Oxycodone in the Opioid Epidemic: High ‘Liking’, ‘Wanting’, and Abuse Liability

Springer Science and Business Media LLC - Tập 41 - Trang 899-926 - 2020
Cherkaouia Kibaly1, Jacob A. Alderete1, Steven H. Liu1, Hazem S. Nasef1, Ping-Yee Law1, Christopher J. Evans1, Catherine M. Cahill1
1Department of Psychiatry and Biobehavioral Sciences, Jane & Terry Semel Institute for Neuroscience and Human Behavior, Shirley and Stefan Hatos Center for Neuropharmacology, University of California, Los Angeles, USA

Tóm tắt

It is estimated that nearly a third of people who abuse drugs started with prescription opioid medicines. Approximately, 11.5 million Americans used prescription drugs recreationally in 2016, and in 2018, 46,802 Americans died as the result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl (National Institutes on Drug Abuse (2020) Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis . Accessed 06 June 2020). Yet physicians will continue to prescribe oral opioids for moderate-to-severe pain in the absence of alternative therapeutics, underscoring the importance in understanding how drug choice can influence detrimental outcomes. One of the opioid prescription medications that led to this crisis is oxycodone, where misuse of this drug has been rampant. Being one of the most highly prescribed opioid medications for treating moderate-to-severe pain as reflected in the skyrocketed increase in retail sales of 866% between 1997 and 2007, oxycodone was initially suggested to be less addictive than morphine. The false-claimed non-addictive formulation of oxycodone, OxyContin, further contributed to the opioid crisis. Abuse was often carried out by crushing the pills for immediate burst release, typically by nasal insufflation, or by liquefying the pills for intravenous injection. Here, we review oxycodone pharmacology and abuse liability as well as present the hypothesis that oxycodone may exhibit a unique pharmacology that contributes to its high likability and abuse susceptibility. We will discuss various mechanisms that likely contribute to the high abuse rate of oxycodone including clinical drug likability, pharmacokinetics, pharmacodynamics, differences in its actions within mesolimbic reward circuity compared to other opioids, and the possibility of differential molecular and cellular receptor interactions that contribute to its selective effects. We will also discuss marketing strategies and drug difference that likely contributes to the oxycodone opioid use disorders and addiction.

Tài liệu tham khảo

Abel GA, Penson RT, Joffe S, Schapira L, Chabner BA, Lynch TJ (2006) Direct-to-consumer advertising in oncology. Oncologist 11(2):217–226. https://doi.org/10.1634/theoncologist.11-2-217 Adler JA, Mallick-Searle T (2018) An overview of abuse-deterrent opioids and recommendations for practical patient care. J Multidiscip Healthc 11:323–332. https://doi.org/10.2147/JMDH.S166915 Ahmed SH, Kenny PJ, Koob GF, Markou A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5(7):625–626. https://doi.org/10.1038/nn872 Alexander L, Mannion RO, Weingarten B, Fanelli RJ, Stiles GL (2014) Development and impact of prescription opioid abuse deterrent formulation technologies. Drug Alcohol Depend 138:1–6. https://doi.org/10.1016/j.drugalcdep.2014.02.006 Altarifi AA, David B, Muchhala KH, Blough BE, Akbarali H, Negus SS (2017) Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents. J Psychopharmacol 31(6):730–739. https://doi.org/10.1177/0269881116689257 Anselme P, Robinson MJ (2016) “Wanting,” “liking,” and their relation to consciousness. J Exp Psychol Anim Learn Cogn 42(2):123–140. https://doi.org/10.1037/xan0000090 Aono Y, Saigusa T, Mizoguchi N, Iwakami T, Takada K, Gionhaku N, Oi Y, Ueda K, Koshikawa N, Cools AR (2008) Role of GABAA receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats. Eur J Pharmacol 580(1–2):87–94. https://doi.org/10.1016/j.ejphar.2007.10.020 Atluri S, Sudarshan G, Manchikanti L (2014) Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011. Pain Physician 17(2):E119-128 Backlund M, Lindgren L, Kajimoto Y, Rosenberg PH (1997) Comparison of epidural morphine and oxycodone for pain after abdominal surgery. J Clin Anesth 9(1):30–35. https://doi.org/10.1016/S0952-8180(96)00212-7 Bailey CP, Smith FL, Kelly E, Dewey WL, Henderson G (2006) How important is protein kinase C in mu-opioid receptor desensitization and morphine tolerance? Trends Pharmacol Sci 27(11):558–565. https://doi.org/10.1016/j.tips.2006.09.006 Ballantyne JC (2015) Opioid therapy in chronic pain. Phys Med Rehabil Clin N Am 26(2):201–218. https://doi.org/10.1016/j.pmr.2014.12.001 Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC (2012) Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions. J Neurosci 32(41):14094–14101. https://doi.org/10.1523/JNEUROSCI.3370-12.2012 Bayer VE, Pickel VM (1990) Ultrastructural localization of tyrosine hydroxylase in the rat ventral tegmental area: relationship between immunolabeling density and neuronal associations. J Neurosci 10(9):2996–3013. https://doi.org/10.1523/JNEUROSCI.10-09-02996.1990 Beckett AH, Casy AF (1954) Stereochemistry of certain analgesics. Nature 173(4417):1231–1232. https://doi.org/10.1038/1731231a0 Bercovitch M, Adunsky A (2006) High dose controlled-release oxycodone in hospice care. J Pain Palliat Care Pharmacother 20(4):33–39 Bergese SD, Brzezinski M, Hammer GB, Beard TL, Pan PH, Mace SE, Berkowitz RD, Cochrane K, Wase L, Minkowitz HS, Habib AS (2019) ATHENA: a phase 3, open-label study of the safety and effectiveness of oliceridine (TRV130), a G-protein selective agonist at the micro-opioid receptor, in patients with moderate to severe acute pain requiring parenteral opioid therapy. J Pain Res 12:3113–3126. https://doi.org/10.2147/JPR.S217563 Berridge KC (2000) Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns. Neurosci Biobehav Rev 24(2):173–198. https://doi.org/10.1016/s0149-7634(99)00072-x Berridge KC (2018) Evolving concepts of emotion and motivation. Front Psychol 9:1647. https://doi.org/10.3389/fpsyg.2018.01647 Berridge KC, Kringelbach ML (2015) Pleasure systems in the brain. Neuron 86(3):646–664. https://doi.org/10.1016/j.neuron.2015.02.018 Berridge KC, Robinson TE (2016) Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol 71(8):670–679. https://doi.org/10.1037/amp0000059 Berridge KC, Valenstein ES (1991) What psychological process mediates feeding evoked by electrical stimulation of the lateral hypothalamus? Behav Neurosci 105(1):3–14 Berridge KC, Venier IL, Robinson TE (1989) Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function. Behav Neurosci 103(1):36–45. https://doi.org/10.1037//0735-7044.103.1.36 Berridge KC, Robinson TE, Aldridge JW (2009) Dissecting components of reward: “liking”, “wanting”, and learning. Curr Opin Pharmacol 9(1):65–73. https://doi.org/10.1016/j.coph.2008.12.014 Berrios J, Stamatakis AM, Kantak PA, McElligott ZA, Judson MC, Aita M, Rougie M, Stuber GD, Philpot BD (2016) Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation. Nat Commun 7:10702. https://doi.org/10.1038/ncomms10702 Bertekap RL, Burford NT, Li Z, Alt A (2015) High-throughput screening for allosteric modulators of GPCRs. Methods Mol Biol 1335:223–240. https://doi.org/10.1007/978-1-4939-2914-6_15 Bisignano P, Burford NT, Shang Y, Marlow B, Livingston KE, Fenton AM, Rockwell K, Budenholzer L, Traynor JR, Gerritz SW, Alt A, Filizola M (2015) Ligand-based discovery of a new scaffold for allosteric modulation of the mu-opioid receptor. J Chem Inf Model 55(9):1836–43. https://doi.org/10.1021/acs.jcim.5b00388 Blackwood CA, McCoy MT, Ladenheim B, Cadet JL (2020) Oxycodone