{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:46:17Z","timestamp":1793645177656,"version":"4.5.1"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T00:00:00Z","timestamp":1747612800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T00:00:00Z","timestamp":1747612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["K12 GM000678"],"award-info":[{"award-number":["K12 GM000678"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022416","name":"Center for Drug Evaluation and Research","doi-asserted-by":"publisher","award":["U01FD007857"],"award-info":[{"award-number":["U01FD007857"]}],"id":[{"id":"10.13039\/100022416","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Psychopharmacology"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1007\/s00213-025-06804-z","type":"journal-article","created":{"date-parts":[[2025,5,18]],"date-time":"2025-05-18T22:31:39Z","timestamp":1747607499000},"page":"1237-1254","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Xylazine potentiates the interoceptive effects of fentanyl in male and female rats"],"prefix":"10.1007","volume":"243","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3296-6144","authenticated-orcid":false,"given":"Brooke N.","family":"Bender","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Carew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madigan L.","family":"Bedard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe A.","family":"McElligott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6187-8376","authenticated-orcid":false,"given":"Joyce","family":"Besheer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"6804_CR1","doi-asserted-by":"publisher","first-page":"110993","DOI":"10.1016\/j.drugalcdep.2023.110993","volume":"253","author":"P Acosta-Mares","year":"2023","unstructured":"Acosta-Mares P, Violante-Soria V, Browne T Jr., Cruz SL (2023) Xylazine potentiates the lethal but not the rewarding effects of Fentanyl in mice. Drug Alcohol Depend 253:110993","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR2","doi-asserted-by":"publisher","first-page":"109646","DOI":"10.1016\/j.drugalcdep.2022.109646","volume":"240","author":"D AlKhelb","year":"2022","unstructured":"AlKhelb D, Kirunda A, Ho TC, Makriyannis A, Desai RI (2022) Effects of the cannabinoid CB(1)-receptor neutral antagonist AM4113 and antagonist\/inverse agonist Rimonabant on Fentanyl discrimination in male rats. Drug Alcohol Depend 240:109646","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR3","doi-asserted-by":"crossref","unstructured":"Bedard ML, Huang XP, Murray JG, Nowlan AC, Conley SY, Mott SE, Loyack SJ, Cline CA, Clodfelter CG, Dasgupta N, Krumm B, Roth BL, McElligott ZA (2024) Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism. Addict Neurosci 11","DOI":"10.1016\/j.addicn.2024.100155"},{"key":"6804_CR4","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/01.ALC.0000057036.64169.C1","volume":"27","author":"J Besheer","year":"2003","unstructured":"Besheer J, Cox AA, Hodge CW (2003) Coregulation of ethanol discrimination by the nucleus accumbens and amygdala. Alcohol Clin Exp Res 27:450\u2013456","journal-title":"Alcohol Clin Exp Res"},{"key":"6804_CR5","doi-asserted-by":"publisher","first-page":"9582","DOI":"10.1523\/JNEUROSCI.2366-09.2009","volume":"29","author":"J Besheer","year":"2009","unstructured":"Besheer J, Grondin JJ, Salling MC, Spanos M, Stevenson RA, Hodge CW (2009) Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci 29:9582\u20139591","journal-title":"J Neurosci"},{"key":"6804_CR6","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/S0740-5472(97)00309-7","volume":"15","author":"M Beuger","year":"1998","unstructured":"Beuger M, Tommasello A, Schwartz R, Clinton M (1998) Clonidine use and abuse among methadone program applicants and patients. J Subst Abuse Treat 15:589\u2013593","journal-title":"J Subst Abuse Treat"},{"key":"6804_CR7","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/0091-3057(93)90331-M","volume":"46","author":"M Bianchi","year":"1993","unstructured":"Bianchi M, Panerai AE (1993) Naloxone-induced analgesia: involvement of kappa-opiate receptors. Pharmacol Biochem Behav 46:145\u2013148","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR8","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1111\/j.1476-5381.1982.tb09322.x","volume":"77","author":"S