1. 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
Koob NIAAA.pptx
Duke Law- National Townhall Meeting

2. 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”

3. “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:

4. Conceptual Framework for Neurobiological Bases Driving Substance Use Disorders
Koob NIAAA slide2
From: Koob and Volkow, 2010 Neuropsychopharmacology Reviews 35:

5. 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)

6. Neural Circuits of the Withdrawal/Negative Affect Stage
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:

7. Neurobiological Circuitry of the Overlap of Pain and Addiction
KoobGCNADdia3c090808jh animated

8. 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: 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: 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:

9. 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

10. 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:

11. 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)

12. 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

13. Thank You! George F. Koob, Ph.D. Director
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health