self-administration activates the mitogen-activated protein kinase/mitogen- and stress-activated protein kinase (MAPK-MSK) signaling pathway in the rat dorsal striatum. bioRxiv. https://doi.org/10.1101/2020.08.31.276253 Blume AJ (1978) Interaction of ligands with the opiate receptors of brain membranes: regulation by ions and nucleotides. Proc Natl Acad Sci USA 75(4):1713–1717. https://doi.org/10.1073/pnas.75.4.1713 Blume AJ, Lichtshtein D, Boone G (1979) Coupling of opiate receptors to adenylate cyclase: requirement for Na+ and GTP. Proc Natl Acad Sci USA 76(11):5626–5630. https://doi.org/10.1073/pnas.76.11.5626 Bostrom E, Hammarlund-Udenaes M, Simonsson US (2008) Blood–brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine. Anesthesiology 108(3):495–505. https://doi.org/10.1097/ALN.0b013e318164cf9e Bourdy R, Barrot M (2012) A new control center for dopaminergic systems: pulling the VTA by the tail. Trends Neurosci 35(11):681–690. https://doi.org/10.1016/j.tins.2012.06.007 Brauer LH, De Wit H (1997) High dose pimozide does not block amphetamine-induced euphoria in normal volunteers. Pharmacol Biochem Behav 56(2):265–272. https://doi.org/10.1016/s0091-3057(96)00240-7 Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68(5):815–834. https://doi.org/10.1016/j.neuron.2010.11.022 Bruera E, Belzile M, Pituskin E, Fainsinger R, Darke A, Harsanyi Z, Babul N, Ford I (1998) Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Clin Oncol 16(10):3222–3229. https://doi.org/10.1200/JCO.1998.16.10.3222 Burford NT, Clark MJ, Wehrman TS, Gerritz SW, Banks M, O’Connell J, Traynor JR, Alt A (2013) Discovery of positive allosteric modulators and silent allosteric modulators of the mu-opioid receptor. Proc Natl Acad Sci USA 110(26):10830–5. https://doi.org/10.1073/pnas.1300393110 Burford NT, Wehrman T, Bassoni D, O’Connell J, Banks M, Zhang L, Alt A (2014) Identification of selective agonists and positive allosteric modulators for micro- and delta-opioid receptors from a single high-throughput screen. J Biomol Screen 19(9):1255–1265. https://doi.org/10.1177/1087057114542975 Burford NT, Livingston KE, Canals M, Ryan MR, Budenholzer LM, Han Y, Shang Y, Herbst JJ, O’Connell J, Banks M, Zhang L, Filizola M, Bassoni DL, Wehrman TS, Christopoulos A, Traynor JR, Gerritz SW, Alt A (2015) Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the delta-opioid receptor. J Med Chem 58(10):4220–4229. https://doi.org/10.1021/acs.jmedchem.5b00007 Butler SF, Fernandez KC, Chang A, Benoit C, Morey LC, Black R, Katz N (2010) Measuring attractiveness for abuse of prescription opioids. Pain Med 11(1):67–80. https://doi.org/10.1111/j.1526-4637.2009.00736.x Butler SF, Black RA, Cassidy TA, Dailey TM, Budman SH (2011) Abuse risks and routes of administration of different prescription opioid compounds and formulations. Harm Reduct J 8:29. https://doi.org/10.1186/1477-7517-8-29 Buynak R, Rappaport SA, Rod K, Arsenault P, Heisig F, Rauschkolb C, Etropolski M (2015) Long-term safety and efficacy of tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial. Clin Ther 37(11):2420–2438. https://doi.org/10.1016/j.clinthera.2015.08.014 Cahill CM (2020) Opioid dose regimen shapes mesolimbic adaptations. Neuropsychopharmacology. https://doi.org/10.1038/s41386-020-0679-y Caldwell JR, Hale ME, Boyd RE, Hague JM, Iwan T, Shi M, Lacouture PG (1999) Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. J Rheumatol 26(4):862–869 Caprioli D, Calu D, Shaham Y (2014) Loss of phasic dopamine: a new addiction marker? Nat Neurosci 17(5):644–646. https://doi.org/10.1038/nn.3699 Caraceni AT, Brunelli C, Rocco P, Minghetti P (2013) Trends in opioid analgesics sales to community pharmacies and hospitals in Italy (2000–2010). Minerva Anestesiol 79(8):906–914 Carlson RG, Nahhas RW, Martins SS, Daniulaityte R (2016) Predictors of transition to heroin use among initially non-opioid dependent illicit pharmaceutical opioid users: A natural history study. Drug Alcohol Depend 160:127–134. https://doi.org/10.1016/j.drugalcdep.2015.12.026 Castro D, Berridge KC (2012) Mu opioid, delta or kappa opioid receptor activation in nucleus accumbens hotspot enhances 'liking' reaction to hedonic impact of tastes. Society for Neuroscience Abstracts Castro DC, Berridge KC (2014) Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness “liking” and “wanting.” J Neurosci 34(12):4239–4250. https://doi.org/10.1523/JNEUROSCI.4458-13.2014 Castro DC, Berridge KC (2017) Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula. Proc Natl Acad Sci USA 114(43):E9125–E9134. https://doi.org/10.1073/pnas.1705753114 Chan S, Edwards SR, Wyse BD, Smith MT (2008) Sex differences in the pharmacokinetics, oxidative metabolism and oral bioavailability of oxycodone in the Sprague-Dawley rat. Clin Exp Pharmacol Physiol 35(3):295–302. https://doi.org/10.1111/j.1440-1681.2007.04821.x Childress AR, Ehrman RN, Wang Z, Li Y, Sciortino N, Hakun J, Jens W, Suh J, Listerud J, Marquez K, Franklin T, Langleben D, Detre J, O’Brien CP (2008) Prelude to passion: limbic activation by “unseen” drug and sexual cues. PLoS ONE 3(1):e1506. https://doi.org/10.1371/journal.pone.0001506 Chu J, Zheng H, Zhang Y, Loh HH, Law PY (2010) Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization. Cell Signal 22(4):684–696. https://doi.org/10.1016/j.cellsig.2009.12.003 Cicero TJ, Ellis MS (2015) Abuse-deterrent formulations and the prescription opioid abuse epidemic in the United States: lessons learned from OxyContin. JAMA Psychiatry 72(5):424–430. https://doi.org/10.1001/jamapsychiatry.2014.3043 Cicero TJ, Inciardi JA, Munoz A (2005) Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002–2004. J Pain 6(10):662–672. https://doi.org/10.1016/j.jpain.2005.05.004 Cicero TJ, Ellis MS, Paradis A, Ortbal Z (2010) Determinants of fentanyl and other potent micro opioid agonist misuse in opioid-dependent individuals. Pharmacoepidemiol Drug Saf 19(10):1057–1063. https://doi.org/10.1002/pds.1989 Cicero TJ, Ellis MS, Surratt HL (2012) Effect of abuse-deterrent formulation of OxyContin. N Engl J Med 367(2):187–189. https://doi.org/10.1056/NEJMc1204141 Cicero TJ, Ellis MS, Surratt HL, Kurtz SP (2013) Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States. Pain 154(12):2639–2648. https://doi.org/10.1016/j.pain.2013.07.025 Codd EE, Shank RP, Schupsky JJ, Raffa RB (1995) Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 274(3):1263–1270 Comer SD, Walker EA, Collins ED (2005) Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology (Berl) 181(4):664–675. https://doi.org/10.1007/s00213-005-0023-6 Comer SD, Sullivan MA, Whittington RA, Vosburg SK, Kowalczyk WJ (2008) Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology 33(5):1179–1191. https://doi.org/10.1038/sj.npp.1301479 Comer SD, Metz VE, Cooper ZD, Kowalczyk WJ, Jones JD, Sullivan MA, Manubay JM, Vosburg SK, Smith ME, Peyser D, Saccone PA (2013) Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts. Behav Pharmacol 24(5–6):504–516. https://doi.org/10.1097/FBP.0b013e328363d1c4 Cone EJ, Darwin WD, Buchwald WF, Gorodetzky CW (1983) Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 11(5):446–450 Cone EJ, Giordano J, Weingarten B (2013) An iterative model for in vitro laboratory assessment of tamper deterrent formulations. Drug Alcohol Depend 131(1–2):100–105. https://doi.org/10.1016/j.drugalcdep.2012.12.006 Conibear AE, Kelly E (2019) A biased view of mu-opioid receptors? Mol Pharmacol 96(5):542–549. https://doi.org/10.1124/mol.119.115956 Connors AL (2009) Big bad pharma: an ethical analysis of physician-directed and consumer-directed marketing tactics. Albany Law Rev 73(1):243–282 Cremeans CM, Gruley