Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KOR-dependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia—G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation.
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Crowley NA, Kash TL. Kappa opioid receptor signaling in the brain: circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2015;62:51–60.
Chavkin C, Koob GF. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology. 2016;41:373–4.
Schindler AG, Messinger DI, Smith JS, Shankar H, Gustin RM, Schattauer SS, et al. Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J Neurosci. 2012;32:17582–96.
Van't Veer A, Carlezon WA Jr. Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology. 2013;229:435–52.
Schenk S, Partridge B, Shippenberg TS. U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking. Psychopharmacology. 1999;144:339–46.
Chartoff EH, Ebner SR, Sparrow A, Potter D, Baker PM, Ragozzino ME, et al. Relative timing between kappa opioid receptor activation and cocaine determines the impact on reward and dopamine release. Neuropsychopharmacology. 2016;41:989–1002.
Chavkin C. The therapeutic potential of kappa-opioids for treatment of pain and addiction. Neuropsychopharmacology. 2011;36:369–70.
Carlezon WA Jr., Krystal AD. Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depress Anxiety. 2016;33:895–906.
Kolodny A, Courtwright DT, Hwang CS, Kreiner P, Eadie JL, Clark TW, et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu Rev Public Health. 2015;36:559–74.
Koh H. Community approaches to the opioid crisis. JAMA. 2015;314:1437–8.
Volkow ND, Collins FS. The role of science in addressing the opioid crisis. N Engl J Med. 2017;377:1798.
Kaski SW, Brooks S, Wen S, Haut MW, Siderovski DP, Berry JH, et al. Four single nucleotide polymorphisms in genes involved in neuronal signaling are associated with Opioid Use Disorder in West Virginia. J Opioid Manag. 2019;15:103–9.
Bohn LM, Aube J. Seeking (and finding) biased ligands of the kappa opioid receptor. ACS Med Chem Lett. 2017;8:694–700.
Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS, Bruchas MR, et al. Kappa opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons. J Neurosci. 2015;35:12917–31.
White KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR, Zjawiony JK, et al. The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J Pharm Exp Ther. 2015;352:98–109.
Brust TF, Morgenweck J, Kim SA, Rose JH, Locke JL, Schmid CL, et al. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal. 2016;9:ra117.
Liu JJ, Sharma K, Zangrandi L, Chen C, Humphrey SJ, Chiu YT, et al. In vivo brain GPCR signaling elucidated by phosphoproteomics. Science. 2018;360:pii: eaao4927.
Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, et al. Functional selectivity and classical concepts of quantitative pharmacology. J Pharm Exp Ther. 2007;320:1–13.
Rankovic Z, Brust TF, Bohn LM. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett. 2016;26:241–50.
Che T, Majumdar S, Zaidi SA, Ondachi P, McCorvy JD, Wang S, et al. Structure of the nanobody-stabilized active state of the kappa opioid receptor. Cell. 2018;172:55–67 e15.
Siderovski DP, Willard FS. The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci. 2005;1:51–66.
Karkhanis A, Holleran KM, Jones SR. Dynorphin/kappa opioid receptor signaling in preclinical models of alcohol, drug, and food addiction. Int Rev Neurobiol. 2017;136:53–88.
Schoffelmeer AN, Rice KC, Jacobson AE, Van Gelderen JG, Hogenboom F, Heijna MH, et al. Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate. Eur J Pharm. 1988;154:169–78.
Tallent M, Dichter MA, Bell GI, Reisine T. The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells. Neuroscience. 1994;63:1033–40.
Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C. Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes. Mol Pharm. 1995;47:551–7.
McLaughlin JP, Xu M, Mackie K, Chavkin C. Phosphorylation of a carboxyl-terminal serine within the kappa-opioid receptor produces desensitization and internalization. J Biol Chem. 2003;278:34631–40.
Bruchas MR, Macey TA, Lowe JD, Chavkin C. Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. J Biol Chem. 2006;281:18081–9.