Browning","year":"1982","unstructured":"Browning S, Lawrence D, Livingston A, Morris B (1982) Interactions of drugs active at opiate receptors and drugs active at alpha 2-receptors on various test systems. Br J Pharmacol 77:487\u2013491","journal-title":"Br J Pharmacol"},{"key":"6804_CR9","doi-asserted-by":"crossref","unstructured":"Burgess GE, Traynor JR, Jutkiewicz EM (2024) The effects of chronic neuropathic pain states on the discriminative stimulus effect of fentanyl and other MOR agonists. bioRxiv: 2024.11.19.624329","DOI":"10.1101\/2024.11.19.624329"},{"key":"6804_CR10","doi-asserted-by":"crossref","unstructured":"Capraro AJ, Wiley JF, 2nd, Tucker JR (2001) Severe intoxication from xylazine inhalation. Pediatr Emerg Care 17:447\u2013448","DOI":"10.1097\/00006565-200112000-00012"},{"key":"6804_CR11","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1038\/s41586-021-04013-0","volume":"598","author":"DC Castro","year":"2021","unstructured":"Castro DC, Oswell CS, Zhang ET, Pedersen CE, Piantadosi SC, Rossi MA, Hunker AC, Guglin A, Mor\u00f3n JA, Zweifel LS, Stuber GD, Bruchas MR (2021) An endogenous opioid circuit determines state-dependent reward consumption. Nature 598:646\u2013651","journal-title":"Nature"},{"key":"6804_CR12","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.tins.2020.10.007","volume":"44","author":"WG Chen","year":"2021","unstructured":"Chen WG, Schloesser D, Arensdorf AM, Simmons JM, Cui C, Valentino R, Gnadt JW, Nielsen L, Hillaire-Clarke CS, Spruance V, Horowitz TS, Vallejo YF, Langevin HM (2021) The emerging science of interoception: sensing, integrating, interpreting, and regulating signals within the self. Trends Neurosci 44:3\u201316","journal-title":"Trends Neurosci"},{"key":"6804_CR13","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1002\/dta.220","volume":"3","author":"C Cole","year":"2011","unstructured":"Cole C, Jones L, McVeigh J, Kicman A, Syed Q, Bellis M (2011) Adulterants in illicit drugs: a review of empirical evidence. Drug Test Anal 3:89\u201396","journal-title":"Drug Test Anal"},{"key":"6804_CR14","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/S0091-3057(99)00047-7","volume":"64","author":"FC Colpaert","year":"1999","unstructured":"Colpaert FC (1999) Drug discrimination in neurobiology. Pharmacol Biochem Behav 64:337\u2013345","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR15","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/S0022-3565(25)21381-7","volume":"230","author":"FC Colpaert","year":"1984","unstructured":"Colpaert FC, Janssen PA (1984) Agonist and antagonist effects of prototype opiate drugs in rats discriminating Fentanyl from saline: characteristics of partial generalization. J Pharmacol Exp Ther 230:193\u2013199","journal-title":"J Pharmacol Exp Ther"},{"key":"6804_CR16","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S0022-3565(25)23948-9","volume":"235","author":"FC Colpaert","year":"1985","unstructured":"Colpaert FC, Janssen PA (1985) Discriminative stimulus properties of xylazine in rat: discriminability and effects of putative alpha-2 adrenoceptor agonists and antagonists. J Pharmacol Exp Ther 235:521\u2013527","journal-title":"J Pharmacol Exp Ther"},{"key":"6804_CR18","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/0024-3205(75)90347-1","volume":"16","author":"FC Colpaert","year":"1975","unstructured":"Colpaert FC, Lal H, Niemegeers CJ, Janssen PA (1975) Investigations on drug produced and subjectively experienced discriminative stimuli. I. The Fentanyl cue, a tool to investigate subjectively experience narcotic drug actions. Life Sci 16:705\u2013715","journal-title":"Life Sci"},{"key":"6804_CR17","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/0091-3057(76)90103-9","volume":"5","author":"FC Colpaert","year":"1976","unstructured":"Colpaert FC, Kuyps JJ, Niemegeers CJ, Janssen PA (1976a) Discriminative stimulus properties of Fentanyl and morphine: tolerance and dependence. Pharmacol Biochem Behav 5:401\u2013408","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR19","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/0028-3908(76)90105-2","volume":"15","author":"FC Colpaert","year":"1976","unstructured":"Colpaert