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Opioid Analgesics: Pathways to Addiction. Chris Evans, Ph.D. UCLA, California

Opioid Analgesics: Pathways to Addiction. Chris Evans, Ph.D. UCLA, California. One side of the story.

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Opioid Analgesics: Pathways to Addiction. Chris Evans, Ph.D. UCLA, California

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  1. Opioid Analgesics: Pathways to Addiction. Chris Evans, Ph.D. UCLA, California

  2. One side of the story - Pain of all types is undertreated in our society. The pediatric and geriatric populations are especially at risk for undertreatment. Physicians’ fears of using opioid therapy, and the fears of other health professionals, contribute to this problem. - Opioid analgesics are generally safe medications when prescribed with appropriate monitoring. There is very little if any evidence of organ damage from the long term therapeutic use of opioids. With appropriate titration and stable dosing, tolerance develops to most of the side effects of opioid therapy, including cognitive impairment. Constipation is the most common persistent side effect and should be managed prophylactically. Use of opioid analgesics for the treatment of chronic noncancer pain - A consensus statement and guidelines from the Canadian Pain Society 1998

  3. % US Population 5.68-7.00 3.78-5.67 2.61-3.75 The Other Side Past Year Nonmedical Use of Pain Relievers (% use 12 or Older, 02-04) Nonmedical New Users of Psychotheraputics 1) New Nonmedical Users of Prescription Pain Relievers Outnumbered New Marijuana Users Between 2002 and 2004 2) 2.7 percent of the population 12 and older in 2003 used prescription psychotherapeutic medications nonmedically in the month prior to being surveyed. This included 4.7 million using pain relievers (compares to 166,000 Heroin users). 3) An estimated 415,000 Americans received treatment for pain reliever abuse in the past year. 4) Past year abuse of Vicodin was 3.0% among 8th-graders, 7.0 % among 10th-graders, and 9.7% among 12th-graders in 2006, (stable since ‘02). Despite a drop in past year abuse of OxyContin among 12th-graders in ‘06, abuse among 8th-graders nearly doubled since 2002 (1.3% in ‘02 - 2.6 % in ‘06) Data from the 2002, 2003 and 2004 National Surveys on Drug Use and Health

  4.   ORL-1 POMC PROENKEPHALIN PROORPHANIN-FQ PRODYNORPHIN Prohormone Convertases (PC’s) CPE and PAM ACTH, MSH ENDOMORPHINS? MORPHINE? MORPHINE, FENTANYL, ETORPHINE, HYDROCODONE, OXYCODONE, CODEINE, BUPRENORPHINE, HEROIN, METHADONE (RARELY RECEPTOR SPECIFIC - Drugs are dirty)

  5. mu • Agonists: rewarding, analgesic, respiratory depression • Antagonists: aversive*, prevent reward • delta • Agonists: not-rewarding, weak analgesics,seizure-inducing • Antagonists: no obvious effects • kappa • Agonists: aversive, hallucinogenic, analgesic • Antagonists: potential antidepressants • ORL-1 • Agonists: Hyperalgesic/block opioid analgesia • Antagonists: no obvious effects 

  6. Methadone (addicts) Morphine (surgery) Buprenorphine (addicts) Oxy/hydrocodone (pain) OH OH CH3O OXY (X=OH) HYDRO (X=H) CODONE O CH3-N-CH3 CH3 O CH3 O O N-CH3 N-CH2 NCH3 X OH CH3O O PERCOSET PERCODAN OXYCODONE OXYCONTIN VICODIN HYDROCODONE HO-C-CH3 C (CH3)3 Fentanyl (epidural, Moscow Siege Gas) Opioid Receptor selectivity Agonist/Partial Agonists Activity at other receptors (NMDA) Rate of onset/duration* Route of Administration Dependency/tolerance Activity at the opioid receptors Receptor occupation? O NCCH2CH3 CH2CH2N

  7. Homologous recombination Mu KO mice have no classical morphine effects (analgesia, respiratory depression, reward, immune modulation). Review - Kieffer