Chavkin C, Schattauer SS, Levin JR. Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences. Handb Exp Pharm. 2014;219:281–292.
Hernandez A, Soto-Moyano R, Mestre C, Eschalier A, Pelissier T, Paeile C, et al. Intrathecal pertussis toxin but not cyclic AMP blocks kappa opioid-induced antinociception in rat. Int J Neurosci. 1995;81:193–7.
Schattauer SS, Kuhar JR, Song A, Chavkin C. Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor. Cell Signal. 2017;32:59–65.
Soundararajan M, Willard FS, Kimple AJ, Turnbull AP, Ball LJ, Schoch GA, et al. Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits. Proc Natl Acad Sci USA. 2008;105:6457–62.
Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, et al. GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. J Biol Chem. 1998;273:17749–55.
Lambert NA, Johnston CA, Cappell SD, Kuravi S, Kimple AJ, Willard FS, et al. Regulators of G-protein signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity. Proc Natl Acad Sci USA. 2010;107:7066–71.
Han MH, Renthal W, Ring RH, Rahman Z, Psifogeorgou K, Howland D, et al. Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biol Psychiatry. 2010;67:761–9.
Traynor J. mu-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2012;121:173–80.
Anderson GR, Posokhova E, Martemyanov KA. The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling. Cell Biochem Biophys. 2009;54:33–46.
Shu FJ, Ramineni S, Hepler JR. RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways. Cell Signal. 2010;22:366–76.
Willard MD, Willard FS, Li X, Cappell SD, Snider WD, Siderovski DP. Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation. EMBO J. 2007;26:2029–40.
Webb CK, McCudden CR, Willard FS, Kimple RJ, Siderovski DP, Oxford GS. D2 dopamine receptor activation of potassium channels is selectively decoupled by Galpha-specific GoLoco motif peptides. J Neurochem. 2005;92:1408–18.
Gross JD, Kaski SW, Schroer AB, Wix KA, Siderovski DP, Setola V. Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants. J Psychopharmacol. 2018;32:191–203.
Chao J, Nestler EJ. Molecular neurobiology of drug addiction. Annu Rev Med. 2004;55:113–32.
Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25.
Bruijnzeel AW. Kappa-Opioid receptor signaling and brain reward function. Brain Res Rev. 2009;62:127–46.
Knoll AT, Carlezon WA Jr. Dynorphin, stress, and depression. Brain Res. 2010;1314:56–73.
Chefer VI, Backman CM, Gigante ED, Shippenberg TS. Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion. Neuropsychopharmacology. 2013;38:2623–31.
Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharm Exp Ther. 1988;244:1067–80.
Donzanti BA, Althaus JS, Payson MM, Von Voigtlander PF. Kappa agonist-induced reduction in dopamine release: site of action and tolerance. Res Commun Chem Pathol Pharm. 1992;78:193–210.
Thompson AC, Zapata A, Justice JB Jr., Vaughan RA, Sharpe LG, Shippenberg TS. Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. J Neurosci. 2000;20:9333–40.
Kivell B, Uzelac Z, Sundaramurthy S, Rajamanickam J, Ewald A, Chefer V, et al. Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism. Neuropharmacology. 2014;86:228–40.
Schmidt KT, Makhijani VH, Boyt KM, Cogan ES, Pati D, Pina MM, et al. Stress-induced alterations of norepinephrine release in the bed nucleus of the Stria terminalis of Mice. ACS Chem Neurosci. 2018;10:1908–14.
Zhou L, Stahl EL, Lovell KM, Frankowski KJ, Prisinzano TE, Aube J, et al. Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPgammaS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting. Neuropharmacology. 2015;99:131–41.
Jordan M, Schallhorn A, Wurm FM. Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation. Nucleic Acids Res. 1996;24:596–601.
Barnea G, Strapps W, Herrada G, Berman Y, Ong J, Kloss B, et al. The genetic design of signaling cascades to record receptor activation. Proc Natl Acad Sci USA. 2008;105:64–69.
Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, et al. Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci USA. 2011;108:18488–93.
Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999;286:2495–8.
Yorgason JT, Espana RA, Jones SR. Demon voltammetry and analysis software: analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures. J Neurosci Methods. 2011;202:158–64.
Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron. 2012;75:58–64.
Melchior JR, Ferris MJ, Stuber GD, Riddle DR, Jones SR. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release. J Neurochem. 2015;134:833–44.
Castellano C, Ammassari-Teule M, Libri V, Pavone F. Effects of kappa-opioid receptor agonists on locomotor activity and memory processes in mice. Pol J Pharm Pharm. 1988;40:507–13.
Bohn LM, Zhou L, Ho JH. Approaches to assess functional selectivity in GPCRs: evaluating G protein signaling in an endogenous environment. Methods Mol Biol. 2015;1335:177–89.
Pan ZZ. mu-Opposing actions of the kappa-opioid receptor. Trends Pharm Sci. 1998;19:94–98.
Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115:1363–81.
Sambi BS, Hains MD, Waters CM, Connell MC, Willard FS, Kimple AJ, et al. The effect of RGS12 on PDGFbeta receptor signalling to p42/p44 mitogen activated protein kinase in mammalian cells. Cell Signal. 2006;18:971–81.
Kimple RJ, Kimple ME, Betts L, Sondek J, Siderovski DP. Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits. Nature. 2002;416:878–81.
Li JG, Chen C, Liu-Chen LY. Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate. J Biol Chem. 2002;277:27545–52.
Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, et al. Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA. 1997;94:1544–9.
Pasternak GW. Molecular insights into mu opioid pharmacology: from the clinic to the bench. Clin J Pain. 2010;26:S3–9.
Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, et al. Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci USA. 2009;106:19168–73.
Vien TN, Gleason CA, Hays SL, McPherson RJ, Chavkin C, Juul SE. Effects of neonatal stress and morphine on kappa opioid receptor signaling. Neonatology. 2009;96:235–43.
Karkhanis AN, Rose JH, Weiner JL, Jones SR. Early-life social isolation stress increases kappa opioid receptor responsiveness and downregulates the dopamine system. Neuropsychopharmacology. 2016;41:2263–74.
Yorgason JT, Calipari ES, Ferris MJ, Karkhanis AN, Fordahl SC, Weiner JL, et al. Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. Neuropharmacology. 2016;101:471–9.
Martin-McCaffrey L, Hains MD, Pritchard GA, Pajak A, Dagnino L, Siderovski DP, et al. Differential expression of regulator of G-protein signaling R12 subfamily members during mouse development. Dev Dyn. 2005;234:438–44.
Butko MT, Savas JN, Friedman B, Delahunty C, Ebner F, Yates JR III, et al. In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation. Proc Natl Acad Sci USA. 2013;110:E726–35.
Sialana FJ, Wang AL, Fazari B, Kristofova M, Smidak R, Trossbach SV, et al. Quantitative proteomics of synaptosomal fractions in a rat overexpressing human DISC1 gene indicates profound synaptic dysregulation in the dorsal striatum. Front Mol Neurosci. 2018;11:26.
Saunders A, Macosko EZ, Wysoker A, Goldman M, Krienen FM, de Rivera H, et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell. 2018;174:1015–30 e1016.
Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Pena CJ, et al. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward. Proc Natl Acad Sci USA. 2016;113:2726–31.
Tejeda HA, Wu J, Kornspun AR, Pignatelli M, Kashtelyan V, Krashes MJ, et al. Pathway and cell-specific kappa-opioid receptor modulation of excitation-inhibition balance differentially gates D1 and D2 accumbens neuron activity. Neuron. 2017;93:147–63.
Melchior JR, Jones SR. Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo. Mol Cell Neurosci. 2017;85:93–104.
Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 1995;18:22–29.
Resendez SL, Keyes PC, Day JJ, Hambro C, Austin CJ, Maina FK, et al. Dopamine and opioid systems interact within the nucleus accumbens to maintain monogamous pair bonds. Elife. 2016;5:pii: e15325.
