Brownstein, M. J. A brief history of opiates, opioid peptides, and opioid receptors. Proc. Natl Acad. Sci. USA 90, 5391–5393 (1993).
World Health Organization. Curbing prescription opioid dependency. WHO http://www.who.int/bulletin/volumes/95/5/17-020517/en/ (2017).
Kolodny, A. et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu. Rev. Publ. Health 36, 559–574 (2015).
Volkow, N. D. & McLellan, A. T. Opioid abuse in chronic pain — misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253–1263 (2016).
Voon, P., Karamouzian, M. & Kerr, T. Chronic pain and opioid misuse: a review of reviews. Subst. Abuse Treat. Prev. Policy 12, 36 (2017).
Compton, W. M., Jones, C. M. & Baldwin, G. T. Relationship between nonmedical prescription-opioid use and heroin use. N. Engl. J. Med. 374, 154–163 (2016).
Suzuki, J. & El-Haddad, S. A review: fentanyl and non-pharmaceutical fentanyls. Drug Alcohol Depend. 171, 107–116 (2017).
Al-Hasani, R. & Bruchas, M. R. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115, 1363–1381 (2011).
Bodnar, R. J. Endogenous opiates and behavior: 2015. Peptides 88, 126–188 (2017).
Kieffer, B. L. & Gaveriaux-Ruff, C. Exploring the opioid system by gene knockout. Prog. Neurobiol. 66, 285–306 (2002).
Charbogne, P., Kieffer, B. L. & Befort, K. 15 years of genetic approaches in vivo for addiction research: opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 76, 204–217 (2014).
Matthes, H. W. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383, 819–823 (1996). This is a genetic demonstration that both therapeutic and unwanted morphine effects are mediated by a single receptor protein (MOR).
Filliol, D. et al. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat. Genet. 25, 195–200 (2000).
Pradhan, A. A., Befort, K., Nozaki, C., Gaveriaux-Ruff, C. & Kieffer, B. L. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol. Sci. 32, 581–590 (2011).
Chu Sin Chung, P. & Kieffer, B. L. Delta opioid receptors in brain function and diseases. Pharmacol. Ther. 140, 112–120 (2013).
Spahn, V. & Stein, C. Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development. Expert Opin. Investig. Drugs 26, 155–160 (2017).
Pfeiffer, A., Brantl, V., Herz, A. & Emrich, H. M. Psychotomimesis mediated by kappa opiate receptors. Science 233, 774–776 (1986).
Tejeda, H. A., Shippenberg, T. S. & Henriksson, R. The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell. Mol. Life Sci. 69, 857–896 (2012).
Koob, G. F. The dark side of emotion: the addiction perspective. Eur. J. Pharmacol. 753, 73–87 (2015).
Kobilka, B. The structural basis of G-protein-coupled receptor signaling (Nobel Lecture). Angew. Chem. Int. Ed Engl. 52, 6380–6388 (2013).
Audet, M. & Bouvier, M. Restructuring G-protein- coupled receptor activation. Cell 151, 14–23 (2012).
Manglik, A. et al. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485, 321–326 (2012). This study reports the atomic structure of the MOR solved by X-ray crystallography and is published back to back with the first atomic structures of the three other opioid and opioid-like receptors, all bound to antagonists.
Granier, S. et al. Structure of the delta-opioid receptor bound to naltrindole. Nature 485, 400–404 (2012). This study reports the atomic structure of the DOR solved by X-ray crystallography and is published back to back with the first atomic structures of the three other opioid and opioid-like receptors, all bound to antagonists.
Wu, H. et al. Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485, 327–332 (2012). This study reports the atomic structure of the KOR solved by X-ray crystallography and is published back to back with the first atomic structures of the three other opioid and opioid-like receptors, all bound to antagonists.
Thompson, A. A. et al. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485, 395–399 (2012). This study reports the atomic structure of the NOR solved by X-ray crystallography and is published back to back with the first atomic structures of the three other opioid and opioid-like receptors, all bound to antagonists.
Manglik, A. et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 (2016). This study reports computational screening based on the MOR structure, allowing the discovery of novel agonist chemotypes unrelated to known opioids and leading to a G
-biased drug with unusual and promising biological properties towards safer analgesics.