FC, Niemegeers CJ, Janssen PA (1976b) Fentanyl and apomorphine: asymmetrical generalization of discriminative stimulus properties. Neuropharmacology 15:541\u2013545","journal-title":"Neuropharmacology"},{"key":"6804_CR20","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/0014-2999(78)90076-6","volume":"49","author":"FC Colpaert","year":"1978","unstructured":"Colpaert FC, Niemegeers CJ, Janssen PA (1978) Drug-cue conditioning to external stimulus conditions. Eur J Pharmacol 49:185\u2013188","journal-title":"Eur J Pharmacol"},{"key":"6804_CR21","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/0028-3908(80)90061-1","volume":"19","author":"FC Colpaert","year":"1980","unstructured":"Colpaert FC, Niemegeers CJ, Janssen PA (1980) Factors regulating drug cue sensitivity: the effect of training dose in fentanyl-saline discrimination. Neuropharmacology 19:705\u2013713","journal-title":"Neuropharmacology"},{"key":"6804_CR22","doi-asserted-by":"publisher","first-page":"107241","DOI":"10.1016\/j.isci.2023.107241","volume":"26","author":"AL Cone","year":"2023","unstructured":"Cone AL, Wu KK, Kravitz AV, Norris AJ (2023) Kappa opioid receptor activation increases thermogenic energy expenditure which drives increased feeding. iScience 26:107241","journal-title":"iScience"},{"key":"6804_CR23","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1097\/00007611-199308000-00021","volume":"86","author":"T Conway","year":"1993","unstructured":"Conway T, Balson A (1993) Concomitant abuse of clonidine and heroin. South Med J 86:954\u2013956","journal-title":"South Med J"},{"key":"6804_CR27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0376-8716(96)01259-8","volume":"42","author":"RM Craft","year":"1996","unstructured":"Craft RM, Stratmann JA (1996) Discriminative stimulus effects of cocaine in female versus male rats. Drug Alcohol Depend 42:27\u201337","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR24","first-page":"764","volume":"7","author":"RM Craft","year":"1996","unstructured":"Craft RM, Kalivas PW, Stratmann JA (1996) Sex differences in discriminative stimulus effects of morphine in the rat. Behav Pharmacol 7:764\u2013778","journal-title":"Behav Pharmacol"},{"key":"6804_CR25","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S0091-3057(98)00124-5","volume":"61","author":"RM Craft","year":"1998","unstructured":"Craft RM, Kruzich PJ, Boyer JS, Harding JW, Hanesworth JM (1998a) Sex differences in discriminative stimulus and diuretic effects of the kappa opioid agonist U69,593 in the rat. Pharmacol Biochem Behav 61:395\u2013403","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR26","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1097\/00008877-199807000-00007","volume":"9","author":"RM Craft","year":"1998","unstructured":"Craft RM, Morgan CL, Bernal SA (1998b) Reinforcement frequency, but not gender, determines sensitivity to discriminative stimulus effects of morphine. Behav Pharmacol 9:357\u2013362","journal-title":"Behav Pharmacol"},{"key":"6804_CR28","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.7326\/M23-2001","volume":"176","author":"J D\u2019Orazio","year":"2023","unstructured":"D\u2019Orazio J, Nelson L, Perrone J, Wightman R, Haroz R (2023) Xylazine adulteration of the Heroin-Fentanyl drug supply: A narrative review. Ann Intern Med 176:1370\u20131376","journal-title":"Ann Intern Med"},{"key":"6804_CR29","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1023\/A:1010375727768","volume":"72","author":"SJ Dennison","year":"2001","unstructured":"Dennison SJ (2001) Clonidine abuse among opiate addicts. Psychiatr Q 72:191\u2013195","journal-title":"Psychiatr Q"},{"key":"6804_CR30","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1097\/00063110-200309000-00022","volume":"10","author":"JI Elejalde","year":"2003","unstructured":"Elejalde JI, Louis CJ, Elcuaz R, Pinillos MA (2003) Drug abuse with inhalated xylazine. Eur J Emerg Med 10:252\u2013253","journal-title":"Eur J Emerg Med"},{"key":"6804_CR31","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/BF00210836","volume":"92","author":"MW Emmett-Oglesby","year":"1987","unstructured":"Emmett-Oglesby MW, Herz A (1987) Opioid modulation of the discriminative stimulus produced by Pentylenetetrazol. Psychopharmacology 