Opposing neural effects of naltrexone on food reward and aversion: implications for the treatment of obesity

RationaleOpioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood.ObjectivesThe aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli.MethodsWe used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated-measures cross-over, design.ResultsRelative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula.ConclusionsThese findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity.

[1]  Karl J. Friston,et al.  Classical and Bayesian Inference in Neuroimaging: Applications , 2002, NeuroImage.

[2]  R. Dubner,et al.  Placebo and naloxone can alter post-surgical pain by separate mechanisms , 1983, Nature.

[3]  Adam Drewnowski,et al.  Taste responses and preferences for sweet high-fat foods: Evidence for opioid involvement , 1992, Physiology & Behavior.

[4]  Katsushi Yamada,et al.  Effects of Ascorbic Acid on Interactions between Ciprofloxacin and Ferrous Sulphate, Sodium Ferrous Citrate or Ferric Pyrophosphate, in Mice , 2000, The Journal of pharmacy and pharmacology.

[5]  S A Alger,et al.  Effect of a tricyclic antidepressant and opiate antagonist on binge-eating behavior in normoweight bulimic and obese, binge-eating subjects. , 1991, The American journal of clinical nutrition.

[6]  D. Mikhailidis,et al.  Naltrexone sustained-release (SR) + bupropion SR combination therapy for the treatment of obesity: ‘A new kid on the block’? , 2011, Annals of medicine.

[7]  M. Viergever,et al.  Anterior cingulate taste activation predicts ad libitum intake of sweet and savory drinks in healthy, normal-weight men. , 2012, The Journal of nutrition.

[8]  Eric Stice,et al.  Reward circuitry responsivity to food predicts future increases in body mass: Moderating effects of DRD2 and DRD4 , 2010, NeuroImage.

[9]  M A Marrazzi,et al.  A detailed longitudinal analysis on the use of naltrexone in the treatment of bulimia. , 1995, International clinical psychopharmacology.

[10]  Israel Liberzon,et al.  μ-Opioid receptors and limbic responses to aversive emotional stimuli , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Silverman,et al.  Intravenous cocaine challenges during naltrexone maintenance: A preliminary study , 1992, Biological Psychiatry.

[12]  E. Rolls,et al.  Representation of umami taste in the human brain. , 2003, Journal of neurophysiology.

[13]  P. Cowen,et al.  The D2 antagonist sulpiride modulates the neural processing of both rewarding and aversive stimuli in healthy volunteers , 2011, Psychopharmacology.

[14]  M. Fantino,et al.  An opioid antagonist, naltrexone, reduces preference for sucrose in humans. , 1986, The American journal of physiology.

[15]  Dennis D. Kim,et al.  Naltrexone/Bupropion Combination Therapy in Overweight or Obese Patients With Major Depressive Disorder: Results of a Pilot Study , 2013, The primary care companion for CNS disorders.

[16]  E. Blass,et al.  Failure of naltrexone to affect the pleasantness or intake of food , 1991, Pharmacology Biochemistry and Behavior.

[17]  Francesca M. Filbey,et al.  Reward circuit function in high BMI individuals with compulsive overeating: Similarities with addiction , 2012, NeuroImage.

[18]  G. Rizzolatti,et al.  Both of Us Disgusted in My Insula The Common Neural Basis of Seeing and Feeling Disgust , 2003, Neuron.

[19]  K. Berridge,et al.  The Neuroscience of Natural Rewards: Relevance to Addictive Drugs , 2002, The Journal of Neuroscience.

[20]  L. Epstein,et al.  Youth at Risk for Obesity Show Greater Activation of Striatal and Somatosensory Regions to Food , 2011, The Journal of Neuroscience.

[21]  F. Greenway,et al.  Combination therapy with naltrexone and bupropion for obesity , 2011, Expert opinion on pharmacotherapy.

[22]  J. Schüttler,et al.  Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans , 2003, Pain.

[23]  A. Drewnowski,et al.  Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters. , 1995, The American journal of clinical nutrition.

[24]  P. Cowen,et al.  ‘It's the way that you look at it’—a cognitive neuropsychological account of SSRI action in depression , 2013, Philosophical Transactions of the Royal Society B: Biological Sciences.

