NeuroPharmacology (NB404):

1. NeuroPharmacology (NB404): Dr. Charles Chavkin Professor of Pharmacology D425 HSB

2. NeuroPharmacology (NB404): • How drugs interact with their targets. • How pharmacology can be used to discover new medicines. • How pharmacology can be used to increase our understanding of healthy and pathological brain functioning. Opiate receptors, endogenous opioid systems in brain, Analgesia, stress adaptation, drug addiction

3. Natural opium alkaloids • Morphine -gold standard • Codeine • Thebaine - (non-analgesic)

4. Opiate chemical structures CH2=CH Naloxone CH3C=0 Heroin CH3C=0

5. Endogenous Opioid Agonists: enkephalin - 2 pentapeptides b-endorphin - POMC, ACTH dynorphin - endog kappa agonist NH2-Tyr-Gly-Gly-Phe-Leu-COOH

6. Opioids NSAIDS

8. Types of Pain Nociceptive pain - mechanical, thermal, chemical activation of nociceptors somatic pain: response to tissue injury inflammatory mediators: prostaglandins, substance P, bradykinin Neuropathic pain - damage to nerves (trigeminal neuralgia, postherpetic pain, diabetic neuropathy)

9. Actions of Opiates: analgesia anxiolytic sedation euphoria gut hypomotility (constipation) cough suppression respiratory depression pupillary constriction nausea and vomiting endocrine suppression itching (specifically morphine)

10. Endogenous opioid peptides (enkephalins and b-endorphin) have Morphine-like effects Analgesia Euphoria Antidepressant Reduction in anxiety Endogenous dynorphin opioid peptides Analgesia Dysphoria Depressant ? Increase in anxiety ? Endogenous opioids form important stress regulating systems in brain Stress-induced analgesia Stress-induced dysphoria Stress-induced priming of relapse?

12. Forced swim stress-induced analgesia is blocked by prodynorphin gene disruption Day 1 Day 2 Dyn KO mice generated by Hochgeschwender; see Sharifi et al., 1998

14. Mechanisms of opiate actions: Activate mu (m) delta (d), or kappa (k) opioid receptors principal therapeutic opiates are selective for mu receptors Opioid receptors are members of the 7TM, G protein- coupled receptor superfamily (>1,000 members) Activation of opioid receptors inhibits neuronal activity increases potassium conductance decreases calcium conductance inhibits neurotransmitter release

15. how do opiates act at a molecular level? GDP GTP GDP GDP GTP PO4 K+ Activated arrestin response G-Receptor Kinase tolerance opioid dose

16. Opiate Tolerance receptor desensitization compensatory adaptations in neuronal circuit learning mechanisms Physical Dependence compensatory adaptations in neuronal circuit Drug Withdrawal removal of opiate unmasks compensatory adaptations Drug Addiction(extremely rare during treatment of pain)

17. b-arrestin produces GPCR tolerance in a series of resolvable steps • GPCR-PO4 activates b-arrestin • Newly exposed b-arr domain binds GPCR • GPCR- b-arr prevents G- protein association • GPCR- b-arr complex is internalized by a dynamin and clathrin dependent mechanism G Protein receptor kinase -arrestin

18. Acutely, morphine inhibits LC firing - sedation Neuron hyperpolarized and NE release inhibited R OR K+ Opiates inhibit Noradrenergic neuron in the locus ceruleus

19. Chronically, this causes a compensatory increase in LC activation decreased auto-inhibition, increased excitatory drive R R Tolerance Receptor desensitization OR R Normal Excitability restored Excitatory drive Noradrenergic neuron in the locus ceruleus

20. Opioid withdrawal - abstinence syndrome • Severity depends on dose used and rate of elimination. • Rhinorrhea • Lacrimation • Chills • Goose flesh - ‘cold turkey’ • Muscle aches • Diarrhea • Yawning • Anxiety • Hostility • Hyperalgesia • Precipitated withdrawal by a partial agonist or antagonist administration

21. Withdrawal R R Clonidine, an 2-adrenergic receptor agonist, is effective at reducing the sympathetic nervous system hyperactivity associated with acute opiate withdrawal. Opiate gone OR R Hyper-Excitability state Excitatory drive Noradrenergic neuron in the locus ceruleus

22. What is drug addiction? Correct use of prescribed medications for pain, anxiety and hypertension produce tolerance and physical dependence. Addiction is: compulsive drug use, obsessive thoughts about drug, use despite objective evidence of harm, loss of control of drug use, high risk of relapse once abstinent. Commonly Abused Prescription Opiates Buprenorphine (Buprenex, Subutex, Suboxone) Codeine Fentanyl (Actiq, Sublimaze, Duragesic) Hydrocodone (Vicodin, Vicoprofen) Hydromorphone (Dilaudid) Meperidine (Demerol) Methadone (Methadose, Dolophine) Morphine (MS Contin, Avinza, Oramorph SR) Oxycodone (OxyContin, Percocet, Percodan) Propoxyphene (Darvon)

23. “Molecular Basis of Addiction” • Voluntary intake tolerance readily reversible physical dependence sensitization • Involuntary - compulsive intake cravings, obsession, self-destructive behavior Addiction - high relapse risk

24. Progression to Addiction challenges at the molecular front: identify molecular and cellular changes in the addicted brain genes controlling risk of addiction molecular events controlling relapse risk

25. Untreated mice, no stress nor-BNI treated FST mice Day: 1 2 3 4 5 6 Free Run, 30 min Forced swim stress exposure Cocaine, box 2, 30 min Vehicle, box 1, 30 min * 1200 Vehicle-treated FST mice 1000 800 600 * * Difference in time spent on drug-paired side (sec) 400 200 0 -200 Baseline Day 5 results Conditioned place preference measures the rewarding properties of drugs • assess drug craving

26. Stress-induced priming of relapse? Drug consumption escalation crash relapse time stress Heroin Cocaine Ethanol Nicotine

27. Working Model - (wild speculation) Stress induces release of endogenous opioids in key brain regions (nAc and VTA). This results in ‘priming’ of the circuit - manifests as craving Activation of the endogenous kappa opioid system during the stress response elicits dysphoria, anxiety depression. Drug self-administration self medicates the depression. Kappa antagonists may be effective in treating this form of depression.

28. SUMMARY: Opiates are important therapeutic tools Endogenous opioids have important role in mediating the adaptive response to stress Opiates can induce addiction - a compulsive use of drug despite adverse consequence