92:313\u2013319","journal-title":"Psychopharmacology"},{"key":"6804_CR32","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/S0022-3565(25)22318-7","volume":"245","author":"MW Emmett-Oglesby","year":"1988","unstructured":"Emmett-Oglesby MW, Shippenberg TS, Herz A (1988) Tolerance and cross-tolerance to the discriminative stimulus properties of Fentanyl and morphine. J Pharmacol Exp Ther 245:17\u201323","journal-title":"J Pharmacol Exp Ther"},{"key":"6804_CR33","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.drugpo.2017.06.005","volume":"46","author":"N Fairbairn","year":"2017","unstructured":"Fairbairn N, Coffin PO, Walley AY (2017) Naloxone for heroin, prescription opioid, and illicitly made Fentanyl overdoses: challenges and innovations responding to a dynamic epidemic. Int J Drug Policy 46:172\u2013179","journal-title":"Int J Drug Policy"},{"key":"6804_CR34","doi-asserted-by":"publisher","first-page":"108599","DOI":"10.1016\/j.drugalcdep.2021.108599","volume":"221","author":"SM Flynn","year":"2021","unstructured":"Flynn SM, France CP (2021) Discriminative stimulus effects of carfentanil in rats discriminating Fentanyl: differential antagonism by Naltrexone. Drug Alcohol Depend 221:108599","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR35","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1124\/jpet.121.000912","volume":"380","author":"SM Flynn","year":"2022","unstructured":"Flynn SM, France CP (2022) Characterization of the discriminative stimulus effects of binary mixtures of mu opioid receptor agonists in rats discriminating Fentanyl. J Pharmacol Exp Ther 380:171\u2013179","journal-title":"J Pharmacol Exp Ther"},{"key":"6804_CR36","doi-asserted-by":"publisher","first-page":"109380","DOI":"10.1016\/j.drugalcdep.2022.109380","volume":"233","author":"J Friedman","year":"2022","unstructured":"Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C (2022) Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend 233:109380","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR37","doi-asserted-by":"publisher","first-page":"109101","DOI":"10.1016\/j.drugalcdep.2021.109101","volume":"229","author":"AD Gaulden","year":"2021","unstructured":"Gaulden AD, Burson N, Sadik N, Ghosh I, Khan SJ, Brummelte S, Kallakuri S, Perrine SA (2021) Effects of Fentanyl on acute locomotor activity, behavioral sensitization, and contextual reward in female and male rats. Drug Alcohol Depend 229:109101","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR38","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1471-2210-6-3","volume":"6","author":"P Gharagozlou","year":"2006","unstructured":"Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J (2006) Pharmacological profiles of opioid ligands at kappa opioid receptors. BMC Pharmacol 6:3","journal-title":"BMC Pharmacol"},{"key":"6804_CR39","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0376-8716(98)00086-6","volume":"52","author":"KL Green","year":"1998","unstructured":"Green KL, Grant KA (1998) Evidence for overshadowing by components of the heterogeneous discriminative stimulus effects of ethanol. Drug Alcohol Depend 52:149\u2013159","journal-title":"Drug Alcohol Depend"},{"key":"6804_CR40","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1093\/jat\/25.4.245","volume":"25","author":"U Hoffmann","year":"2001","unstructured":"Hoffmann U, Meister CM, Golle K, Zschiesche M (2001) Severe intoxication with the veterinary tranquilizer xylazine in humans. J Anal Toxicol 25:245\u2013249","journal-title":"J Anal Toxicol"},{"key":"6804_CR41","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/0091-3057(95)02151-5","volume":"53","author":"CE Hughes","year":"1996","unstructured":"Hughes CE, Habash T, Dykstra LA, Picker MJ (1996) Discriminative-stimulus effects of morphine in combination with alpha- and beta-noradrenergic agonists and antagonists in rats. Pharmacol Biochem Behav 53:979\u2013986","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR43","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1111\/ejn.13374","volume":"44","author":"AA Jaramillo","year":"2016","unstructured":"Jaramillo AA, Randall PA, Frisbee S, Besheer J (2016) Modulation of sensitivity to alcohol by cortical and thalamic brain regions. Eur J Neurosci 