[25]  P. Cowen,et al.  Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment , 2010, Biological Psychiatry.

[26]  R. Gibbons,et al.  Assessing anhedonia in psychiatric patients. , 1983, Archives of general psychiatry.

[27]  Michael A. Nader,et al.  Behavioral/systems/cognitive Cocaine Self-administration Produces a Progressive Involvement of Limbic, Association, and Sensorimotor Striatal Domains , 2022 .

[28]  M. J. Vazquez,et al.  The Opioid System and Food Intake: Homeostatic and Hedonic Mechanisms , 2012, Obesity Facts.

[29]  Edmund T. Rolls,et al.  Sensory specific satiety in man , 1981, Physiology & Behavior.

[30]  R. Bodnar,et al.  Opioid antagonists in the periaqueductal gray inhibit morphine and β-endorphin analgesia elicited from the amygdala of rats , 1996, Brain Research.

[31]  E. Stein,et al.  Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. , 2000, The American journal of psychiatry.

[32]  R. C. Oldfield.  The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[33]  S. Bartlett,et al.  δ-Opioid Receptor Function in the Dorsal Striatum Plays a Role in High Levels of Ethanol Consumption in Rats , 2012, The Journal of Neuroscience.

[34]  E. Rolls,et al.  Human cortical responses to water in the mouth, and the effects of thirst. , 2003, Journal of neurophysiology.

[35]  M. Erb,et al.  Brain activity underlying emotional valence and arousal: A response‐related fMRI study , 2004, Human brain mapping.

[36]  David H Zald,et al.  Neural correlates of tasting concentrated quinine and sugar solutions. , 2002, Journal of neurophysiology.

[37]  William A. Cunningham,et al.  Type I and Type II error concerns in fMRI research: re-balancing the scale. , 2009, Social cognitive and affective neuroscience.

[38]  H. Akil,et al.  Autoradiographic differentiation of mu, delta and kappa opioid receptors in the rat forebrain and midbrain A. Mansour H. Khachaturian, M.E. Lewis, H. Akil and S.J. Watson, Neuroscience, 7 (1987) 2445–2464 , 1988, Pain.

[39]  Steven C. R. Williams,et al.  The Neural Correlates of Anhedonia in Major Depressive Disorder , 2005, Biological Psychiatry.

[40]  H. Frieling,et al.  Opioid modulators for alcohol dependence , 2011, Expert opinion on investigational drugs.

[41]  Jin Fan,et al.  Common and distinct networks underlying reward valence and processing stages: A meta-analysis of functional neuroimaging studies , 2011, Neuroscience & Biobehavioral Reviews.

[42]  M. Yeomans,et al.  Lower pleasantness of palatable foods in nalmefene-treated human volunteers , 1991, Appetite.

[43]  Karl J. Friston,et al.  Assessing the significance of focal activations using their spatial extent , 1994, Human brain mapping.

[44]  J. Frost,et al.  Imaging Brain Mu-Opioid Receptors in Abstinent Cocaine Users: Time Course and Relation to Cocaine Craving , 2005, Biological Psychiatry.

[45]  P. Cowen,et al.  Effects of 7 days of treatment with the cannabinoid type 1 receptor antagonist, rimonabant, on emotional processing , 2012, Journal of psychopharmacology.

[46]  Jan Wacker,et al.  The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EEG, fMRI, and volumetric techniques , 2009, NeuroImage.

[47]  M. Hamilton,et al.  A Scale for the Assessment of Hedonic Tone the Snaith–Hamilton Pleasure Scale , 1995, British Journal of Psychiatry.

[48]  R. Gibbons,et al.  Assessing Anhedonia in Psychiatric Patients: The Pleasure Scale , 1983 .

[49]  U. Ghitza,et al.  Brain Mu-Opioid Receptor Binding Predicts Treatment Outcome in Cocaine-Abusing Outpatients , 2010, Biological Psychiatry.

[50]  Axel Schäfer,et al.  Binge-Eating Disorder: Reward Sensitivity and Brain Activation to Images of Food , 2009, Biological Psychiatry.

