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Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement

  • George F. Koob
    Correspondence
    Address correspondence to George F. Koob, Ph.D., National Institute on Alcohol Abuse and Alcoholism, 5635 Fishers Lane, Room 2001, Suite 2000, Rockville, MD 20852.
    Affiliations
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

    National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland
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      Abstract

      Opioids are powerful drugs that usurp and overpower the reward function of endogenous opioids and engage dramatic tolerance and withdrawal via molecular and neurocircuitry neuroadaptations within the same reward system. However, they also engage the brain systems for stress and pain (somatic and emotional) while producing hyperalgesia and hyperkatifeia, which drive pronounced drug-seeking behavior via processes of negative reinforcement. Hyperkatifeia (derived from the Greek “katifeia” for dejection or negative emotional state) is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of abuse. In animal models, repeated extended access to drugs or opioids results in negative emotion-like states, reflected by the elevation of reward thresholds, lower pain thresholds, anxiety-like behavior, and dysphoric-like responses. Such negative emotional states that drive negative reinforcement are hypothesized to derive from the within-system dysregulation of key neurochemical circuits that mediate incentive-salience and/or reward systems (dopamine, opioid peptides) in the ventral striatum and from the between-system recruitment of brain stress systems (corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids, and neuroimmune factors) in the extended amygdala. Hyperkatifeia can extend into protracted abstinence and interact with learning processes in the form of conditioned withdrawal to facilitate relapse to compulsive-like drug seeking. Compelling evidence indicates that plasticity in the brain pain emotional systems is triggered by acute excessive drug intake and becomes sensitized during the development of compulsive drug taking with repeated withdrawal. It then persists into protracted abstinence and contributes to the development and persistence of compulsive opioid-seeking behavior.

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      Linked Article

      • Perpetual Hunger: The Neurobiological Consequences of Long-Term Opioid Use
        Biological PsychiatryVol. 87Issue 1
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          In 1944, 36 conscientious objectors responded to a government brochure that asked, “Will You Starve That They Be Better Fed?” These healthy young men were brought into the corridors of the University of Minnesota football stadium. There, over the next 6 months, they were made to lose 25% of their normal body weight. They showed slowing of most physiologic processes, including basal metabolism and heart rate. The psychological sequelae were equally profound. They became obsessed with food and lost interest in sex and social interactions.
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