44:2569\u20132580","journal-title":"Eur J Neurosci"},{"key":"6804_CR42","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1111\/adb.12551","volume":"23","author":"AA Jaramillo","year":"2018","unstructured":"Jaramillo AA, Agan VE, Makhijani VH, Pedroza S, McElligott ZA, Besheer J (2018) Functional role for suppression of the insular-striatal circuit in modulating interoceptive effects of alcohol. Addict Biol 23:1020\u20131031","journal-title":"Addict Biol"},{"key":"6804_CR44","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1136\/injuryprev-2020-043968","volume":"27","author":"J Johnson","year":"2021","unstructured":"Johnson J, Pizzicato L, Johnson C, Viner K (2021) Increasing presence of xylazine in heroin and\/or Fentanyl deaths, Philadelphia, Pennsylvania, 2010\u20132019. Inj Prev 27:395\u2013398","journal-title":"Inj Prev"},{"key":"6804_CR45","doi-asserted-by":"publisher","first-page":"721","DOI":"10.15585\/mmwr.mm7226a4","volume":"72","author":"M Kariisa","year":"2023","unstructured":"Kariisa M, O\u2019Donnell J, Kumar S, Mattson CL, Goldberger BA (2023) Illicitly manufactured Fentanyl-Involved overdose deaths with detected Xylazine - United States, January 2019-June 2022. MMWR Morb Mortal Wkly Rep 72:721\u2013727","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"6804_CR46","doi-asserted-by":"crossref","unstructured":"Keyes KM, Rutherford C, Hamilton A, Barocas JA, Gelberg KH, Mueller PP, Feaster DJ, El-Bassel N, Cerd\u00e1 M (2022) What is the prevalence of and trend in opioid use disorder in the united States from 2010 to 2019? Using multiplier approaches to estimate prevalence for an unknown population size. Drug Alcohol Depend Rep 3","DOI":"10.1016\/j.dadr.2022.100052"},{"key":"6804_CR47","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1111\/jvp.12724","volume":"42","author":"T Kitano","year":"2019","unstructured":"Kitano T, Kobayashi T, Yamaguchi S, Otsuguro K (2019) The \u03b1(2A) -adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine. J Vet Pharmacol Ther 42:243\u2013247","journal-title":"J Vet Pharmacol Ther"},{"key":"6804_CR48","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/0740-5472(92)90078-3","volume":"9","author":"P Lauzon","year":"1992","unstructured":"Lauzon P (1992) Two cases of clonidine abuse\/dependence in methadone-maintained patients. J Subst Abuse Treat 9:125\u2013127","journal-title":"J Subst Abuse Treat"},{"key":"6804_CR49","doi-asserted-by":"publisher","first-page":"108807","DOI":"10.1016\/j.neuropharm.2021.108807","volume":"200","author":"DF Lovelock","year":"2021","unstructured":"Lovelock DF, Tyler RE, Besheer J (2021) Interoception and alcohol: mechanisms, networks, and implications. Neuropharmacology 200:108807","journal-title":"Neuropharmacology"},{"key":"6804_CR50","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1097\/00008877-199608000-00008","volume":"7","author":"EA Mariathasan","year":"1996","unstructured":"Mariathasan EA, White JA, Stolerman IP (1996) Training dose as a decisive factor for discrimination of a drug mixture in rats. Behav Pharmacol 7:364\u2013372","journal-title":"Behav Pharmacol"},{"key":"6804_CR51","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1038\/npp.2013.63","volume":"38","author":"ZA McElligott","year":"2013","unstructured":"McElligott ZA, Fox ME, Walsh PL, Urban DJ, Ferrel MS, Roth BL, Wightman RM (2013) Noradrenergic synaptic function in the bed nucleus of the stria terminalis varies in animal models of anxiety and addiction. Neuropsychopharmacology 38:1665\u20131673","journal-title":"Neuropsychopharmacology"},{"key":"6804_CR52","doi-asserted-by":"crossref","unstructured":"Morley JE, Levine AS, Gosnell BA, Billington CJ (1984) Which opioid receptor mechanism modulates feeding? Appetite 5:61\u20138","DOI":"10.1016\/S0195-6663(84)80051-3"},{"key":"6804_CR53","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s00429-010-0268-7","volume":"214","author":"NH Naqvi","year":"2010","unstructured":"Naqvi NH, Bechara A (2010) The Insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making. Brain Struct Funct 214:435\u2013450","journal-title":"Brain Struct Funct"},{"key":"6804_CR54","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1159\/000338163","volume":"5","author":"R