[51]  M. Herkenham,et al.  Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[52]  M. A. Jurado,et al.  Neural responses to visual food cues: insights from functional magnetic resonance imaging. , 2013, European eating disorders review : the journal of the Eating Disorders Association.

[53]  S. Hyman,et al.  Acute Effects of Cocaine on Human Brain Activity and Emotion , 1997, Neuron.

[54]  Morten L. Kringelbach,et al.  Fast, Fully Automated Global and Local Magnetic Field Optimization for fMRI of the Human Brain , 2002, NeuroImage.

[55]  K. Fujioka,et al.  Naltrexone for the treatment of obesity: review and update , 2009, Expert opinion on pharmacotherapy.

[56]  Rita Z. Goldstein,et al.  Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. , 2002, The American journal of psychiatry.

[57]  E. Bullmore,et al.  Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects , 2012, Molecular Psychiatry.

[58]  F. Greenway,et al.  Effects of Naltrexone Sustained- Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes , 2013, Diabetes Care.

[59]  E. Bullmore,et al.  Multiple‐Dose Safety, Pharmacokinetics, and Pharmacodynamics of the μ‐Opioid Receptor Inverse Agonist GSK1521498 , 2012, Journal of clinical pharmacology.

[60]  N. Volkow,et al.  Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction , 2006, The Journal of Neuroscience.

[61]  J S Fowler,et al.  Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction. , 1999, The American journal of psychiatry.

[62]  L. Becerra,et al.  fMRI measurement of CNS responses to naloxone infusion and subsequent mild noxious thermal stimuli in healthy volunteers. , 2004, Journal of neurophysiology.

[63]  L. Clancy,et al.  Tuberculosis management in Europe. Task Force of the European Respiratory Society (ERS), the World Health Organisation (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD) Europe Region. , 1999, The European respiratory journal.

[64]  P. Matthews,et al.  Endogenous Opioid Release in the Human Brain Reward System Induced by Acute Amphetamine Administration , 2012, Biological Psychiatry.

[65]  W. Ling,et al.  Naltrexone and dysphoria: fact or myth? , 2002, The American journal on addictions.

[66]  E T Bullmore,et al.  Molecular and functional neuroimaging of human opioid receptor pharmacology , 2011, Molecular Psychiatry.

[67]  E. Rabiner,et al.  Opioids and anxiety , 2011, Journal of psychopharmacology.

[68]  Richard J. Davidson,et al.  Functional neuroanatomy of aversion and its anticipation , 2006, NeuroImage.

[69]  R. F. Westbrook,et al.  Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. , 1995, Behavioral neuroscience.

[70]  Joseph J. Paton,et al.  The primate amygdala represents the positive and negative value of visual stimuli during learning , 2006, Nature.

[71]  K. Wesnes,et al.  A Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Acamprosate and Naltrexone , 2002, Neuropsychopharmacology.

[72]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[73]  R. Young,et al.  Does naltrexone treatment lead to depression? Findings from a randomized controlled trial in subjects with opioid dependence. , 2006, Journal of psychiatry & neuroscience : JPN.

[74]  H. Flor,et al.  Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. , 2005, The journal of pain : official journal of the American Pain Society.

[75]  R. Dannals,et al.  Regional mu-opioid receptor binding in insular cortex is decreased in bulimia nervosa and correlates inversely with fasting behavior. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[76]  F. Strian,et al.  Evaluation of depressive states, especially in longitudinal studies. , 1974, Modern problems of pharmacopsychiatry.

[77]  P. Cowen,et al.  Reduced neural response to reward following 7 days treatment with the cannabinoid CB1 antagonist rimonabant in healthy volunteers. , 2010, The international journal of neuropsychopharmacology.

[78]  S. Haber,et al.  Opioid modulation of taste hedonics within the ventral striatum , 2002, Physiology & Behavior.

[79]  G. Whelan,et al.  Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. , 2001, Alcohol and alcoholism.

[80]  B. Pitt.  Psychopharmacology , 1968, Mental Health.

[81]  W. Zieglgänsberger,et al.  Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. , 2003, The American journal on addictions.