Bradley, S. J. & Tobin, A. B. Design of next-generation G protein-coupled receptor drugs: linking novel pharmacology and in vivo animal models. Annu. Rev. Pharmacol. Toxicol. 56, 535–559 (2016).
Kim, C. K., Adhikari, A. & Deisseroth, K. Integration of optogenetics with complementary methodologies in systems neuroscience. Nat. Rev. Neurosci. 18, 222–235 (2017).
Van Essen, D. C. Cartography and connectomes. Neuron 80, 775–790 (2013).
Bruehl, S. et al. Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges. J. Pain 14, 103–113 (2013).
Luo, S. X. & Levin, F. R. Towards precision addiction treatment: new findings in co-morbid substance use and attention-deficit hyperactivity disorders. Curr. Psychiatry Rep. 19, 14 (2017).
Hu, H. Reward and aversion. Annu. Rev. Neurosci. 39, 297–324 (2016).
Borsook, D. et al. Reward-aversion circuitry in analgesia and pain: implications for psychiatric disorders. Eur. J. Pain 11, 7–20 (2007).
Mechling, A. E. et al. Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome. Proc. Natl Acad. Sci. USA 113, 11603–11608 (2016). This study analyses functional connectivity by non-invasive MRI in live mutant mice and reveals a fingerprint of Oprm1 activity over the whole brain, opening the way to connectome genetics in animal research.
Navratilova, E., Atcherley, C. W. & Porreca, F. Brain circuits encoding reward from pain relief. Trends Neurosci. 38, 741–750 (2015).
Lutz, P. E. & Kieffer, B. L. The multiple facets of opioid receptor function: implications for addiction. Curr. Opin. Neurobiol. 23, 473–479 (2013).
Eisenberger, N. I. The pain of social disconnection: examining the shared neural underpinnings of physical and social pain. Nat. Rev. Neurosci. 13, 421–434 (2012).
Lutz, P. E. & Kieffer, B. L. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 36, 195–206 (2013).
Koob, G. F. & Volkow, N. D. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3, 760–773 (2016). This seminal review summarizes current knowledge on animal addiction research, including conceptual frameworks, behavioural models, brain circuitry and neurobiology.
Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).
Baler, R. D. & Volkow, N. D. Drug addiction: the neurobiology of disrupted self-control. Trends Mol. Med. 12, 559–566 (2006).
Belin, D., Belin-Rauscent, A., Murray, J. E. & Everitt, B. J. Addiction: failure of control over maladaptive incentive habits. Curr. Opin. Neurobiol. 23, 564–572 (2013).
Koob, G. F. et al. Addiction as a stress surfeit disorder. Neuropharmacology 76, 370–382 (2014).
Goeldner, C. et al. Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine. Biol. Psychiatry 69, 236–244 (2011).
Chu Sin Chung, P. et al. A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons. Biol. Psychiatry 77, 404–415 (2015).
Contet, C., Kieffer, B. L. & Befort, K. Mu opioid receptor: a gateway to drug addiction. Curr. Opin. Neurobiol. 14, 370–378 (2004).
Badiani, A., Belin, D., Epstein, D., Calu, D. & Shaham, Y. Opiate versus psychostimulant addiction: the differences do matter. Nat. Rev. Neurosci. 12, 685–700 (2011).
Becker, J. A. J., Kieffer, B. L. & Le Merrer, J. Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol. Addict. Biol. 22, 1205–1217 (2017).
Moles, A., Kieffer, B. L. & D’Amato, F. R. Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science 304, 1983–1986 (2004). This study demonstrates, using a genetic approach, that the MOR is essential for social bonding very early on (in 4–8 day old pups), providing key evidence for a MOR contribution to process natural rewards and a strong premise to the rising interest in MOR function in the social brain.
Becker, J. A. et al. Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology 39, 2049–2060 (2014).
Papaleo, F., Kieffer, B. L., Tabarin, A. & Contarino, A. Decreased motivation to eat in mu-opioid receptor-deficient mice. Eur. J. Neurosci. 25, 3398–3405 (2007).
Skoubis, P. D., Matthes, H. W., Walwyn, W. M., Kieffer, B. L. & Maidment, N. T. Naloxone fails to produce conditioned place aversion in mu-opioid receptor knock-out mice. Neuroscience 106, 757–763 (2001).