  8. BUPRENORPHINE METHADONE • - long duration of action • antagonist () and partial agonist() • - high affinity, weak  partial agonist • respiratory depression ceiling • active with sublingual administration • - minimal withdrawal symptoms • bell-shaped dose response (analgesia) • used as an analgesic for many years • potential antidepressant (? Kappa)* • - naloxone addition prevents IV abuse • considered a very safe drug • may precipitate withdrawal • *Bodkin JA, et al., Buprenorphine treatment of refractory depression. J. Clin Psychopharmacol. 1995;15(1):49-57 • long duration of action • Selective  agonist • High affinity/efficacy mu agonist • - respiratory depression (risk of death) • - active orally • - strong withdrawal symptoms • used as an analgesic for many years

  9. ORL-1 AGONISTS ARE HYPERALGESIC AND/OR BLOCK OPIOID ANALGESIA Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Civelli O. Orphanin FQ: a neuropeptide that activates an opioid like G protein-coupled receptor. Science. 1995. Mogil JS, Grisel JE, Zhangs G, Belknap JK, Grandy DK. Functional antagonism of mu-, delta- and kappa-opioid antinociception by orphanin FQ. Neurosci Lett. 1996 King M, Chang A, Pasternak GW. Functional blockade of opioid analgesia by orphanin FQ/nociceptin. Biochem Pharmacol. 1998. Lutfy K, Maidment NT. Blockade of mu-opioid receptors reveals the hyperalgesic effect of orphanin FQ/nociceptin in the rat hot plate test. Br J Pharmacol. 2000 Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, Kieffer BL, Takeshima H, Carroll FI, Maidment NT, Evans CJ. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci. 2003;23(32):10331-7.

  10. BUPRENORPHINE HAS INCREASED ANALGESIC EFFICACY IN ORL-1 RECEPTOR KO MICE Cut off WT WT ORL-1KO ORL-1KO 12 12 9 Tail flick latency (sec) 9 6 6 3 3 0 0 +J-113397 0.1 0.3 1 3 Cont. Baseline Baseline Bup. (mg/kg s.c.) Bup. (0.3mg/kg s.c.) ORL-1 Receptor KO Mice Courtesy of Hiroshi Takeshima, J-113397 Ivy Carroll

  11. Wanting The drug is desired for its remembered effects (analgesia, rewarding, calming, combating withdrawal, physiologic effect). In extreme cases this can become craving Liking Taking the drug feels good - is rewarding and/or satisfies the reasons for taking the drug. Habit Taking the drug as a result of automatic response to a stimulus - after eating - smoke Stressed or anxious - drink or take a vicodin

  12. OPIOID RECEPTOR KNOCKOUT MICE Homologous Recombination • MU OPIOD RECEPTOR KO-MICE • No Morphine/many other opioid drug effects on analgesia, respiratory depression, reward*, immune system. • No longer is alcohol, nicotine or THC rewarding!

  13. SYSTEM INTERDEPENDANCE FOR REWARD Morphine/Heroin THC Nicotine Alcohol CB-1 ACh GABA/NMDA Mu Opioid Receptors Kappa receptor activation Mu receptor activation by endogenous opioids CB-1 and NK-1 receptor activation by endogenous ligands Antagonism Naloxone Activation of Mesolimbic Dopamine system AVERSION REWARD

  14. ACUTE OPIOID EFFECTS Analgesia, Antitussive Constipation, Euphoria, Nausea, Calming Decreased Respiration GENES PAIN? oxycontin, vicodin heroin, morphine MOOD PEERS molecular, cellular and behavioral adaptations relapse MOOD ? STRESS ? PAIN? CHRONIC PEERS PROCESSES OPPONENT WITHDRAWAL CHRONIC OPIOID EFFECTS Tolerance to acute effects, normalization of physiology & psychology in presence of drug Hyperalgesia, Dysphoria, Anxiety, Sweating, Runny nose, Chills, Diarrhea, Nausea drug/action associations

  15. Methadone maintenance patients are hyperalgesic. Control Methadone Maintained Time in ice-cold water (seconds) Pain Tolerance Pain Detection Pain Tolerance Pain Detection 3hr after Methadone Slide kindly provided by Walter Ling, UCLA

  16. A B 5 30 150’ post-morphine 25 4 baseline tail withdrawal Latency (s) 20 3 hot plate latency (s) 15 2 10 1 5 0 0 saline control chronic morphine saline control chronic morphine Hyperalgesia Following Chronic Morphine (TAD)- Pain Paradigm Specific * * * 48ºC