E, Kyle DJ, Ko MC (2012) Roles of mu-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther 343(1):72–81. https://doi.org/10.1124/jpet.112.194308 Dahan A, van Dam CJ, Niesters M, van Velzen M, Fossler MJ, Demitrack MA, Olofsen E (2020) Benefit and risk evaluation of biased mu-receptor agonist oliceridine versus morphine. Anesthesiology 133(3):559–568. https://doi.org/10.1097/ALN.0000000000003441 Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, Green JL (2015) Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med 372(3):241–248. https://doi.org/10.1056/NEJMsa1406143 Davis MP (2012) Drug management of visceral pain: concepts from basic research. Pain Res Treat 2012:265605. https://doi.org/10.1155/2012/265605 de Wit H, Phillips TJ (2012) Do initial responses to drugs predict future use or abuse? Neurosci Biobehav Rev 36:1565–1576. https://doi.org/10.1016/j.neubiorev.2012.04.005 de Guglielmo G, Matzeu A, Kononoff J, Mattioni J, Martin-Fardon R, George O (2017) Cebranopadol blocks the escalation of cocaine intake and conditioned reinstatement of cocaine seeking in rats. J Pharmacol Exp Ther 362(3):378–384. https://doi.org/10.1124/jpet.117.241042 De Schepper HU, Cremonini F, Park MI, Camilleri M (2004) Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil 16(4):383–394. https://doi.org/10.1111/j.1365-2982.2004.00513.x Deeks ED (2018) Tapentadol prolonged release: a review in pain management. Drugs 78(17):1805–1816. https://doi.org/10.1007/s40265-018-1007-2 Defalque RJ, Wright AJ (2003) Scophedal (SEE) was it a fad or a miracle drug? Bull Anesth Hist 21(4):12–14. https://doi.org/10.1016/s1522-8649(03)50051-8 Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85(14):5274–5278. https://doi.org/10.1073/pnas.85.14.5274 Di Giannuario A, Pieretti S (2000) Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats. Peptides 21(7):1125–1130. https://doi.org/10.1016/s0196-9781(00)00250-3 Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE, Lu JJ, Czoty PW, Kishioka S, Zaveri NT, Ko MC (2018) A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aar3483 Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS, Bruchas MR, Zweifel LS, Kieffer BL, Phillips PE, Chavkin C (2015) Kappa opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons. J Neurosci 35(37):12917–12931. https://doi.org/10.1523/JNEUROSCI.2444-15.2015 Emery MA, Bates ML, Wellman PJ, Eitan S (2015) Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors. Behav Brain Res 284:37–41. https://doi.org/10.1016/j.bbr.2015.01.023 Emery MA, Bates ML, Wellman PJ, Eitan S (2016) Differential effects of oxycodone, hydrocodone, and morphine on activation levels of signaling molecules. Pain Med 17(5):908–914. https://doi.org/10.1111/pme.12918 English DF, Ibanez-Sandoval O, Stark E, Tecuapetla F, Buzsaki G, Deisseroth K, Tepper JM, Koos T (2011) GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons. Nat Neurosci 15(1):123–130. https://doi.org/10.1038/nn.2984 Evans CJ, Cahill CM (2016) Neurobiology of opioid dependence in creating addiction vulnerability. F1000Res. https://doi.org/10.12688/f1000research.8369.1 Fain KM, Alexander GC (2014) Mind the gap: understanding the effects of pharmaceutical direct-to-consumer advertising. Med Care 52(4):291–293. https://doi.org/10.1097/MLR.0000000000000126 Fawzi AB, Macdonald D, Benbow LL, Smith-Torhan A, Zhang H, Weig BC, Ho G, Tulshian D, Linder ME, Graziano MP (2001) SCH-202676: an allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors. Mol Pharmacol 59(1):30–7. https://doi.org/10.1124/mol.59.1.30 Fenalti G, Giguere PM, Katritch V, Huang XP, Thompson AA, Cherezov V, Roth BL, Stevens RC (2014) Molecular control of delta-opioid receptor signalling. Nature 506(7487):191–196. https://doi.org/10.1038/nature12944 Ford CP, Mark GP, Williams JT (2006) Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location. J Neurosci 26(10):2788–2797. https://doi.org/10.1523/JNEUROSCI.4331-05.2006 Frank ST, Krumm B, Spanagel R (2008) Cocaine-induced dopamine overflow within the nucleus accumbens measured by in vivo microdialysis: a meta-analysis. Synapse 62(4):243–252. https://doi.org/10.1002/syn.20489 Fraser HF, Van Horn GD, Martin WR, Wolbach AB, Isbell H (1961) Methods for evaluating addiction liability. (A) “Attitude” of opiate addicts toward opiate-like drugs. (B) a short-term “direct” addiction test. J Pharmacol Exp Ther 133:371–387 Gavin PD, Tremper L, Smith A, Williams G, Brooker C (2017) Transdermal oxycodone patch for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled trial. Pain Manag 7(4):255–267. https://doi.org/10.2217/pmt-2016-0067 Gorka SM, Fitzgerald DA, de Wit H, Angstadt M, Phan KL (2014) Opioid modulation of resting-state anterior cingulate cortex functional connectivity. J Psychopharmacol 28(12):1115–1124. https://doi.org/10.1177/0269881114548436 Gould RW, Gunter BW, Bubser M, Matthews RT, Teal LB, Ragland MG, Bridges TM, Garrison AT, Winder DG, Lindsley CW, Jones CK (2019) Acute negative allosteric modulation of M5 muscarinic acetylcholine receptors inhibits oxycodone self-Administration and cue-induced reactivity with no effect on antinociception. ACS Chem Neurosci 10(8):3740–3750. https://doi.org/10.1021/acschemneuro.9b00274 Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK (2012) Structure of the delta-opioid receptor bound to naltrindole. Nature 485(7398):400–404. https://doi.org/10.1038/nature11111 Grau LE, Dasgupta N, Harvey AP, Irwin K, Givens A, Kinzly ML, Heimer R (2007) Illicit use of opioids: is OxyContin a “gateway drug”? Am J Addict 16(3):166–173. https://doi.org/10.1080/10550490701375293 Grim TW, Acevedo-Canabal A, Bohn LM (2020) Toward directing opioid receptor signaling to refine opioid therapeutics. Biol Psychiatry 87(1):15–21. https://doi.org/10.1016/j.biopsych.2019.10.020 Guo KK, Deng CQ, Lu GJ, Zhao GL (2018) Comparison of analgesic effect of oxycodone and morphine on patients with moderate and advanced cancer pain: a meta-analysis. BMC Anesthesiol 18(1):132. https://doi.org/10.1186/s12871-018-0583-8 Hagen NA, Babul N (1997) Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain. Cancer 79(7):1428–1437 Halls ML, Yeatman HR, Nowell CJ, Thompson GL, Gondin AB, Civciristov S, Bunnett NW, Lambert NA, Poole DP, Canals M (2016) Plasma membrane localization of the mu-opioid receptor controls spatiotemporal signaling. Sci Signal 9(414):16. https://doi.org/10.1126/scisignal.aac9177 Hamunen K, Paakkari P, Kalso E (2009) Trends in opioid consumption in the Nordic countries 2002–2006. Eur J Pain 13(9):954–962. https://doi.org/10.1016/j.ejpain.2008.11.006 Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, Mercadante S, Meynadier J, Poulain P, Ripamonti C, Radbruch L, Casas JR, Sawe J, Twycross RG, Ventafridda V (2001) Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 84(5):587–593. https://doi.org/10.1054/bjoc.2001.1680 Hansen TM, Lelic D, Olesen AE, Drewes AM, Frokjaer JB (2018) Differential effects of oxycodone and venlafaxine on resting state functional connectivity-A randomized placebo-controlled magnetic resonance imaging study. CNS Neurosci Ther 24(9):820–827. https://doi.org/10.1111/cns.12827 Harris SC, Perrino PJ, Smith I, Shram MJ, Colucci SV, Bartlett C, Sellers EM (2014) Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol 54(4):468–477. https://doi.org/10.1002/jcph.235 Heiskanen T, Kalso E (1997) Controlled-release oxycodone and morphine in cancer related pain. Pain 73(1):37–45. https://doi.org/10.1016/s0304-3959(97)00072-9 Hinkle C, Dedkov E, Buono B, Ferraro T (2019) Colocalization of MOR1 and GAD67 in mouse nucleus accumbens. bioRxiv. https://doi.org/10.1101/574434 Hirsch