Erbs, E. et al. A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct. Funct. 220, 677–702 (2015).
Le Merrer, J., Becker, J. A., Befort, K. & Kieffer, B. L. Reward processing by the opioid system in the brain. Physiol. Rev. 89, 1379–1412 (2009).
Johnson, S. W. & North, R. A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12, 483–488 (1992).
Wise, R. A. & Rompre, P. P. Brain dopamine and reward. Annu. Rev. Psychol. 40, 191–225 (1989).
Fields, H. L. & Margolis, E. B. Understanding opioid reward. Trends Neurosci. 38, 217–225 (2015).
Cui, Y. et al. Targeted expression of mu-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat. Neurosci. 17, 254–261 (2014).
Charbogne, P. et al. Mu opioid receptors in gamma-aminobutyric acidergic forebrain neurons moderate motivation for heroin and palatable food. Biol. Psychiatry 81, 778–788 (2017).
Ettenberg, A., Pettit, H. O., Bloom, F. E. & Koob, G. F. Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78, 204–209 (1982).
Hnasko, T. S., Sotak, B. N. & Palmiter, R. D. Morphine reward in dopamine-deficient mice. Nature 438, 854–857 (2005).
Laviolette, S. R. & van der Kooy, D. GABAA receptors signal bidirectional reward transmission from the ventral tegmental area to the tegmental pedunculopontine nucleus as a function of opiate state. Eur. J. Neurosci. 20, 2179–2187 (2004).
Narayanan, S. et al. Endogenous opioids mediate basal hedonic tone independent of dopamine D-1 or D-2 receptor activation. Neuroscience 124, 241–246 (2004).
Ben Hamida, S., Boulos, L. J., McNicholas, M., Charbogne, P. & Kieffer, B. L. Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking. Addict. Biol. https://doi.org/10.1111/adb.12576 (2017).
Laurent, V., Morse, A. K. & Balleine, B. W. The role of opioid processes in reward and decision-making. Br. J. Pharmacol. 172, 449–459 (2015).
Dalley, J. W. & Robbins, T. W. Fractionating impulsivity: neuropsychiatric implications. Nat. Rev. Neurosci. 18, 158–171 (2017).
Olmstead, M. C., Ouagazzal, A. M. & Kieffer, B. L. Mu and delta opioid receptors oppositely regulate motor impulsivity in the signaled nose poke task. PLoS ONE 4, e4410 (2009).
Gardon, O. et al. Expression of mu opioid receptor in dorsal diencephalic conduction system: new insights for the medial habenula. Neuroscience 277, 595–609 (2014).
Hikosaka, O. The habenula: from stress evasion to value-based decision-making. Nat. Rev. Neurosci. 11, 503–513 (2010).
Boulos, L. J., Darcq, E. & Kieffer, B. L. Translating the habenula-from rodents to humans. Biol. Psychiatry 81, 296–305 (2017).
Boulos, L. J. Mu opioid receptors in the habenula: dissecting reward and aversion in addiction. Program No. 78.11. 2016 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2016.
Williams, J. T. et al. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 65, 223–254 (2013).
Cahill, C. M., Walwyn, W., Taylor, A. M. W., Pradhan, A. A. A. & Evans, C. J. Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation. Trends Pharmacol. Sci. 37, 963–976 (2016).
Lutz, P. E. et al. Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence. Neuropsychopharmacology 39, 2694–2705 (2014).
Ng, E., Browne, C. J., Samsom, J. N. & Wong, A. H. C. Depression and substance use comorbidity: what we have learned from animal studies. Am. J. Drug Alcohol Abuse 43, 456–474 (2017).
Ranganathan, M. et al. Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the kappa opioid agonist Salvinorin A in humans. Biol. Psychiatry 72, 871–879 (2012).
Koob, G. F. & Le Moal, M. Addiction and the brain antireward system. Annu. Rev. Psychol. 59, 29–53 (2008).
Crowley, N. A. & Kash, T. L. Kappa opioid receptor signaling in the brain: circuitry and implications for treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 62, 51–60 (2015).
Land, B. B. et al. The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J. Neurosci. 28, 407–414 (2008).
Zhou, Y. & Kreek, M. J. Alcohol: a stimulant activating brain stress responsive systems with persistent neuroadaptation. Neuropharmacology 87, 51–58 (2014).
