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 Integrative Neuroscience Research Branch Intramural Research Program National Institute on Drug Abuse 051514 Koob NIAAA.pptx 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 Reinforcement 2. 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” 053118 Koob NIAAA slide01c 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 112116 Koob NIAAA slide2 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 011017 Koob NIAAA slide3 Key Neurochemical Systems • CRF • dynorphin • norepinephrine • vasopressin • hypocretin (orexin) • neuroimmune Adapted from: George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Neurobiological Circuitry of the Overlap of Pain and Addiction KoobGCNADdia3c090808jh animated

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 KoobG/CNAD/gra7/041812jh Effects of Drug History on Ischemic Pain Threshold and Tolerance. The submaximal Tourniquet procedure was used to induce ischemic pain- standard blood pressure cuff. Acute withdrawal: 24-72 hours after last heroin dose; Ex- users group- mean length of opioid abstinence was 30 months 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.

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

Increased Pain Sensitivity in Alcohol Withdrawal KoobG/CNAD/gra1/041812jh From: Jochum T, Boettger MK, Burkhardt C, Juckel G, Bar KJ. Eur J Pain, 2010, 14:713-718.

Hyperkatifeia 1. Defined as the increased intensity of negative emotional/motivational symptoms and signs observed during withdrawal from abused drugs 2. 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 Reward Dependence Relapse Reward Relief Individual factors: Genetics, Life Stress Relapse Relief negative reinforcement Reward positive reinforcement Protracted Abstinence Progression of the Addictive Process Escalating/Compulsive Use Dependence/Withdrawal 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. Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health