A, Proescholdbell SK, Bronson W, Dasgupta N (2014) Prescription histories and dose strengths associated with overdose deaths. Pain Med 15(7):1187–1195. https://doi.org/10.1111/pme.12391 Hser YI, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Huang D (2017) Chronic pain among patients with opioid use disorder: results from electronic health records data. J Subst Abuse Treat 77:26–30. https://doi.org/10.1016/j.jsat.2017.03.006 Hu E, Calo G, Guerrini R, Ko MC (2010) Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain 148(1):107–113 Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598. https://doi.org/10.1146/annurev.neuro.29.051605.113009 Ibanez-Sandoval O, Tecuapetla F, Unal B, Shah F, Koos T, Tepper JM (2010) Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum. J Neurosci 30(20):6999–7016. https://doi.org/10.1523/JNEUROSCI.5996-09.2010 Ibanez-Sandoval O, Tecuapetla F, Unal B, Shah F, Koos T, Tepper JM (2011) A novel functionally distinct subtype of striatal neuropeptide Y interneuron. J Neurosci 31(46):16757–16769. https://doi.org/10.1523/JNEUROSCI.2628-11.2011 Ikemoto S (2010) Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35(2):129–50. https://doi.org/10.1016/j.neubiorev.2010.02.001 Iriah SC, Trivedi M, Kenkel W, Grant SE, Moore K, Yee JR, Madularu D, Kulkarni P, Ferris CF (2019) Oxycodone exposure: a magnetic resonance imaging study in response to acute and chronic oxycodone treatment in rats. Neuroscience 398:88–101. https://doi.org/10.1016/j.neuroscience.2018.11.042 Ito R, Dalley JW, Howes SR, Robbins TW, Everitt BJ (2000) Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J Neurosci 20(19):7489–7495. https://doi.org/10.1523/JNEUROSCI.20-19-07489.2000 Jalabert M, Bourdy R, Courtin J, Veinante P, Manzoni OJ, Barrot M, Georges F (2011) Neuronal circuits underlying acute morphine action on dopamine neurons. Proc Natl Acad Sci USA 108(39):16446–16450. https://doi.org/10.1073/pnas.1105418108 Jang CG, Whitfield T, Schulteis G, Koob GF, Wee S (2013) A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats. Psychopharmacology (Berl) 225(3):753–763. https://doi.org/10.1007/s00213-012-2864-0 Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12(2):483–488. https://doi.org/10.1523/JNEUROSCI.12-02-00483.1992 Johnson EA, Oldfield S, Braksator E, Gonzalez-Cuello A, Couch D, Hall KJ, Mundell SJ, Bailey CP, Kelly E, Henderson G (2006) Agonist-selective mechanisms of mu-opioid receptor desensitization in human embryonic kidney 293 cells. Mol Pharmacol 70(2):676–685. https://doi.org/10.1124/mol.106.022376 Jones JD, Mumtaz M, Manubay JM, Mogali S, Sherwin E, Martinez S, Comer SD (2019) Assessing the contribution of opioid- and dopamine-related genetic polymorphisms to the abuse liability of oxycodone. Pharmacol Biochem Behav 186:172778. https://doi.org/10.1016/j.pbb.2019.172778 Jullié D, Gondin AB, von Zastrow M, Canals M (2020) Opioid pharmacology under the microscope. Mol Pharmacol 98(4):425–432. https://doi.org/10.1124/mol.119.119321 Jutkiewicz EM, Palleiko BA, Dripps IJ, Rice KC (2019) The opioid receptor positive allosteric modulator BMS-986187 enhances some, but not all, delta-opioid receptor mediated behaviors. FASEB J 33(S1):6665. https://doi.org/10.1096/fasebj.2019.33.1_supplement.666.5 Kaiko RF, Benziger DP, Fitzmartin RD, Burke BE, Reder RF, Goldenheim PD (1996) Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone. Clin Pharmacol Ther 59(1):52–61. https://doi.org/10.1016/S0009-9236(96)90024-7 Kalso E (2005) Oxycodone. J Pain Symptom Manage 29:S47-56. https://doi.org/10.1016/j.jpainsymman.2005.01.010 Kalso E, Vainio A (1990) Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther 47(5):639–646. https://doi.org/10.1038/clpt.1990.85 Kalso E, Poyhia R, Onnela P, Linko K, Tigerstedt I, Tammisto T (1991) Intravenous morphine and oxycodone for pain after abdominal surgery. Acta Anaesthesiol Scand 35(7):642–646. https://doi.org/10.1111/j.1399-6576.1991.tb03364.x Kapitzke D, Vetter I, Cabot PJ (2005) Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control. Ther Clin Risk Manag 1(4):279–297 Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E (2006) Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 372(5):354–361. https://doi.org/10.1007/s00210-006-0033-x Katz N, Fernandez K, Chang A, Benoit C, Butler SF (2008) Internet-based survey of nonmedical prescription opioid use in the United States. Clin J Pain 24(6):528–535. https://doi.org/10.1097/AJP.0b013e318167a087 Kemp JM, Powell TP (1971) The structure of the caudate nucleus of the cat: light and electron microscopy. Philos Trans R Soc Lond B Biol Sci 262(845):383–401. https://doi.org/10.1098/rstb.1971.0102 Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF (2006) Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J Neurosci 26(22):5894–5900. https://doi.org/10.1523/JNEUROSCI.0740-06.2006 Kim JI, Ganesan S, Luo SX, Wu YW, Park E, Huang EJ, Chen L, Ding JB (2015) Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons. Science 350(6256):102–106. https://doi.org/10.1126/science.aac4690 Kim MK, Ahn SE, Shin E, Park SW, Choi JH, Kang HY (2018) Comparison of analgesic efficacy of oxycodone and fentanyl after total hip replacement surgery: a randomized controlled trial. Medicine (Baltimore) 97(49):e13385. https://doi.org/10.1097/MD.0000000000013385 King SJ, Reid C, Forbes K, Hanks G (2011) A systematic review of oxycodone in the management of cancer pain. Palliat Med 25(5):454–470. https://doi.org/10.1177/0269216311401948 Kliewer A, Gillis A, Hill R, Schmiedel F, Bailey C, Kelly E, Henderson G, Christie MJ, Schulz S (2020) Morphine-induced respiratory depression is independent of beta-arrestin2 signalling. Br J Pharmacol 177(13):2923–2931. https://doi.org/10.1111/bph.15004 Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278(5335):52–58. https://doi.org/10.1126/science.278.5335.52 Kopruszinski CM, Swiokla J, Lee YS, Navratilova E, VanderVeen L, Yang M, Liu Y, Miyazaki T, Schmidt WK, Zalevsky J, Porreca F (2020) Preclinical assessment of the analgesic pharmacology of NKTR-181 in rodents. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-020-00816-3 Kringelbach ML (2010) The hedonic brain: A functional neuroanatomy of human pleasure. In: Kringelbach ML, Berridge KC (eds) Pleasures of the brain. Oxford University Press, Oxford, pp 202–221 Kringelbach ML, O’Doherty J, Rolls ET, Andrews C (2003) Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb Cortex 13(10):1064–1071. https://doi.org/10.1093/cercor/13.10.1064 Kuypers KPC, Desousafernandesperna EB, Dolder PC, Toennes SW, Theunissen EL, Mason NL, Hutten N, Ramaekers JG (2018) Drug liking and wanting, not impulsive action or reflection is increased by 4-fluoroamphetamine. Psychopharmacology (Berl) 235(8):2349–2356. https://doi.org/10.1007/s00213-018-4931-7 Labouèbe G, Lomazzi M, Cruz HG, Creton C, Lujan R, Li M, Yanagawa Y, Obata K, Watanabe M, Wickman K, Boyer SB, Slesinger PA, Luscher C (2007) RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nat Neurosci 10(12):1559–1568. https://doi.org/10.1038/nn2006 Lalovic B, Phillips B, Risler LL, Howald W, Shen DD (2004) Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 32(4):447–454. https://doi.org/10.1124/dmd.32.4.447 Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79(5):461–479. https://doi.org/10.1016/j.clpt.2006.01.009 Lauretti GR, Oliveira GM, Pereira NL (2003) Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer 89(11):2027–2030. https://doi.org/10.1038/sj.bjc.6601365 Law PY, Hom DS, Loh HH (1983) Opiate receptor down-regulation and desensitization in neuroblastoma X glioma NG108-15 hybrid cells are two separate cellular adaptation