Massaly, N., Moron, J. A. & Al-Hasani, R. A. Trigger for opioid misuse: chronic pain and stress dysregulate the mesolimbic pathway and kappa opioid system. Front. Neurosci. 10, 480 (2016).
Lalanne, L. et al. Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence. Addict. Biol. 22, 1010–1021 (2017).
Bruchas, M. R., Land, B. B. & Chavkin, C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 1314, 44–55 (2010).
Chavkin, C. & Koob, G. F. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology 41, 373–374 (2016).
Spanagel, R., Herz, A. & Shippenberg, T. S. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc. Natl Acad. Sci. USA 89, 2046–2050 (1992).
Bals-Kubik, R., Ableitner, A., Herz, A. & Shippenberg, T. S. Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats. J. Pharmacol. Exp. Ther. 264, 489–495 (1993).
Chefer, V. I., Backman, C. M., Gigante, E. D. & Shippenberg, T. S. Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion. Neuropsychopharmacology 38, 2623–2631 (2013).
Van’t Veer, A. et al. Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity. Neuropsychopharmacology 38, 1585–1597 (2013).
Margolis, E. B. et al. Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc. Natl Acad. Sci. USA 103, 2938–2942 (2006).
Tejeda, H. A. et al. Prefrontal cortical kappa-opioid receptor modulation of local neurotransmission and conditioned place aversion. Neuropsychopharmacology 38, 1770–1779 (2013).
Tejeda, H. A. et al. Pathway- and cell-specific kappa-opioid receptor modulation of excitation-inhibition balance differentially gates D1 and D2 accumbens neuron activity. Neuron 93, 147–163 (2017).
Al-Hasani, R. et al. Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 87, 1063–1077 (2015). This report reveals regional heterogeneity within a well-known opioid peptide-expressing brain area for the first time, as dynorphin-expressing cells in either the dorsal or ventral part of the NAc shell drive opposing behaviours (that is, reward or aversion, respectively).
Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012).
Abraham, A. D. et al. Kappa-opioid receptor activation in dopamine neurons disrupts behavioral inhibition. Neuropsychopharmacology 43, 362–372 (2018).
Tao, R. & Auerbach, S. B. Mu-opioids disinhibit and kappa-opioids inhibit serotonin efflux in the dorsal raphe nucleus. Brain Res. 1049, 70–79 (2005).
Land, B. B. 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 106, 19168–19173 (2009).
Bruchas, M. R. et al. Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 71, 498–511 (2011).
Crowley, N. A. et al. Dynorphin controls the gain of an amygdalar anxiety circuit. Cell Rep. 14, 2774–2783 (2016).
Kissler, J. L. & Walker, B. M. Dissociating motivational from physiological withdrawal in alcohol dependence: role of central amygdala kappa-opioid receptors. Neuropsychopharmacology 41, 560–567 (2016).
Kang-Park, M., Kieffer, B. L., Roberts, A. J., Siggins, G. R. & Moore, S. D. Kappa-opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. J. Pharmacol. Exp. Ther. 346, 130–137 (2013).
Gilpin, N. W., Roberto, M., Koob, G. F. & Schweitzer, P. Kappa opioid receptor activation decreases inhibitory transmission and antagonizes alcohol effects in rat central amygdala. Neuropharmacology 77, 294–302 (2014).
Kang-Park, M., Kieffer, B. L., Roberts, A. J., Siggins, G. R. & Moore, S. D. Interaction of CRF and kappa opioid systems on GABAergic neurotransmission in the mouse central amygdala. J. Pharmacol. Exp. Ther. 355, 206–211 (2015).
Klenowski, P., Morgan, M. & Bartlett, S. E. The role of delta-opioid receptors in learning and memory underlying the development of addiction. Br. J. Pharmacol. 172, 297–310 (2015).
Gendron, L., Cahill, C. M., von Zastrow, M., Schiller, P. W. & Pineyro, G. Molecular pharmacology of delta-opioid receptors. Pharmacol. Rev. 68, 631–700 (2016).
Pellissier, L. P., Pujol, C. N., Becker, J. A. & Le Merrer, J. Delta opioid receptors: learning and motivation. Handb Exp. Pharmacol. https://doi.org/10.1007/164_2016_89 (2016).
