Neurobiology of Addiction The Gain in the Brain is in the Pain Director National Institute on Alcohol Abuse and Alcoholism NIAAA National Institutes of Health Senior Investigator Neurobiology of Addiction Section ID: 770452
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Neurobiology of Addiction: The Gain in the Brain is in the Pain DirectorNational Institute on Alcohol Abuse and Alcoholism (NIAAA)National Institutes of HealthSenior InvestigatorNeurobiology of Addiction SectionIntegrative Neuroscience Research BranchIntramural Research Program National Institute on Drug Abuse Duke Law- National Townhall Meeting 2-28-19
Flow of Talk 1. What is the Negative Affect Side of Addiction?Conceptual Framework, Opponent Process, Hyperkatifeia, Negative Reinforcement2. Neuroplasticity in Brain Negative Emotion Circuits: CRF, dynorphin and Beyond 3. Overlap in the Brain Negative Emotion and Pain Neurocircuits: Implications for Neurobiology of Addiction, Opioid Crisis and “Deaths of Despair”
“ Deaths of Despair”Source: Case, A and Deaton, A (2015) Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. PNAS 112: 15078-15083.
Conceptual Framework for Neurobiological Bases Driving Substance Use Disorders From: Koob and Volkow, 2010 Neuropsychopharmacology Reviews 35: 217- 238
Positive and Negative Reinforcement - Definitions Positive Reinforcement — a process by which presentation of a stimulus (drug) increases the probability of a response (nondependent drug taking paradigms). Negative Reinforcement — a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response (dependence-induced drug taking)
Neural Circuits of the Withdrawal/Negative Affect Stage Adapted from: George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166. Key Neurochemical Systems • CRF • dynorphin • norepinephrine • vasopressin• hypocretin (orexin)• neuroimmune
Neurobiological Circuitry of the Overlap of Pain and Addiction
From: Carcoba LM, Contreras AE, Cepeda-Benito A, Meagher MW. Negative Affect Heightens Opiate Withdrawal-Induced Hyperalgesia in Heroin Dependent Individuals J Addict Dis, 2011, 30:258-270.Opiate Withdrawal-induced Hyperalgesia in Heroin-dependent Individuals Effects of Drug History on Ischemic Pain Threshold and Tolerance. The submaximal tourniquet procedure was used to induce ischemic pain using a standard blood pressure cuff. Acute withdrawal: 24-72 h after last heroin dose. Ex-users group: average of 30 months of opioid abstinence
Martha Woodroof: Alcohol Provided Relief from my Emotional Pain I grew up professionally focused and personally adrift. There's a long history of depression in my family, and my childhood home was dominated by my mother's mental illness that was not recognized, let alone treated. Sometime in my mid-thirties I started using alcohol to provide relief from the pain of childhood damage and organic depression. Bourbon was the only thing that would make the loop tape of despair in my head pipe down. -Martha Woodroof, former public radio journalist and late-blooming novelist
From: Jochum T, Boettger MK, Burkhardt C, Juckel G, Bar KJ. Eur J Pain , 2010, 14:713-718. Increased Pain Sensitivity in AlcoholWithdrawal
Hyperkatifeia 1. Defined as the increased intensity of negative emotional/motivational symptoms and signs observed during withdrawal from abused drugs2. Derived from the Greek word katifeia for dejection, sadness, or negative emotional state 3 “Hyperkatifeia ” refers to the increases in emotional distress and emotional pain experienced by addicts during abstinence. 4. “Hyperkatifeia” is hypothesized to represent elements such as dysphoria, irritability, alexithymia, or simply symptoms often described as ill at ease, uncomfortable within one’s own skin, or simply not hedonically normal, symptoms historically difficult to define . Shurman, J, Koob, GF, Gutstein , HB. Opioids, pain, the brain and hyperkatifeia: A framework for the rational use of opioids. Pain Medicine 11 (2010) 1092- 1098
Etiology of Addiction Progression of the Addictive Process Individual factors: Genetics, Life Stress Escalating/Compulsive Use Dependence/Withdrawal Reward positive reinforcement Relief negative reinforcement Protracted Abstinence Relapse Reward DA, 5-HT, GABA, GLU Opioid Peptides Glucocorticoids Dependence Dysregulation of reward NTs Stress Systems CRF, Dynorphin, Substance P NPY, Nociceptin ( OrphFQ ) Glucocorticoids Relapse Glutamate Dopamine CRF
Thank You! George F. Koob, Ph.D.DirectorNational Institute on Alcohol Abuse and AlcoholismNational Institutes of Health