Nogueiras","year":"2012","unstructured":"Nogueiras R, Romero-Pic\u00f3 A, Vazquez MJ, Novelle MG, L\u00f3pez M, Di\u00e9guez C (2012) The opioid system and food intake: homeostatic and hedonic mechanisms. Obes Facts 5:196\u2013207","journal-title":"Obes Facts"},{"key":"6804_CR55","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1097\/PAF.0000000000000622","volume":"42","author":"J Nunez","year":"2021","unstructured":"Nunez J, DeJoseph ME, Gill JR (2021) Xylazine, a veterinary tranquilizer, detected in 42 accidental Fentanyl intoxication deaths. Am J Forensic Med Pathol 42:9\u201311","journal-title":"Am J Forensic Med Pathol"},{"key":"6804_CR56","doi-asserted-by":"crossref","unstructured":"Obeng S, Crowley ML, Mottinelli M, Le\u00f3n F, Zuarth Gonzalez JD, Chen Y, Gamez-Jimenez LR, Restrepo LF, Ho NP, Patel A, Martin-Rocha J, Alvarez MA, Thadisetti AM, Park CR, Pallares VLC, Milner MJ, Canal CE, Hampson AJ, McCurdy CR, McMahon LR, Wilkerson JL, Hiranita T (2024) The Mitragyna speciosa (kratom) alkaloid Mitragynine: analysis of adrenergic \u03b1(2) receptor activity in vitro and in vivo. Eur J Pharmacol 176863","DOI":"10.1016\/j.ejphar.2024.176863"},{"key":"6804_CR57","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1126\/science.462182","volume":"205","author":"DA Overton","year":"1979","unstructured":"Overton DA (1979) Drug discrimination training with progressively Lowered doses. Science 205:720\u2013721","journal-title":"Science"},{"key":"6804_CR58","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/164_2017_34","volume":"244","author":"GW Pasternak","year":"2017","unstructured":"Pasternak GW (2017) Allosteric modulation of opioid G-Protein coupled receptors by Sigma(1) receptors. Handb Exp Pharmacol 244:163\u2013175","journal-title":"Handb Exp Pharmacol"},{"key":"6804_CR59","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/S0022-3565(25)12589-5","volume":"254","author":"MJ Picker","year":"1990","unstructured":"Picker MJ, Doty P, Negus SS, Mattox SR, Dykstra LA (1990) Discriminative stimulus properties of U50,488 and morphine: effects of training dose on stimulus substitution patterns produced by mu and kappa opioid agonists. J Pharmacol Exp Ther 254:13\u201322","journal-title":"J Pharmacol Exp Ther"},{"key":"6804_CR60","doi-asserted-by":"publisher","first-page":"e12782","DOI":"10.1111\/adb.12782","volume":"25","author":"PA Randall","year":"2020","unstructured":"Randall PA, McElligott ZA, Besheer J (2020) Role of mPFC and nucleus accumbens circuitry in modulation of a nicotine plus alcohol compound drug state. Addict Biol 25:e12782","journal-title":"Addict Biol"},{"key":"6804_CR61","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.lfs.2010.10.007","volume":"88","author":"K Rasakham","year":"2011","unstructured":"Rasakham K, Liu-Chen LY (2011) Sex differences in kappa opioid Pharmacology. Life Sci 88:2\u201316","journal-title":"Life Sci"},{"key":"6804_CR62","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1021\/acs.jcim.0c00890","volume":"61","author":"A Ricarte","year":"2021","unstructured":"Ricarte A, Dalton JAR, Giraldo J (2021) Structural assessment of agonist efficacy in the \u00b5-Opioid receptor: morphine and Fentanyl elicit different activation patterns. J Chem Inf Model 61:1251\u20131274","journal-title":"J Chem Inf Model"},{"key":"6804_CR63","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ejphar.2009.02.019","volume":"608","author":"TR Romero","year":"2009","unstructured":"Romero TR, de Castro Perez A, de Francischi JN, Gama Duarte ID (2009) Probable involvement of alpha(2\u00a0C)-adrenoceptor subtype and endogenous opioid peptides in the peripheral antinociceptive effect induced by xylazine. Eur J Pharmacol 608:23\u201327","journal-title":"Eur J Pharmacol"},{"key":"6804_CR64","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.biopsych.2013.07.042","volume":"76","author":"SE Russell","year":"2014","unstructured":"Russell SE, Rachlin AB, Smith KL, Muschamp J, Berry L, Zhao Z, Chartoff EH (2014) Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats. Biol Psychiatry 76:213\u2013222","journal-title":"Biol Psychiatry"},{"key":"6804_CR65","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.pbb.2004.03.004","volume":"78","author":"H Sahraei","year":"2004","unstructured":"Sahraei