Le Merrer, J. et al. Deletion of the delta opioid receptor gene impairs place conditioning but preserves morphine reinforcement. Biol. Psychiatry 69, 700–703 (2011).
Bruchas, M. R. & Roth, B. L. New technologies for elucidating opioid receptor function. Trends Pharmacol. Sci. 37, 279–289 (2016).
Koob, G. F. & Mason, B. J. Existing and future drugs for the treatment of the dark side of addiction. Annu. Rev. Pharmacol. Toxicol. 56, 299–322 (2016).
Aboujaoude, E. & Salame, W. O. Naltrexone: a pan-addiction treatment? CNS Drugs 30, 719–733 (2016).
Schuckit, M. A. Treatment of opioid-use disorders. N. Engl. J. Med. 375, 357–368 (2016).
Volkow, N. D. & Skolnick, P. New medications for substance use disorders: challenges and opportunities. Neuropsychopharmacology 37, 290–292 (2012).
Ayanga, D., Shorter, D. & Kosten, T. R. Update on pharmacotherapy for treatment of opioid use disorder. Expert Opin. Pharmacother. 17, 2307–2318 (2016).
Carlezon, W. A. Jr & Krystal, A. D. Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depress Anxiety 33, 895–906 (2016).
Helal, M. A., Habib, E. S. & Chittiboyina, A. G. Selective kappa opioid antagonists for treatment of addiction, are we there yet? Eur. J. Med. Chem. 141, 632–647 (2017).
Goldman, D., Oroszi, G. & Ducci, F. The genetics of addictions: uncovering the genes. Nat. Rev. Genet. 6, 521–532 (2005).
Reed, B., Butelman, E. R., Yuferov, V., Randesi, M. & Kreek, M. J. Genetics of opiate addiction. Curr. Psychiatry Rep. 16, 504 (2014).
Levran, O., Yuferov, V. & Kreek, M. J. The genetics of the opioid system and specific drug addictions. Hum. Genet. 131, 823–842 (2012).
Butelman, E. R., Yuferov, V. & Kreek, M. J. Kappa-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci. 35, 587–596 (2012).
Belzeaux, R., Lalanne, L., Kieffer, B. L. & Lutz, P. E. Focusing on the opioid system for addiction biomarker discovery. Trends Mol. Med. 24, 206–220 (2018).
Crist, R. C. & Berrettini, W. H. Pharmacogenetics of OPRM1. Pharmacol. Biochem. Behav. 123, 25–33 (2014).
Kroslak, T. et al. The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J. Neurochem. 103, 77–87 (2007).
Oertel, B. G. et al. A common human μ-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J. Biol. Chem. 284, 6530–6535 (2009).
Colantuoni, C. et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519–523 (2011).
Hancock, D. B. et al. Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1. Biol. Psychiatry 78, 474–484 (2015).
Kong, X. et al. Lack of associations of the opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with alcohol dependence: review and meta-analysis of retrospective controlled studies. BMC Med. Genet. 18, 120 (2017).
Otto, J. M., Gizer, I. R., Deak, J. D., Fleming, K. A. & Bartholow, B. D. A cis-eQTL in OPRM1 is associated with subjective response to alcohol and alcohol use. Alcohol Clin. Exp. Res. 41, 929–938 (2017).
Smith, A. H. et al. Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1. Mol. Psychiatry 22, 346–352 (2017).
Mague, S. D. et al. Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. Proc. Natl Acad. Sci. USA 106, 10847–10852 (2009).
Ramchandani, V. A. et al. A genetic determinant of the striatal dopamine response to alcohol in men. Mol. Psychiatry 16, 809–817 (2011). This is a translational study to elucidate the role of the MOR A118G SNP in response to alcohol, and data show that 118G carriers in both humans and a humanized A118G genetic mouse mutant release higher levels of DA following alcohol exposure.
Bernardi, R. E. et al. A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology. Transl Psychiatry 6, e861 (2016).
Cabrera, E. A. et al. Neuroimaging the effectiveness of substance use disorder treatments. J. Neuroimmune Pharmacol. 11, 408–433 (2016).
Henriksen, G. & Willoch, F. Imaging of opioid receptors in the central nervous system. Brain 131, 1171–1196 (2008).