[82]  E T Bullmore,et al.  Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans , 2011, Molecular Psychiatry.

[83]  E. Rolls,et al.  Different representations of pleasant and unpleasant odours in the human brain , 2003, The European journal of neuroscience.

[84]  D. Garner,et al.  The Eating Attitudes Test: psychometric features and clinical correlates , 1982, Psychological Medicine.

[85]  C. Makowski,et al.  Naltrexone/Bupropion: An Investigational Combination for Weight Loss and Maintenance , 2011, Obesity Facts.

[86]  J. Grafman,et al.  The Human Amygdala: An Evolved System for Relevance Detection , 2003, Reviews in the neurosciences.

[87]  A. Ścińska,et al.  An opioid receptor antagonist, naltrexone, does not alter taste and smell responses in humans. , 2000, Polish journal of pharmacology.

[88]  E. Rolls,et al.  Representation of pleasant and aversive taste in the human brain. , 2001, Journal of neurophysiology.

[89]  M. Yeomans,et al.  Selective effects of naltrexone on food pleasantness and intake , 1996, Physiology & Behavior.

[90]  M. Yeomans,et al.  Opioid peptides and the control of human ingestive behaviour , 2002, Neuroscience & Biobehavioral Reviews.

[91]  P. Cowen,et al.  Neural representation of reward in recovered depressed patients , 2009, Psychopharmacology.

[92]  Robin Christensen,et al.  Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials , 2007, The Lancet.

[93]  K. Phan,et al.  Neural correlates of internally-generated disgust via autobiographical recall: a functional magnetic resonance imaging investigation , 2004, Neuroscience Letters.

[94]  Edward E. Smith,et al.  Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain , 2004, Science.

[95]  E. Bullmore,et al.  Neural and Behavioral Effects of a Novel Mu Opioid Receptor Antagonist in Binge-Eating Obese People , 2013, Biological Psychiatry.

[96]  H. Fields,et al.  Nucleus accumbens opioid signaling conditions short-term flavor preferences , 2007, Neuroscience.

[97]  Edmund T Rolls,et al.  Enhanced affective brain representations of chocolate in cravers vs. non‐cravers , 2007, The European journal of neuroscience.

[98]  Sara E. Morrison,et al.  Re-valuing the amygdala , 2010, Current Opinion in Neurobiology.

[99]  E. Bullmore,et al.  Neuropsychiatric Adverse Effects of Centrally Acting Antiobesity Drugs , 2011, CNS neuroscience & therapeutics.

[100]  D. Le Bihan,et al.  fMRI Study of Taste Cortical Areas in Humans , 1998, Annals of the New York Academy of Sciences.

[101]  F. Greenway,et al.  Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial , 2010, The Lancet.

[102]  P. Cowen,et al.  Neural Processing of Reward and Punishment in Young People at Increased Familial Risk of Depression , 2012, Biological Psychiatry.

[103]  J. Michael Schurr,et al.  Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by Taq IA A 1 Allele , 2022 .

[104]  Nu-Chu Liang,et al.  Additive feeding inhibitory and aversive effects of naltrexone and exendin-4 combinations , 2012, International Journal of Obesity.

[105]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[106]  H. Critchley,et al.  Blocking Central Opiate Function Modulates Hedonic Impact and Anterior Cingulate Response to Rewards and Losses , 2008, The Journal of Neuroscience.

[107]  Shaun R. Patel,et al.  Human Dorsal Anterior Cingulate Cortex Neurons Mediate Ongoing Behavioral Adaptation , 2012, Nature.

[108]  B. Everitt,et al.  Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum , 2008, Neuron.

[109]  N. Volkow,et al.  Addiction: Beyond dopamine reward circuitry , 2011, Proceedings of the National Academy of Sciences.

[110]  E. Bullmore,et al.  From taste hedonics to motivational drive: central μ-opioid receptors and binge-eating behaviour. , 2009, The international journal of neuropsychopharmacology.

[111]  Brian Knutson,et al.  Anticipation of Increasing Monetary Reward Selectively Recruits Nucleus Accumbens , 2001, The Journal of Neuroscience.