H, Ghazzaghi H, Zarrindast MR, Ghoshooni H, Sepehri H, Haeri-Rohan A (2004) The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice. Pharmacol Biochem Behav 78:135\u2013141","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR66","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.pbb.2007.09.013","volume":"88","author":"M Samini","year":"2008","unstructured":"Samini M, Kardan A, Mehr SE (2008) Alpha-2 agonists decrease expression of morphine-induced conditioned place preference. Pharmacol Biochem Behav 88:403\u2013406","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR67","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1176\/ajp.140.12.1625","volume":"140","author":"J Schaut","year":"1983","unstructured":"Schaut J, Schnoll SH (1983) Four cases of clonidine abuse. Am J Psychiatry 140:1625\u20131627","journal-title":"Am J Psychiatry"},{"key":"6804_CR68","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1097\/ADM.0b013e31828ab8d4","volume":"7","author":"EA Schindler","year":"2013","unstructured":"Schindler EA, Tirado-Morales DJ, Kushon D (2013) Clonidine abuse in a methadone-maintained, clonazepam-abusing patient. J Addict Med 7:218\u2013219","journal-title":"J Addict Med"},{"key":"6804_CR69","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1046\/j.1365-2885.1998.00113.x","volume":"21","author":"DD Schwartz","year":"1998","unstructured":"Schwartz DD, Clark TP (1998) Affinity of detomidine, Medetomidine and xylazine for alpha-2 adrenergic receptor subtypes. J Vet Pharmacol Ther 21:107\u2013111","journal-title":"J Vet Pharmacol Ther"},{"key":"6804_CR70","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.neuropharm.2019.01.020","volume":"150","author":"KL Schwienteck","year":"2019","unstructured":"Schwienteck KL, Faunce KE, Rice KC, Obeng S, Zhang Y, Blough BE, Grim TW, Negus SS, Banks ML (2019) Effectiveness comparisons of G-protein biased and unbiased mu opioid receptor ligands in warm water tail-withdrawal and drug discrimination in male and female rats. Neuropharmacology 150:200\u2013209","journal-title":"Neuropharmacology"},{"key":"6804_CR71","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1034\/j.1601-0825.2003.03967.x","volume":"9","author":"C Scully","year":"2003","unstructured":"Scully C (2003) Drug effects on salivary glands: dry mouth. Oral Dis 9:165\u2013176","journal-title":"Oral Dis"},{"key":"6804_CR72","doi-asserted-by":"publisher","first-page":"204512532211396","DOI":"10.1177\/20451253221139616","volume":"12","author":"A Shafi","year":"2022","unstructured":"Shafi A, Berry AJ, Sumnall H, Wood DM, Tracy DK (2022) Synthetic opioids: a review and clinical update. Ther Adv Psychopharmacol 12:20451253221139616","journal-title":"Ther Adv Psychopharmacol"},{"key":"6804_CR73","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/0091-3057(82)90157-5","volume":"16","author":"GT Shearman","year":"1982","unstructured":"Shearman GT, Herz A (1982) D-Ala2,D-Leu5-enkephalin generalizes to a discriminative stimulus produced by Fentanyl but not Ethylketocyclazocine. Pharmacol Biochem Behav 16:249\u2013252","journal-title":"Pharmacol Biochem Behav"},{"key":"6804_CR74","doi-asserted-by":"publisher","first-page":"1280289","DOI":"10.3389\/fphar.2023.1280289","volume":"14","author":"MA Smith","year":"2023","unstructured":"Smith MA, Biancorosso SL, Camp JD, Hailu SH, Johansen AN, Morris MH, Carlson HN (2023) Tranq-dope overdose and mortality: lethality induced by Fentanyl and xylazine. Front Pharmacol 14:1280289","journal-title":"Front Pharmacol"},{"key":"6804_CR75","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1038\/nprot.2006.167","volume":"1","author":"M Solinas","year":"2006","unstructured":"Solinas M, Panlilio LV, Justinova Z, Yasar S, Goldberg SR (2006) Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1:1194\u20131206","journal-title":"Nat Protoc"},{"key":"6804_CR76","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1097\/ADM.0000000000001216","volume":"17","author":"A Spadaro","year":"2023","unstructured":"Spadaro A, O\u2019Connor K, Lakamana S, Sarker A, Wightman R, Love JS, Perrone J (2023) Self-reported xylazine experiences: A Mixed-methods study of Reddit subscribers. J Addict Med 17:691\u2013694","journal-title":"J Addict