Kuwabara, H. et al. Mu opioid receptor binding correlates with nicotine dependence and reward in smokers. PLoS ONE 9, e113694 (2014).
Nuechterlein, E. B., Ni, L., Domino, E. F. & Zubieta, J. K. Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms. Prog. Neuropsychopharmacol. Biol. Psychiatry 69, 69–77 (2016).
Hermann, D. et al. Low mu-opioid receptor status in alcohol dependence identified by combined positron emission tomography and post-mortem brain analysis. Neuropsychopharmacology 42, 606–614 (2017).
Mick, I. et al. Blunted endogenous opioid release following an oral amphetamine challenge in pathological gamblers. Neuropsychopharmacology 41, 1742–1750 (2016).
Majuri, J. et al. Dopamine and opioid neurotransmission in behavioral addictions: a comparative PET study in pathological gambling and binge eating. Neuropsychopharmacology 42, 1169–1177 (2017).
Karlsson, H. K. et al. Obesity is associated with decreased μ-opioid but unaltered dopamine D2 receptor availability in the brain. J. Neurosci. 35, 3959–3965 (2015).
Saanijoki, T. et al. Opioid release after high-intensity interval training in healthy human subjects. Neuropsychopharmacology 43, 246–254 (2018).
Nummenmaa, L. et al. Social touch modulates endogenous mu-opioid system activity in humans. Neuroimage 138, 242–247 (2016).
Manninen, S. et al. Social laughter triggers endogenous opioid release in humans. J. Neurosci. 37, 6125–6131 (2017).
Nummenmaa, L. & Tuominen, L. Opioid system and human emotions. Br. J. Pharmacol. https://doi.org/10.1111/bph.13812 (2017).
Borsook, D., Becerra, L. & Hargreaves, R. A role for fMRI in optimizing CNS drug development. Nat. Rev. Drug Discov. 5, 411–424 (2006).
Becerra, L., Harter, K., Gonzalez, R. G. & Borsook, D. Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers. Anesth. Analg. 103, 208–216 (2006).
Becerra, L. et al. Parallel buprenorphine phMRI responses in conscious rodents and healthy human subjects. J. Pharmacol. Exp. Ther. 345, 41–51 (2013). This is a study using phMRI to compare the effect of buprenorphine on the BOLD signal in both humans and rats and reveals a similar activity pattern across pain-related regions in the two species.
Fareed, A. et al. Effect of heroin use on changes of brain functions as measured by functional magnetic resonance imaging, a systematic review. J. Addict. Dis. 36, 105–116 (2017).
Ieong, H. F. & Yuan, Z. Resting-state neuroimaging and neuropsychological findings in opioid use disorder during abstinence: a review. Front. Hum. Neurosci. 11, 169 (2017).
Zhang, Y. et al. Granger causality reveals a dominant role of memory circuit in chronic opioid dependence. Addict. Biol. 22, 1068–1080 (2017).
Moore, K. et al. 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 (2016).
Kenakin, T. The effective application of biased signaling to new drug discovery. Mol. Pharmacol. 88, 1055–1061 (2015).
Madariaga-Mazon, A. et al. Mu-opioid receptor biased ligands: a safer and painless discovery of analgesics? Drug Discov. Today 22, 1719–1729 (2017).
Spangler, S. & Bruchas, M. R. Tuning biased GPCR signaling for physiological gain. Cell 171, 989–991 (2017).
Kieffer, B. L. Drug discovery: designing the ideal opioid. Nature 537, 170–171 (2016).
Bohn, L. M. et al. Enhanced morphine analgesia in mice lacking β-arrestin 2. Science 286, 2495–2498 (1999).
Raehal, K. M., Walker, J. K. & Bohn, L. M. Morphine side effects in β-arrestin 2 knockout mice. J. Pharmacol. Exp. Ther. 314, 1195–1201 (2005).
DeWire, S. M. et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344, 708–717 (2013).
Siuda, E. R., Carr, R. 3rd, Rominger, D. H. & Violin, J. D. Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics. Curr. Opin. Pharmacol. 32, 77–84 (2017).
Varadi, A. et al. Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2. J. Med. Chem. 59, 8381–8397 (2016).
Schmid, C. L. et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171, 1165–1175 (2017). This work provides compelling evidence for the physiological relevance of MOR biased signalling, as comparing biased signalling with behavioural effects of a range of MOR agonists reveals strong correlation between G
/β-arrestin bias factors and the analgesia–respiratory depression therapeutic window.