processes. Mol Pharmacol 24(3):413–424 Law PY, Wong YH, Loh HH (2000) Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 40:389–430. https://doi.org/10.1146/annurev.pharmtox.40.1.389 Lee K, Vuong HE, Nusbaum DJ, Hsiao EY, Evans CJ, Taylor AMW (2018) The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Neuropsychopharmacology 43(13):2606–2614. https://doi.org/10.1038/s41386-018-0211-9 Lefevre EM, Pisansky MT, Toddes C, Baruffaldi F, Pravetoni M, Tian L, Kono TJY, Rothwell PE (2020) Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system. Neuropsychopharmacology. https://doi.org/10.1038/s41386-020-0643-x Lemberg KK, Kontinen VK, Siiskonen AO, Viljakka KM, Yli-Kauhaluoma JT, Korpi ER, Kalso EA (2006) Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats. Anesthesiology 105(4):801–812. https://doi.org/10.1097/00000542-200610000-00027 Lemberg KK, Siiskonen AO, Kontinen VK, Yli-Kauhaluoma JT, Kalso EA (2008) Pharmacological characterization of noroxymorphone as a new opioid for spinal analgesia. Anesth Analg 106(2):463–470. https://doi.org/10.1213/ane.0b013e3181605a15 Lemberg KK, Heiskanen TE, Kontinen VK, Kalso EA (2009) Pharmacology of oxycodone: does it explain why oxycodone has become a bestselling strong opioid? Scand J Pain 1:S18–S23. https://doi.org/10.1016/S1877-8860(09)70005-9 Lenz H, Sandvik L, Qvigstad E, Bjerkelund CE, Raeder J (2009) A comparison of intravenous oxycodone and intravenous morphine in patient-controlled postoperative analgesia after laparoscopic hysterectomy. Anesth Analg 109(4):1279–1283. https://doi.org/10.1213/ane.0b013e3181b0f0bb Lester PA, Traynor JR (2006) Comparison of the in vitro efficacy of mu, delta, kappa and ORL1 receptor agonists and non-selective opioid agonists in dog brain membranes. Brain Res 1073–1074:290–296. https://doi.org/10.1016/j.brainres.2005.12.066 Leyton M (2010) The neurobiology of desire: dopamine and the regulation of mood and motivational states in humans. In: Kringelbach ML, Berridge KC (eds) Pleasures of the brain. Oxford University Press, Oxford, pp 222–243 Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schroder W, Kogel BY, Beier H, Englberger W, Schunk S, De Vry J, Jahnel U, Frosch S (2014) Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349(3):535–548. https://doi.org/10.1124/jpet.114.213694 Litman RS, Pagan OH, Cicero TJ (2018) Abuse-deterrent opioid formulations. Anesthesiology 128(5):1015–1026. https://doi.org/10.1097/ALN.0000000000002031 Liu SS, Pickens S, Burma NE, Ibarra-Lecue I, Yang H, Xue L, Cook C, Hakimian JK, Severino AL, Lueptow L, Komarek K, Taylor AMW, Olmstead MC, Carroll FI, Bass CE, Andrews AM, Walwyn W, Trang T, Evans CJ, Leslie FM, Cahill CM (2019) Kappa opioid receptors drive a tonic aversive component of chronic pain. J Neurosci 39(21):4162–4178. https://doi.org/10.1523/JNEUROSCI.0274-19.2019 Livingston KE, Traynor JR (2014) Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor. Proc Natl Acad Sci USA 111(51):18369–18374. https://doi.org/10.1073/pnas.1415013111 Livingston KE, Traynor JR (2018) Allostery at opioid receptors: modulation with small molecule ligands. Br J Pharmacol 175(14):2846–2856. https://doi.org/10.1111/bph.13823 Livingston KE, Stanczyk MA, Burford NT, Alt A, Canals M, Traynor JR (2018) Pharmacologic evidence for a putative conserved allosteric site on opioid receptors. Mol Pharmacol 93(2):157–167. https://doi.org/10.1124/mol.117.109561 Lobb CJ, Wilson CJ, Paladini CA (2010) A dynamic role for GABA receptors on the firing pattern of midbrain dopaminergic neurons. J Neurophysiol 104(1):403–413. https://doi.org/10.1152/jn.00204.2010 Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, Kieffer BL, Takeshima H, Carroll FI, Maidment NT, Evans CJ (2003) Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci 23(32):10331–10337. https://doi.org/10.1523/jneurosci.23-32-10331.2003 Lynch WJ, Nicholson KL, Dance ME, Morgan RW, Foley PL (2010) Animal models of substance abuse and addiction: implications for science, animal welfare, and society. Comp Med 60(3):177–188 Ma YY, Cepeda C, Chatta P, Franklin L, Evans CJ, Levine MS (2012) Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons. ASN Neuro. https://doi.org/10.1042/AN20110063 MacKillop J, de Wit H (2013) The Wiley-Blackwell handbook of addiction psychopharmacology. Wiley-Blackwell, Hoboken Maddocks I, Somogyi A, Abbott F, Hayball P, Parker D (1996) Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone. J Pain Symptom Manage 12(3):182–189. https://doi.org/10.1016/0885-3924(96)00050-4 Maincent J, Zhang F (2016) Recent advances in abuse-deterrent technologies for the delivery of opioids. Int J Pharm 510(1):57–72. https://doi.org/10.1016/j.ijpharm.2016.06.012 Malenka RC, Nestler EJ, Hyman SE (2009) Molecular neuropharmacology: a foundation for clinical neuroscience (2nd edn). McGraw-Hill Medical, New York, pp 147–148 Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485(7398):321–326. https://doi.org/10.1038/nature10954 Margolis EB, Toy B, Himmels P, Morales M, Fields HL (2012) Identification of rat ventral tegmental area GABAergic neurons. PLoS ONE 7(7):e42365. https://doi.org/10.1371/journal.pone.0042365 Margolis EB, Hjelmstad GO, Fujita W, Fields HL (2014) Direct bidirectional mu-opioid control of midbrain dopamine neurons. J Neurosci 34(44):14707–14716. https://doi.org/10.1523/JNEUROSCI.2144-14.2014 Markman J, Gudin J, Rauck R, Argoff C, Rowbotham M, Agaiby E, Gimbel J, Katz N, Doberstein SK, Tagliaferri M, Lu L, Siddhanti S, Hale M (2019) SUMMIT-07: a randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain. Pain 160(6):1374–1382. https://doi.org/10.1097/j.pain.0000000000001517 Mars SG, Bourgois P, Karandinos G, Montero F, Ciccarone D (2014) "Every 'never' I ever said came true": transitions from opioid pills to heroin injecting. Int J Drug Policy 25(2):257–266. doi: https://doi.org/10.1016/j.drugpo.2013.10.004 Matsui A, Jarvie BC, Robinson BG, Hentges ST, Williams JT (2014) Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron 82(6):1346–1356. https://doi.org/10.1016/j.neuron.2014.04.030 McMillan DM, Tyndale RF (2018) CYP-mediated drug metabolism in the brain impacts drug response. Pharmacol Ther 184:189–200. https://doi.org/10.1016/j.pharmthera.2017.10.008 Melief EJ, Miyatake M, Bruchas MR, Chavkin C (2010) Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling. Proc Natl Acad Sci USA 107(25):11608–11613. https://doi.org/10.1073/pnas.1000751107 Meredith GE, Agolia R, Arts MP, Groenewegen HJ, Zahm DS (1992) Morphological differences between projection neurons of the core and shell in the nucleus accumbens of the rat. Neuroscience 50(1):149–162. https://doi.org/10.1016/0306-4522(92)90389-j Minami K, Hasegawa M, Ito H, Nakamura A, Tomii T, Matsumoto M, Orita S, Matsushima S, Miyoshi T, Masuno K, Torii M, Koike K, Shimada S, Kanemasa T, Kihara T, Narita M, Suzuki T, Kato A (2009) Morphine, oxycodone, and fentanyl exhibit different analgesic profiles in mouse pain models. J Pharmacol Sci 111(1):60–72. https://doi.org/10.1254/jphs.09139fp Miyazaki T, Choi IY, Rubas W, Anand NK, Ali C, Evans J, Gursahani H, Hennessy M, Kim G, McWeeney D, Pfeiffer J, Quach P, Gauvin D, Riley TA, Riggs JA, Gogas K, Zalevsky J, Doberstein SK (2017) NKTR-181: a novel mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther 363(1):104–113. https://doi.org/10.1124/jpet.117.243030 Moore K, Madularu D, Iriah S, Yee JR, Kulkarni P, Darcq E, Kieffer BL, Ferris CF (2016) BOLD imaging in awake wild-Type and mu-Opioid receptor knock-out mice reveals on-target activation maps in response to oxycodone. Front Neurosci 10:471. https://doi.org/10.3389/fnins.2016.00471 Moradi M, Esmaeili