  17. FORSKOLIN-STIMULATED cAMP ACCUMULATION FOLLOWING ACUTE AND CHRONIC OPIOID TREATMENT - CYCLASE SUPERSENSITIVITY 400 Acute: opiod + forskolin 300 [cAMP ] % CHANGE 200 Chronic: 24h opioid then wash out +forskolin RTI-1d 100 0 Control 0.1nM 1nM 10nM 100nM [DAMGO]

  18. MU OPIOID RECEPTOR COMPLEX (diversity) COMPLEX DETERMINATION Cellular Proteome Mu receptor alternative splicing Cellular Compartment Oligomerization (Hetro/Homo) The Receptor Activation State History of Receptor/Environment TRAFFICKING 2+proteins REGULATION 5+proteins SIGNALING 8+proteins 100+proteins 100+proteins 100+proteins Arrestins/G-proteins/GRK’s/Src’s/RGS’s

  19. Desensitized Receptor Agonist Binding P P Re-sensitized Receptor P Signaling P Signaling Signaling GRK 2 (1-6) Phosphorylation Beta-arrestin 1-2 (cSrc) Recruitment of Clathrin Recycling P P Lysosomes Downregulation Endosome Uncoating of CCV and Fusion with Endosome P P Severing of CCV by Dynamin Dephosphorylation

  20. FLAG & MOR-C12 STAINING OF 293-CELLS TRANSFECTED WITH MU RECEPTORS CONTROL ETORPHINE DAMGO ETOR/NALOX MORPHINE (100nM) (100nM) (100nM/10µM) (20µM)

  21. There is a correlation between ligands’ abilities to alter surface receptor number and their abilities to modulate G protein activation in 293-SF-MOR cells r2 = .8873 r2 = .9893 (without morphine) 140 Naloxone Buprenorphine 120 Morphine 100 % of control surface staining after one hour ligand treatment 80 60 Fentanyl 40 0 20 40 60 80 100 120 % of maximal stimulation of [35S]-GTPS binding

  22. 4 0 DAMGO Morphine 6 0 Clonidine Challenge 3 0 5 0 4 0 # Calcium Current Inhibition(%) 2 0 Calcium Current Inhibition(%) 3 0 * * * * 2 0 1 0 * 1 0 1 2 1 1 1 9 6 2 1 0 1 0 7 1 2 6 0 0 4 h r 0 h r 4 h r + C T 4 h r 4 h r 0 h r 0 h r DAMGO Pretreated Morphine Pretreated Opioid Pretreatment Time DAMGO Challenge Morphine Challenge D A M G O t e s t M o r p h i n e t e s t 6 0 # # 5 0 * * 4 0 * Calcium Current Inhibition(%) 3 0 2 0 1 0 1 0 1 8 7 6 2 9 8 0 0 h r 4 h r + Y o h 0 h r 4 h r 4 h r 4 h r + Y o h Clonidine Pretreated Mouse DRG Cells 2AMerged Tracy Xie Lab 2006, submitted

  23. Morphine 0 min 10 min 30 min  2AMerged 4 hr DAMGO Clonidine 0 min 0 min 10 min 10 min 30 min 30 min 4 hr 4 hr +CTAP +Yoh 2AMerged  2AMerged DAMGO and Clonidine induce both mu and alpha2A internalization but not Morphine.

  24. 2AMerged P 38 inhibition blocks cross-desensitization and mu internalization but not Clonidine-induced alpha2A internalization and desensitization. 4 hr Clonidine Treatment (P38 inhibitor PD169316) 2AMerged

  25. LAYER II RAT PARIETAL CORTEX saline m receptor etorphine + naloxone m receptor morphine µ receptor etorphine m receptor etorphine TfR etorphine TfR/ m receptor LIGAND-DIRECTED TRAFFICKING DIFFERS IN DENDRITES AND CELL BODIES - Different Complexes? CONTROL METHADONE MORPHINE Haberstock-Debic H, Wein M, Barrot M, Colago EE, Rahman Z, Neve RL, Pickel VM, Nestler EJ, von Zastrow M, Svingos AL. J Neurosci. 2003;23:4324-32.

  26. NK-1/CB-1 antagonists? Slow on- and off rate? Receptor selectivity Kappa antagonists? Salience to other rewards REWARD/ANALGESIA PLASTICITY ENVIRONMENT DRUG ACCESS Relapse Adaptive Changes Partial Agonists? Mu-agonists selective signaling and trafficking Withdrawal

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