Altarifi, A. A. et al. 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, 730–739 (2017).
Irannejad, R. et al. Functional selectivity of GPCR-directed drug action through location bias. Nat. Chem. Biol. 13, 799–806 (2017).
Urs, N. M. et al. Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc. Natl Acad. Sci. USA 113, E8178–E8186 (2016).
Olson, K. M., Lei, W., Keresztes, A., LaVigne, J. & Streicher, J. M. Novel molecular strategies and targets for opioid drug discovery for the treatment of chronic pain. Yale J. Biol. Med. 90, 97–110 (2017).
Pasternak, G. W. Opioids and their receptors: are we there yet? Neuropharmacology 76, 198–203 (2014).
Majumdar, S. et al. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc. Natl Acad. Sci. USA 108, 19778–19783 (2011).
Convertino, M. et al. Mu-opioid receptor 6-transmembrane isoform: a potential therapeutic target for new effective opioids. Prog. Neuropsychopharmacol. Biol. Psychiatry 62, 61–67 (2015).
Huang, W. et al. Structural insights into micro-opioid receptor activation. Nature 524, 315–321 (2015).
Spahn, V. et al. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355, 966–969 (2017). This article reports a highly innovative approach to design safer opioid pain killers, in which ligand docking to a ‘pathological’ (acidic) receptor structure identifies a MOR agonist acting at the receptor only under conditions of inflammation, leaving other receptors at rest.
Livingston, K. E. & Traynor, J. R. Allostery at opioid receptors: modulation with small molecule ligands. Br. J. Pharmacol. https://doi.org/10.1111/bph.13823 (2017).
Burford, N. T. et al. Discovery of positive allosteric modulators and silent allosteric modulators of the mu-opioid receptor. Proc. Natl Acad. Sci. USA 110, 10830–10835 (2013).
Livingston, K. E. & Traynor, J. R. 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, 18369–18374 (2014).
Galadrin, S. et al. The evasive nature of drug efficacy: implications for drug discovery. Trends Pharm. Sci. 28, 423–430 (2007).
Roth, B. L. et al. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc. Natl Acad. Sci. USA 99, 11934–11939 (2002).
Sheffler, D. J. & Roth, B. L. Salvinorin A: the “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol. Sci. 24, 107–109 (2003).
Cruz, A., Domingos, S., Gallardo, E. & Martinho, A. A unique natural selective kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeutics. Phytochemistry 137, 9–14 (2017).
Butelman, E. R. & Kreek, M. J. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders. Front. Pharmacol. 6, 190 (2015).
Civelli, O. et al. G protein-coupled receptor deorphanizations. Annu. Rev. Pharmacol. Toxicol. 53, 127–146 (2013).
Reinscheid, R. K. et al. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270, 792–794 (1995).
Meunier, J. C. et al. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377, 532–535 (1995).
Zaveri, N. T. Nociceptin opioid receptor (NOP) as a therapeutic target: progress in translation from preclinical research to clinical utility. J. Med. Chem. 59, 7011–7028 (2016).
Toll, L., Bruchas, M. R., Calo, G., Cox, B. M. & Zaveri, N. T. Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol. Rev. 68, 419–457 (2016).
Witkin, J. M. et al. The biology of nociceptin/orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharmacol. Ther. 141, 283–299 (2014).
Sounier, R. et al. Propagation of conformational changes during mu-opioid receptor activation. Nature 524, 375–378 (2015).
Raehal, K. M., Schmid, C. L., Groer, C. E. & Bohn, L. M. Functional selectivity at the mu-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharmacol. Rev. 63, 1001–1019 (2011).
Pradhan, A. A., Smith, M. L., Kieffer, B. L. & Evans, C. J. Ligand-directed signalling within the opioid receptor family. Br. J. Pharmacol. 167, 960–969 (2012).
Ehrich, J. M. et al. Kappa opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons. J. Neurosci. 35, 12917–12931 (2015).
Scherrer, G. et al. Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo. Proc. Natl Acad. Sci. USA 103, 9691–9696 (2006). This study provides a unique knock-in mouse mutant line, and is the first of a series to visualize a GPCR in vivo; it shows DOR subcellular localization and trafficking, opening the way to understand tolerance mechanisms.