S, Shoar S, Safari S (2012) Use of oxycodone in pain management. Anesth Pain Med 1(4):262–264. https://doi.org/10.5812/aapm.4529 Morales M, Margolis EB (2017) Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci 18(2):73–85 Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O’Malley SS (2013) The drug effects questionnaire: psychometric support across three drug types. Psychopharmacology (Berl) 227(1):177–192. https://doi.org/10.1007/s00213-012-2954-z Mucci-LoRusso P, Berman BS, Silberstein PT, Citron ML, Bressler L, Weinstein SM, Kaiko RF, Buckley BJ, Reder RF (1998) Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study. Eur J Pain 2(3):239–249. https://doi.org/10.1016/s1090-3801(98)90020-9 Murphy DL, Lebin JA, Severtson SG, Olsen HA, Dasgupta N, Dart RC (2018) Comparative rates of mortality and serious adverse effects among commonly prescribed opioid analgesics. Drug Saf 41(8):787–795. https://doi.org/10.1007/s40264-018-0660-4 Narita M, Nakamura A, Ozaki M, Imai S, Miyoshi K, Suzuki M, Suzuki T (2008) Comparative pharmacological profiles of morphine and oxycodone under a neuropathic pain-like state in mice: evidence for less sensitivity to morphine. Neuropsychopharmacology 33(5):1097–1112. https://doi.org/10.1038/sj.npp.1301471 Nasseef MT, Singh JP, Ehrlich AT, McNicholas M, Park DW, Ma W, Kulkarni P, Kieffer BL, Darcq E (2019) Oxycodone-mediated activation of the mu opioid receptor reduces whole brain functional connectivity in mice. ACS Pharmacol Transl Sci 2(4):264–274. https://doi.org/10.1021/acsptsci.9b00021 Neelakantan H, Ward SJ, Walker EA (2015) Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice. Exp Clin Psychopharmacol 23(4):217–227. https://doi.org/10.1037/pha0000028 Nesse RM, Berridge KC (1997) Psychoactive drug use in evolutionary perspective. Science 278(5335):63–66. https://doi.org/10.1126/science.278.5335.63 Nestler EJ, Malenka RC (2004) The addicted brain. Sci Am 290(3):78–85. https://doi.org/10.1038/scientificamerican0304-78 Nguyen JD, Grant Y, Taffe MA (2019) Paradoxical changes in brain reward status during opioid self-administration in a novel test of the negative reinforcement hypothesis. bioRxiv. https://doi.org/10.1101/460048 Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT (2007) Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 132(3):289–300. https://doi.org/10.1016/j.pain.2007.03.022 Nozaki C, Saitoh A, Kamei J (2006) Characterization of the antinociceptive effects of oxycodone in diabetic mice. Eur J Pharmacol 535(1–3):145–151. https://doi.org/10.1016/j.ejphar.2006.02.002 Ohbuchi K, Miyagi C, Suzuki Y, Mizuhara Y, Mizuno K, Omiya Y, Yamamoto M, Warabi E, Sudo Y, Yokoyama A, Miyano K, Hirokawa T, Uezono Y (2016) Ignavine: a novel allosteric modulator of the mu opioid receptor. Sci Rep 6:31748. https://doi.org/10.1038/srep31748 Olson KM, Duron DI, Womer D, Fell R, Streicher JM (2019) Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PLoS ONE 14(6):e0217371. https://doi.org/10.1371/journal.pone.0217371 Orlowski JP, Wateska L (1992) The effects of pharmaceutical firm enticements on physician prescribing patterns. There’s no such thing as a free lunch. Chest 102(1):270–273. https://doi.org/10.1378/chest.102.1.270 Osgood ED, Eaton TA, Trudeau JJ, Katz NP (2012) A brief survey to characterize oxycodone abuse patterns in adolescents enrolled in two substance abuse recovery high schools. Am J Drug Alcohol Abuse 38(2):166–170. https://doi.org/10.3109/00952990.2011.643994 Ostlund SB, LeBlanc KH, Kosheleff AR, Wassum KM, Maidment NT (2014) Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. Neuropsychopharmacology 39(10):2441–2449. https://doi.org/10.1038/npp.2014.96 Pappagallo M, Campbell JN (1994) Chronic opioid therapy as alternative treatment for post-herpetic neuralgia. Ann Neurol 35:S54-56. https://doi.org/10.1002/ana.410350716 Pasternak GW, Snyder SH (1975) Identification of novel high affinity opiate receptor binding in rat brain. Nature 253(5492):563–565. https://doi.org/10.1038/253563a0 Paulozzi LJ, Budnitz DS, Xi Y (2006) Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf 15(9):618–627 Pecina S, Berridge KC (2000) Opioid site in nucleus accumbens shell mediates eating and hedonic “liking” for food: map based on microinjection Fos plumes. Brain Res 863(1–2):71–86. https://doi.org/10.1016/s0006-8993(00)02102-8 Pecina S, Berridge KC (2005) Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness? J Neurosci 25(50):11777–11786. https://doi.org/10.1523/JNEUROSCI.2329-05.2005 Peckham EM, Traynor JR (2006) Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats. J Pharmacol Exp Ther 316(3):1195–1201. https://doi.org/10.1124/jpet.105.094276 Pena DA, Duarte ML, Pramio DT, Devi LA, Schechtman D (2018) Exploring morphine-triggered PKC-targets and their interaction with signaling pathways leading to pain via TrkA. Proteomes. https://doi.org/10.3390/proteomes6040039 Phillips PE, Robinson DL, Stuber GD, Carelli RM, Wightman RM (2003) Real-time measurements of phasic changes in extracellular dopamine concentration in freely moving rats by fast-scan cyclic voltammetry. Methods Mol Med 79:443–464. https://doi.org/10.1385/1-59259-358-5:443 Pitman KA, Puil E, Borgland SL (2014) GABA(B) modulation of dopamine release in the nucleus accumbens core. Eur J Neurosci 40(10):3472–34780. https://doi.org/10.1111/ejn.12733 Plummer JL, Cmielewski PL, Reynolds GD, Gourlay GK, Cherry DA (1990) Influence of polarity on dose-response relationships of intrathecal opioids in rats. Pain 40(3):339–347. https://doi.org/10.1016/0304-3959(90)91131-2 Pollini RA, Banta-Green CJ, Cuevas-Mota J, Metzner M, Teshale E, Garfein RS (2011) Problematic use of prescription-type opioids prior to heroin use among young heroin injectors. Subst Abuse Rehabil 2(1):173–180. https://doi.org/10.2147/SAR.S24800 Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci USA 92(26):12304–12308. https://doi.org/10.1073/pnas.92.26.12304 Pool E, Sennwald V, Delplanque S, Brosch T, Sander D (2016) Measuring wanting and liking from animals to humans: a systematic review. Neurosci Biobehav Rev 63:124–142. https://doi.org/10.1016/j.neubiorev.2016.01.006 Poyhia R, Kalso EA (1992) Antinociceptive effects and central nervous system depression caused by oxycodone and morphine in rats. Pharmacol Toxicol 70(2):125–130. https://doi.org/10.1111/j.1600-0773.1992.tb00441.x Poyhia R, Olkkola KT, Seppala T, Kalso E (1991) The pharmacokinetics of oxycodone after intravenous injection in adults. Br J Clin Pharmacol 32(4):516–518. https://doi.org/10.1111/j.1365-2125.1991.tb03942.x Raff M, Belbachir A, El-Tallawy S, Ho KY, Nagtalon E, Salti A, Seo JH, Tantri AR, Wang H, Wang T, Buemio KC, Gutierrez C, Hadjiat Y (2019) Intravenous oxycodone versus other intravenous strong opioids for acute postoperative pain control: a systematic review of randomized controlled trials. Pain Ther 8(1):19–39. https://doi.org/10.1007/s40122-019-0122-4 Raffa RB, Burdge G, Gambrah J, Kinecki HE, Lin F, Lu B, Nguyen JT, Phan V, Ruan A, Sesay MA, Watkins TN (2017) Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. J Clin Pharm Ther 42(1):8–17. https://doi.org/10.1111/jcpt.12461 Rappaport B (2008) Overview of the November 13, 2008 ALSDAC Meeting to Discuss NDA 22-324 for Remoxy (Oxycodone Hydrochloride Controlled-Release) Capsules. A. Division of Anesthesia, and Rheumatology Products, Office of Drug Evaluation II, editor. Remesic M, Hruby VJ, Porreca F, Lee YS (2017) Recent advances in the realm of allosteric modulators for opioid receptors for future therapeutics. ACS Chem Neurosci 8(6):1147–1158. https://doi.org/10.1021/acschemneuro.7b00090 Remillard D, Kaye