Nirenberg MJ, Chan J, Pohorille A, Vaughan RA, Uhl GR, Kuhar MJ, et al. The dopamine transporter: comparative ultrastructure of dopaminergic axons in limbic and motor compartments of the nucleus accumbens. J Neurosci. 1997;17:6899–907.
Chen N, Reith ME. Substrates and inhibitors display different sensitivity to expression level of the dopamine transporter in heterologously expressing cells. J Neurochem. 2007;101:377–88.
Robinson DL, Venton BJ, Heien ML, Wightman RM. Detecting subsecond dopamine release with fast-scan cyclic voltammetry in vivo. Clin Chem. 2003;49:1763–73.
Phillips PE, Hancock PJ, Stamford JA. Time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release. Synapse. 2002;44:15–22.
McGinnis MM, Siciliano CA, Jones SR. Dopamine D3 autoreceptor inhibition enhances cocaine potency at the dopamine transporter. J Neurochem. 2016;138:821–9.
Bermingham DP, Blakely RD. Kinase-dependent regulation of monoamine neurotransmitter transporters. Pharm Rev. 2016;68:888–53.
Richardson BD, Saha K, Krout D, Cabrera E, Felts B, Henry LK, et al. Membrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane. Nat Commun. 2016;7:10423.
Gowrishankar R, Gresch PJ, Davis GL, Katamish RM, Riele JR, Stewart AM, et al. Region-specific regulation of presynaptic dopamine homeostasis by D2 autoreceptors shapes the in vivo impact of the neuropsychiatric disease-associated DAT variant Val559. J Neurosci. 2018;38:5302–12.
Gray AM, Rawls SM, Shippenberg TS, McGinty JF. The kappa-opioid agonist, U-69593, decreases acute amphetamine-evoked behaviors and calcium-dependent dialysate levels of dopamine and glutamate in the ventral striatum. J Neurochem. 1999;73:1066–74.
Marcott PF, Gong S, Donthamsetti P, Grinnell SG, Nelson MN, Newman AH, et al. Regional heterogeneity of D2-receptor signaling in the dorsal striatum and nucleus accumbens. Neuron. 2018;98:575–87 e574.
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.
Lipp J. Possible mechanisms of morphine analgesia. Clin Neuropharmacol. 1991;14:131–47.
Jensen TS. Opioids in the brain: supraspinal mechanisms in pain control. Acta Anaesthesiol Scand. 1997;41:123–32.
Altier N, Stewart J. The role of dopamine in the nucleus accumbens in analgesia. Life Sci. 1999;65:2269–87.
Gear RW, Aley KO, Levine JD. Pain-induced analgesia mediated by mesolimbic reward circuits. J Neurosci. 1999;19:7175–81.
Hylden JL, Nahin RL, Traub RJ, Dubner R. Effects of spinal kappa-opioid receptor agonists on the responsiveness of nociceptive superficial dorsal horn neurons. Pain. 1991;44:187–93.
Cai X, Huang H, Kuzirian MS, Snyder LM, Matsushita M, Lee MC, et al. Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling. Genesis. 2016;54:29–37.
Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010;11:823–36.
Tsai NP, Tsui YC, Pintar JE, Loh HH, Wei LN. Kappa opioid receptor contributes to EGF-stimulated neurite extension in development. Proc Natl Acad Sci USA. 2010;107:3216–21.
Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, et al. Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci. 2004;24:4576–84.
Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, et al. Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO J. 1998;17:886–97.
Shippenberg TS, Bals-Kubik R, Herz A. Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors. J Pharm Exp Ther. 1993;265:53–59.
Bruchas MR, Chavkin C. Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology. 2010;210:137–47.
We thank Dr. Gilad Barnea for furnishing HTLA cells for in-house Tango assays.
The authors declare no competing interests.
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Gross, J.D., Kaski, S.W., Schmidt, K.T. et al. Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior. Neuropsychopharmacol. 44, 1728–1741 (2019). https://doi.org/10.1038/s41386-019-0423-7
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