Pradhan, A. A. et al. Ligand-directed trafficking of the delta-opioid receptor in vivo: two paths toward analgesic tolerance. J. Neurosci. 30, 16459–16468 (2010).
Su, D. et al. One-step generation of mice carrying a conditional allele together with an HA-tag insertion for the delta opioid receptor. Sci. Rep. 7, 44476 (2017).
Siuda, E. R. et al. Spatiotemporal control of opioid signaling and behavior. Neuron 86, 923–935 (2015).
Marchant, N. J. et al. Behavioral and physiological effects of a novel kappa-opioid receptor-based DREADD in rats. Neuropsychopharmacology 41, 402–409 (2016).
Marchant, N. J. et al. Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence. J. Neurosci. 36, 3281–3294 (2016).
Harris, J. A. et al. Anatomical characterization of Cre driver mice for neural circuit mapping and manipulation. Front. Neural Circuits 8, 76 (2014).
Cai, X. et al. Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling. Genesis 54, 29–37 (2016).
Kumar, D., Chakraborty, J. & Das, S. Epistatic effects between variants of kappa-opioid receptor gene and A118G of mu-opioid receptor gene increase susceptibility to addiction in Indian population. Prog. Neuropsychopharmacol. Biol. Psychiatry 36, 225–230 (2012).
Deb, I., Chakraborty, J., Gangopadhyay, P. K., Choudhury, S. R. & Das, S. Single-nucleotide polymorphism (A118G) in exon 1 of OPRM1 gene causes alteration in downstream signaling by mu-opioid receptor and may contribute to the genetic risk for addiction. J. Neurochem. 112, 486–496 (2010).
Kapur, S., Sharad, S., Singh, R. A. & Gupta, A. K. A118G polymorphism in mu opioid receptor gene (OPRM1): association with opiate addiction in subjects of Indian origin. J. Integr. Neurosci. 6, 511–522 (2007).
Bart, G. et al. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. Mol. Psychiatry 9, 547–549 (2004).
Szeto, C. Y., Tang, N. L., Lee, D. T. & Stadlin, A. Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport 12, 1103–1106 (2001).
Li, T. et al. Association analysis of polymorphisms in the mu opioid gene and heroin abuse in Chinese subjects. Addict. Biol. 5, 181–186 (2000).
Hendershot, C. S., Claus, E. D. & Ramchandani, V. A. Associations of OPRM1 A118G and alcohol sensitivity with intravenous alcohol self-administration in young adults. Addict. Biol. 21, 125–135 (2016).
Bart, G. et al. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 30, 417–422 (2005).
Schinka, J. A. et al. A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances. Mol. Psychiatry 7, 224–228 (2002).
Town, T. et al. Association of a functional mu-opioid receptor allele (+118A) with alcohol dependency. Am. J. Med. Genet. 88, 458–461 (1999).
Dlugos, A. M. et al. OPRM1 gene variants modulate amphetamine-induced euphoria in humans. Genes Brain Behav. 10, 199–209 (2011).
Schuck, K., Otten, R., Engels, R. C. & Kleinjan, M. Initial responses to the first dose of nicotine in novel smokers: the role of exposure to environmental smoking and genetic predisposition. Psychol. Health 29, 698–716 (2014).
Zhang, Y. et al. Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice. Neuropsychopharmacology 40, 1091–1100 (2015).
Browne, C. A., Erickson, R. L., Blendy, J. A. & Lucki, I. Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism. Neuropharmacology 117, 401–407 (2017).
Briand, L. A. et al. Mouse model of OPRM1 (A118G) polymorphism increases sociability and dominance and confers resilience to social defeat. J. Neurosci. 35, 3582–3590 (2015).
Robinson, J. E. et al. Receptor reserve moderates mesolimbic responses to opioids in a humanized mouse model of the OPRM1 A118G polymorphism. Neuropsychopharmacology 40, 2614–2622 (2015).
Henderson-Redmond, A. N. et al. Morphine-induced antinociception and reward in “humanized” mice expressing the mu opioid receptor A118G polymorphism. Brain Res. Bull. 123, 5–12 (2016).
Bilbao, A. et al. A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. Biol. Psychiatry 77, 850–858 (2015).