Med"},{"key":"6804_CR77","doi-asserted-by":"crossref","unstructured":"Spoerke DG, Hall AH, Grimes MJ, Honea BN, 3rd, Rumack BH (1986) Human overdose with the veterinary tranquilizer xylazine. Am J Emerg Med 4:222\u2013224","DOI":"10.1016\/0735-6757(86)90070-7"},{"key":"6804_CR78","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1097\/FBP.0b013e328349ab37","volume":"22","author":"IP Stolerman","year":"2011","unstructured":"Stolerman IP, Childs E, Ford MM, Grant KA (2011) Role of training dose in drug discrimination: a review. Behav Pharmacol 22:415\u2013429","journal-title":"Behav Pharmacol"},{"key":"6804_CR79","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1097\/ADM.0000000000001264","volume":"18","author":"M Tan","year":"2024","unstructured":"Tan M, Nassau T, Kuncio D, Higgins D, Teixeira da Silva D, Tomlinson D, Brady KA (2024) Xylazine use among people who inject drugs, Philadelphia 2022. J Addict Med 18:194\u2013200","journal-title":"J Addict Med"},{"key":"6804_CR80","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.bbr.2018.11.023","volume":"359","author":"MA Tapia","year":"2019","unstructured":"Tapia MA, Lee JR, Weise VN, Tamasi AM, Will MJ (2019) Sex differences in hedonic and homeostatic aspects of palatable food motivation. Behav Brain Res 359:396\u2013400","journal-title":"Behav Brain Res"},{"key":"6804_CR81","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.alcohol.2022.07.002","volume":"104","author":"RE Tyler","year":"2022","unstructured":"Tyler RE, Bluitt MN, Van Voorhies K, Ornelas LC, Weinberg BZS, Besheer J (2022) Predator odor (TMT) exposure potentiates interoceptive sensitivity to alcohol and increases GABAergic gene expression in the anterior insular cortex and nucleus accumbens in male rats. Alcohol 104:1\u201311","journal-title":"Alcohol"},{"key":"6804_CR82","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1016\/j.neubiorev.2012.05.007","volume":"36","author":"A Verdejo-Garcia","year":"2012","unstructured":"Verdejo-Garcia A, Clark L, Dunn BD (2012) The role of interoception in addiction: a critical review. Neurosci Biobehav Rev 36:1857\u20131869","journal-title":"Neurosci Biobehav Rev"},{"key":"6804_CR83","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.yrtph.2010.12.007","volume":"59","author":"DA Volpe","year":"2011","unstructured":"Volpe DA, McMahon Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T, Kropp TJ, Verbois SL (2011) Uniform assessment and ranking of opioid \u039c receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol 59:385\u2013390","journal-title":"Regul Toxicol Pharmacol"},{"key":"6804_CR84","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/0028-3908(88)90141-4","volume":"27","author":"M Yeadon","year":"1988","unstructured":"Yeadon M, Kitchen I (1988) Comparative binding of mu and delta selective ligands in whole brain and Pons\/medulla homogenates from rat: affinity profiles of Fentanyl derivatives. Neuropharmacology 27:345\u2013348","journal-title":"Neuropharmacology"}],"container-title":["Psychopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00213-025-06804-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00213-025-06804-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00213-025-06804-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T05:02:38Z","timestamp":1780722158000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00213-025-06804-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,19]]},"references-count":84,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["6804"],"URL":"https:\/\/doi.org\/10.1007\/s00213-025-06804-z","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.02.07.637099","asserted-by":"object"}]},"ISSN":["0033-3158","1432-2072"],"issn-type":[{"value":"0033-3158","type":"print"},{"value":"1432-2072","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,19]]},"assertion":[{"value":"12 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures were conducted in accordance with the NIH Guide to Care and Use of Laboratory Animals following the protocols approved by the UNC Institutional Animal Care and Use Committee (Protocol Number: 24\u2013196.0).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"All authors have no conflicts of interest.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}