AD, McAnally H (2019) Oxycodone’s unparalleled addictive potential: is it time for a moratorium? Curr Pain Headache Rep 23(2):15. https://doi.org/10.1007/s11916-019-0751-7 Riley J, Eisenberg E, Muller-Schwefe G, Drewes AM, Arendt-Nielsen L (2008) Oxycodone: a review of its use in the management of pain. Curr Med Res Opin 24(1):175–192. https://doi.org/10.1185/030079908x253708 Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18(3):247–291. https://doi.org/10.1016/0165-0173(93)90013-p Robinson TE, Berridge KC (2003) Addiction. Annu Rev Psychol 54:25–53 Rosenblum A, Parrino M, Schnoll SH, Fong C, Maxwell C, Cleland CM, Magura S, Haddox JD (2007) Prescription opioid abuse among enrollees into methadone maintenance treatment. Drug Alcohol Depend 90(1):64–71. https://doi.org/10.1016/j.drugalcdep.2007.02.012 Ross FB, Smith MT (1997) The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 73(2):151–157. https://doi.org/10.1016/s0304-3959(97)00093-6 Rothman RB, Murphy DL, Xu H, Godin JA, Dersch CM, Partilla JS, Tidgewell K, Schmidt M, Prisinzano TE (2007) Salvinorin A: allosteric interactions at the mu-opioid receptor. J Pharmacol Exp Ther 320(2):801–810. https://doi.org/10.1124/jpet.106.113167 Ruan X, Mancuso KF, Kaye AD (2017) Revisiting Oxycodone Analgesia: A Review And Hypothesis. Anesthesiol Clin 35(2):e163–e174. https://doi.org/10.1016/j.anclin.2017.01.022 Saigusa T, Aono Y, Mizoguchi N, Iwakami T, Takada K, Oi Y, Ueda K, Koshikawa N, Cools AR (2008) Role of GABA B receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats. Eur J Pharmacol 581(3):276–282. https://doi.org/10.1016/j.ejphar.2007.12.008 Setnik B, Roland CL, Goli V, Pixton GC, Levy-Cooperman N, Smith I, Webster L (2015) Self-reports of prescription opioid abuse and diversion among recreational opioid users in a Canadian and a United States city. J Opioid Manag 11(6):463–473. https://doi.org/10.5055/jom.2015.0299 Severino AL, Shadfar A, Hakimian JK, Crane O, Singh G, Heinzerling K, Walwyn WM (2018) Pain therapy guided by purpose and perspective in light of the opioid epidemic. Front Psychiatry 9:119. https://doi.org/10.3389/fpsyt.2018.00119 Sheik Amamuddy O, Veldman W, Manyumwa C, Khairallah A, Agajanian S, Oluyemi O, Verkhivker G, Tastan Bishop O (2020) Integrated computational approaches and tools for allosteric drug discovery. Int J Mol Sci. https://doi.org/10.3390/ijms21030847 Shimura T, Imaoka H, Yamamoto T (2006) Neurochemical modulation of ingestive behavior in the ventral pallidum. Eur J Neurosci 23(6):1596–1604. https://doi.org/10.1111/j.1460-9568.2006.04689.x Shippenberg TS, LeFevour A, Chefer VI (2008) Targeting endogenous mu- and delta-opioid receptor systems for the treatment of drug addiction. CNS Neurol Disord Drug Targets 7(5):442–453. https://doi.org/10.2174/187152708786927813 Shirayama Y, Chaki S (2006) Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. Curr Neuropharmacol 4(4):277–291. https://doi.org/10.2174/157015906778520773 Siegal HA, Carlson RG, Kenne DR, Swora MG (2003) Probable relationship between opioid abuse and heroin use. Am Fam Physician 67(5):942–945 Singla NK, Skobieranda F, Soergel DG, Salamea M, Burt DA, Demitrack MA, Viscusi ER (2019) APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the mu-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty. Pain Pract 19(7):715–731. https://doi.org/10.1111/papr.12801 Small DM, Zatorre RJ, Dagher A, Evans AC, Jones-Gotman M (2001) Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain 124:1720–1733. https://doi.org/10.1093/brain/124.9.1720 Smith KS, Berridge KC (2005) The ventral pallidum and hedonic reward: neurochemical maps of sucrose “liking” and food intake. J Neurosci 25(38):8637–8649. https://doi.org/10.1523/JNEUROSCI.1902-05.2005 Smith KS, Berridge KC (2007) Opioid limbic circuit for reward: interaction between hedonic hotspots of nucleus accumbens and ventral pallidum. J Neurosci 27(7):1594–1605. https://doi.org/10.1523/JNEUROSCI.4205-06.2007 Smith FL, Javed RR, Elzey MJ, Dewey WL (2003) The expression of a high level of morphine antinociceptive tolerance in mice involves both PKC and PKA. Brain Res 985(1):78–88. https://doi.org/10.1016/s0006-8993(03)03170-6 Smith FL, Gabra BH, Smith PA, Redwood MC, Dewey WL (2007) Determination of the role of conventional, novel and atypical PKC isoforms in the expression of morphine tolerance in mice. Pain 127(1–2):129–139. https://doi.org/10.1016/j.pain.2006.08.009 Smith KS, Berridge KC, Aldridge JW (2011) Disentangling pleasure from incentive salience and learning signals in brain reward circuitry. Proc Natl Acad Sci USA 108(27):E255-264. https://doi.org/10.1073/pnas.1101920108 Smith K, Hopp M, Mundin G, Bond S, Bailey P, Woodward J, Bell D (2012) Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther 50(5):360–367. https://doi.org/10.5414/cp201646 Song Z, Zou W, Liu C, Guo Q (2010) Gene knockdown with lentiviral vector-mediated intrathecal RNA interference of protein kinase C gamma reverses chronic morphine tolerance in rats. J Gene Med 12(11):873–880. https://doi.org/10.1002/jgm.1514 Steiner JE, Glaser D, Hawilo ME, Berridge KC (2001) Comparative expression of hedonic impact: affective reactions to taste by human infants and other primates. Neurosci Biobehav Rev 25(1):53–74. https://doi.org/10.1016/s0149-7634(00)00051-8 Svingos AL, Clarke CL, Pickel VM (1999) Localization of the delta-opioid receptor and dopamine transporter in the nucleus accumbens shell: implications for opiate and psychostimulant cross-sensitization. Synapse 34(1):1–10 Taylor R Jr, Raffa RB, Pergolizzi JV Jr (2012) Controlled release formulation of oxycodone in patients with moderate to severe chronic osteoarthritis: a critical review of the literature. J Pain Res 5:77–87. https://doi.org/10.2147/JPR.S21965 Tepper JM, Wilson CJ, Koos T (2008) Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons. Brain Res Rev 58(2):272–281. https://doi.org/10.1016/j.brainresrev.2007.10.008 Tepper JM, Tecuapetla F, Koos T, Ibanez-Sandoval O (2010) Heterogeneity and diversity of striatal GABAergic interneurons. Front Neuroanat 4:150. https://doi.org/10.3389/fnana.2010.00150 Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE (2004) Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther 308(2):547–554. https://doi.org/10.1124/jpet.103.058602 Tian JH, Xu W, Fang Y, Mogil JS, Grisel JE, Grandy DK, Han JS (1997) Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat. Br J Pharmacol 120(4):676–680. https://doi.org/10.1038/sj.bjp.0700942 Tritsch NX, Oh WJ, Gu C, Sabatini BL (2014) Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis. Elife 3:e01936. https://doi.org/10.7554/eLife.01936 Tzschentke TM, Rutten K (2018) Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat. Neuropharmacology 129:100–108. https://doi.org/10.1016/j.neuropharm.2017.11.026 Upadhyay J, Maleki N, Potter J, Elman I, Rudrauf D, Knudsen J, Wallin D, Pendse G, McDonald L, Griffin M, Anderson J, Nutile L, Renshaw P, Weiss R, Becerra L, Borsook D (2010) Alterations in brain structure and functional connectivity in prescription opioid-dependent patients. Brain 133(Pt7):2098–2114. https://doi.org/10.1093/brain/awq138 Van Zee A (2009) The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health 99(2):221–227. https://doi.org/10.2105/AJPH.2007.131714 van Zessen R, Phillips JL, Budygin EA, Stuber GD (2012) Activation of VTA GABA neurons disrupts reward consumption. Neuron 73(6):1184–1194. https://doi.org/10.1016/j.neuron.2012.02.016 Vander Weele CM, Porter-Stransky KA, Mabrouk OS, Lovic V, Singer BF, Kennedy RT, Aragona BJ (2014) Rapid dopamine transmission within the nucleus accumbens: dramatic difference