on to C., responses hormones Kirschbaum, W., hypothalamic-pituitary-adrenocortical steroid S. and medicine Kim, gonadal matic G., pain of Nordehn, in D., differences Effects Ellestad, Sex E., L. (2008). Wittmers, M., M. system. al’Absi, nervous Jorjani, central rat & the B., in transcription Kazemi, N., Ahangar, References Interest: of the Conflict approved authors All draft. for manuscript. final this manuscript the writing the on submit Acknowledgements: collaborated to MS decision and JLS the manuscript. drafts. in final initial or the manuscript wrote and the of writing Contributors: the in role no publication. had NIH The Source: Funding of Role under- public remain and that translational Disclosures meaningful topics and carry several Funding may identifies that research review of This lines management several impact. disorders. clinical proposes health and use better A area to substance this lead and reinforcement. in would studied pain and outcomes reward chronic on these opioid-mediated pain both influence consequences to to androgens of functional regard how sensitivity in of andro- to and particularly understanding circulating lead analgesia, relevance, greater clinical opioid of receptors have to control and consequences sensitivity tonic these peptides sensitivity, of under these Some are of behavior. receptors opioid-mediated modulations and Androgen-induced peptides opioid gens. disorder. of as use serves concentrations opioid activity an Endogenous androgenic developing estrous of whether likelihood determine the Conclusions the to and in needed 6. hormones influence) be ovarian protective ultimately (or of will factor influence studies risk potential of a the types These consideration into cycle. taking reinforcement, and , A n Pdvlpdteie.T n L efre h eiwo h rmr literature primary the of review the performed JLS and TP idea. the developed TP and MAS 66 2,198-206. (2), anMedicine Pain h uhr iht hn r alShitfrcmet napeiu eso of version previous a on comments for Schmidt Karl Dr. thank to wish authors The ocnitdeclared. conflict No Psychopharmacology , hswr a upre yNHGat A434 A375 n DA045714. and DA031725, DA045364, Grants NIH by supported was work This 9 1,1-10. (1), , 20 2,301-313. (2), ersineletters Neuroscience , 58 14 2,175-179. (2), ersineLetters Neuroscience eairlneuroscience Behavioral , 431 3,201-205. (3), , 361 13,262-264. (1-3), , 108 Pain Reproductive Psychoso- 2,424. (2), , 132 , Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. ekr .B,&Ko,G .(06.Sxdffrne naia oes ou naddiction. on focus models: animal addic- in and differences Sex reward mediating (2016). F. mechanisms G. neural Koob, reviews in & differences B., J. 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(1), , , 160 Pharmacological 65 7 4,373-379. (4), 2,327-332. (2), 2,170-181. (2), , 103 (1), Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. ffcso nblcadoei triso h erdciesse fahee n erainlues a users: recreational (2017). S. and Tigas, athletes pain & of and G., system Gender Mastorakos, reproductive A., (2002). the Tsatsoulis, N. on P. G., steroids Wang, Markozannes, androgenic & A., a anabolic P., P. of L. analgesia: Christou, Effects patient-controllediv Ger, A., postoperative K., M. for Liu, Christou, patients. requirements C., Chinese the 2,298 C. of with Hung, survey associated prospective H., are L. movement Chow, upon potential Y., their ef- and Y. Side function receptor (2003). Chia, opioid kappa L. in B. differences Sex addiction. Strom, on (2015). & M. impact Mavrikaki, race. 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(2), http://dx.doi.org/10.15585/mmwr.mm6911a4 12,90-101. (1-2), eaiua pharmacology Behavioural rnir nPharmacology in Frontiers Psychoneuroendocrinology , 95 , 2,206-220. (2), 51 ersineletters Neuroscience , 5,605-610. (5), 14 ersineletters Neuroscience 1,77-85. (1), hraooyBohmsr n Behavior and Biochemistry Pharmacology , β- 10 nopi,CriorpnLk nemdaeLb etd,and Peptide, Lobe Intermediate Corticotropin-Like Endorphin, 295. , , ri research Brain 33 α- 26 euts niio,ptnitsatnccpieeffects antinociceptive potentiates inhibitor, reductase 3,386-394. (3), , 328 , 552 Psychopharmacology 2,160-164. (2), 66-70. , iev endocrinologica Minerva , hraooyBohmsr n Behavior and Biochemistry Pharmacology 398 Pain 1,157-163. (1), , 85 Endocrinology 12,153-159. (1-2), , 163 , 99 2,183-193. (2), 3,500-508. (3), , 43 , N drugs CNS 119 4,476-488. (4), Neurobiology 1,19-24. (1), Pain , 19 Posted on Authorea 2 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160167496.62768848 — This a preprint and has not been peer reviewed. Data may be preliminary. hn,X,Zag . sa,J,Nu .Y,Le . e,K . o .Y 21) e differences Sex (2014). Y. J. Ro, & . . . S., K. Lee, J., Lee, Y., K. males Niu, in pain effects J., stimulus butorphanol Asgar, and on Y., in stimulus Gender cold-water Zhang, a (2007). X., of L. Zhang, effects Lu, The & (2004). J. females. N. . . and Beckman, . & H., P., Qin, J. Zacny, J., by Shi, users. regulation Y., heroin Fang, abstinent 485-492. pituitary: in H., (3), anterior responses D. rat cue-induced Epstein, in the difference S., in Zhang, system J., enkephalin Yu, The drugs. psychotropic (1983). and hormones S. the steroid J. in gonadal weights Hong, Influence testicular & and (1999). K., body H. Yoshikawa, and Kelestimur, levels, & testosterone R., FSH, M. rat. 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