between morphine and oxycodone delivery. Eur J Neurosci 40(7):3041–3054. https://doi.org/10.1111/ejn.12709 Vaysse PJ, Gardner EL, Zukin RS (1987) Modulation of rat brain opioid receptors by cannabinoids. J Pharmacol Exp Ther 241(2):534–539 Ventola CL (2011) Direct-to-consumer pharmaceutical advertising: therapeutic or toxic? P T 36(10):669–684 Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F (2016) A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain 157(1):264–272. https://doi.org/10.1097/j.pain.0000000000000363 Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N (2019) APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the micro-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy. J Pain Res 12:927–943. https://doi.org/10.2147/JPR.S171013 Wade CL, Vendruscolo LF, Schlosburg JE, Hernandez DO, Koob GF (2015) Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology 40(2):421–428. https://doi.org/10.1038/npp.2014.188 Walentiny DM, Moisa LT, Beardsley PM (2019) Oxycodone-like discriminative stimulus effects of fentanyl-related emerging drugs of abuse in mice. Neuropharmacology 150:210–216. https://doi.org/10.1016/j.neuropharm.2019.02.007 Watson CP, Babul N (1998) Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 50(6):1837–1841. https://doi.org/10.1212/wnl.50.6.1837 Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J (2003) Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 105(1–2):71–78. https://doi.org/10.1016/s0304-3959(03)00160-x Webster LR, Johnson FK, Stauffer J, Setnik B, Ciric S (2011) Impact of intravenous naltrexone on intravenous morphine-induced high, drug liking, and euphoric effects in experienced, nondependent male opioid users. Drugs R D 11(3):259–275. https://doi.org/10.2165/11593390-000000000-00000 Webster LR, Bath B, Medve RA, Marmon T, Stoddard GJ (2012) Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone. Pain Med 13(6):790–801. https://doi.org/10.1111/j.1526-4637.2012.01380.x Webster L, Henningfield J, Buchhalter AR, Siddhanti S, Lu L, Odinecs A, Di Fonzo CJ, Eldon MA (2018) Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med 19(2):307–318. https://doi.org/10.1093/pm/pnw344 Werling LL, Brown SR, Puttfarcken P, Cox BM (1986) Sodium regulation of agonist binding at opioid receptors. II. Effects of sodium replacement on opioid binding in guinea pig cortical membranes. Mol Pharmacol 30(2):90–95 Wightman R, Perrone J, Portelli I, Nelson L (2012) Likeability and abuse liability of commonly prescribed opioids. J Med Toxicol 8(4):335–340. https://doi.org/10.1007/s13181-012-0263-x Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ (2013) Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65(1):223–254. https://doi.org/10.1124/pr.112.005942 Willuhn I, Burgeno LM, Groblewski PA, Phillips PE (2014) Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat Neurosci 17(5):704–709. https://doi.org/10.1038/nn.3694 Wirz S, Wartenberg HC, Nadstawek J (2005) Pain management procedures used by dental and maxillofacial surgeons: an investigation with special regard to odontalgia. Head Face Med 1:14. https://doi.org/10.1186/1746-160X-1-14 Wise RA (1985) The anhedonia hypothesis: Mark III. Behav Brain Sci 8:178–186. https://doi.org/10.1017/s0140525x00020306 Witteman J, Post H, Tarvainen M, de Bruijn A, Perna Ede S, Ramaekers JG, Wiers RW (2015) Cue reactivity and its relation to craving and relapse in alcohol dependence: a combined laboratory and field study. Psychopharmacology (Berl) 232(20):3685–3696. https://doi.org/10.1007/s00213-015-4027-6 Woolley JD, Lee BS, Fields HL (2006) Nucleus accumbens opioids regulate flavor-based preferences in food consumption. Neuroscience 143(1):309–317. https://doi.org/10.1016/j.neuroscience.2006.06.067 Wu J, Lu Y, Cao X (2019) Different effects of oxycodone and remifentanil in patients undergoing ultrasound-guided percutaneous radiofrequency ablation of hepatic cancer: a randomized trial. Drug Des Devel Ther 13:365–372. https://doi.org/10.2147/DDDT.S188728 Yager LM, Garcia AF, Wunsch AM, Ferguson SM (2015) The ins and outs of the striatum: role in drug addiction. Neuroscience 301:529–541. https://doi.org/10.1016/j.neuroscience.2015.06.033 Yang PP, Yeh GC, Yeh TK, Xi J, Loh HH, Law PY, Tao PL (2016) Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. Pharmacol Res 111:867–876. https://doi.org/10.1016/j.phrs.2016.05.034 Yang H, de Jong JW, Tak Y, Peck J, Bateup HS, Lammel S (2018) Nucleus accumbens subnuclei regulate motivated behavior via direct inhibition and disinhibition of VTA dopamine subpopulations. Neuron 97(2):434–449. https://doi.org/10.1016/j.neuron.2017.12.022 Yang PP, Yeh TK, Loh HH, Law PY, Wang Y, Tao PL (2019) Delta-opioid receptor antagonist naltrindole reduces oxycodone addiction and constipation in mice. Eur J Pharmacol 852:265–273. https://doi.org/10.1016/j.ejphar.2019.04.009 Young AM, Havens JR (2012) Transition from first illicit drug use to first injection drug use among rural Appalachian drug users: a cross-sectional comparison and retrospective survival analysis. Addiction 107(3):587–596. https://doi.org/10.1111/j.1360-0443.2011.03635.x Yu Y, Li D, Duan J, Xu H, Li L, Tan D, Yan H (2020) The pro- and anti-cancer effects of oxycodone are associated with epithelial growth factor receptor level in cancer cells. Biosci Rep 40:2 Zacny JP, Gutierrez S (2003) Characterizing the subjective, psychomotor, and physiological effects of oral oxycodone in non-drug-abusing volunteers. Psychopharmacology (Berl) 170(3):242–254. https://doi.org/10.1007/s00213-003-1540-9 Zacny JP, Gutierrez S (2008) Subjective, psychomotor, and physiological effects profile of hydrocodone/acetaminophen and oxycodone/acetaminophen combination products. Pain Med 9(4):433–443. https://doi.org/10.1111/j.1526-4637.2007.00359.x Zacny JP, Gutierrez S (2009) Within-subject comparison of the psychopharmacological profiles of oral hydrocodone and oxycodone combination products in non-drug-abusing volunteers. Drug Alcohol Depend 101(1–2):107–114. https://doi.org/10.1016/j.drugalcdep.2008.11.013 Zacny JP, Lichtor SA (2008) Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers. Psychopharmacology (Berl) 196(1):105–116. https://doi.org/10.1007/s00213-007-0937-2 Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C (2003) College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend 69(3):215–232. https://doi.org/10.1016/s0376-8716(03)00003-6 Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA (1995) Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain 63(1):65–76 Zhang M, Gosnell BA, Kelley AE (1998) Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens. J Pharmacol Exp Ther 285(2):908–914 Zhang L, Zhang JT, Hang L, Liu T (2020) Mu opioid receptor heterodimers emerge as novel therapeutic targets: recent progress and future perspective. Front Pharmacol 11:1078. https://doi.org/10.3389/fphar.2020.01078 Zheng H, Loh HH, Law PY (2008) Beta-arrestin-dependent mu-opioid receptor-activated extracellular signal-regulated kinases (ERKs) Translocate to Nucleus in Contrast to G protein-dependent ERK activation. Mol Pharmacol 73(1):178–190. https://doi.org/10.1124/mol.107.039842 Zheng H, Chu J, Zhang Y, Loh HH, Law PY (2011) Modulating micro-opioid receptor phosphorylation switches agonist-dependent signaling as reflected in PKCepsilon activation and dendritic spine stability. J Biol Chem 286(14):12724–12733. https://doi.org/10.1074/jbc.M110.177089 Zhou Y, Li X, Zhang M, Zhang F, Zhu C, Shen M (2012) Behavioural approach tendencies to heroin-related stimuli in abstinent heroin abusers. Psychopharmacology (Berl) 221(1):171–176. https://doi.org/10.1007/s00213-011-2557-0