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NEUROBIOLOGICAL MECHANISMS INVOLVED IN OPIOID PHARMACOLOGICAL EFFECTS

NEUROBIOLOGICAL MECHANISMS INVOLVED IN OPIOID PHARMACOLOGICAL EFFECTS. Rafael MALDONADO Laboratory of Neuropharmacology University Pompeu Fabra Barcelona, Spain.

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NEUROBIOLOGICAL MECHANISMS INVOLVED IN OPIOID PHARMACOLOGICAL EFFECTS

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  1. NEUROBIOLOGICAL MECHANISMS INVOLVED IN OPIOID PHARMACOLOGICAL EFFECTS Rafael MALDONADO Laboratory of Neuropharmacology University Pompeu Fabra Barcelona, Spain

  2. Mu-opioid receptor1993. Chen et al., Thompson et al.Seven transmembrane domains (398 AA) CNS & peripheral tissues Delta-opioid receptor1992. Evans et al., Kieffer et al. Seven transmembrane domains (372 AA) CNS & peripheral tissuesKappa-opioid receptor1993. Meng et al., Yasuda et al. Seven transmembrane domains (380 AA) CNS & peripheral tissues

  3. Neuroanatomical distribution of the mu-opioid receptors from Mansour, TINS, 1995

  4. agonist opioid receptor G Protein K+ Ca++ B/g a * GTP Protein Kinase A Protein Kinase C MAP Kinases

  5. PROOPIO- MELANOCORTINb-endorphin (m , d) PROENKEPHALINLeu-enkephalin (d)Met-enkephalin (d) PRODYNORPHINDynorphin A (k)Dynorphin B (k)a-neoendorphin (k)b-neoendorphin (k)Leu-enkephalin (d)(ENDOMORPHINS)????

  6. MU-OPIOID RELEASE DELTA-OPIOID SYNTHESIS AXONIC TRANSPORT KAPPA-OPIOID ENZYMATIC DEGRADATION

  7. Mechanisms involved in opioid-induced analgesia

  8. Neural pathways involved in pain transmission and integration CORTEX BRAIN THALAMUS BRAIN HIPOTHALAMUS LIMBIC SYSTEM PAG BRAIN STEM BRAIN STEM LOCUS COERULEUS SPINOTHALAMIC PATHWAY BRAIN STEM N. RAPHE MAGNUS SPINAL CORD

  9. Pharmacological activation of the endogenous opioid system produces antinociception 3 1 BRAIN CORTEX 3 THALAMUS BRAIN HYPOTHALAMUS LIMBIC SYSTEM BRAIN STEM 2 PAG BRAIN STEM 2 LOCUS COERULEUS SPINOTHALAMIC PATHWAY BRAIN STEM 2 N. RAPHE MAGNUS SPINAL CORD 1 1

  10. ADDICTION Compulsive drug intake in order to obtain rewarding effects and/or to avoid the negative effects of drug withdrawal, which is maintained despite adverse consequences for the user

  11. Mechanisms involved in opioid-induced physical dependence

  12. NALOXONE-PRECIPITATED SOMATIC SIGNS OF MORPHINEWITHDRAWAL IN MOR KNOCKOUT MICE 40 8 10 30 6 8 6 SNIFFING 20 4 WET DOG SHAKES JUMPPIMNG 4 10 2 2 0 0 0 SALINE MORPHINE SALINE MORPHINE SALINE MORPHINE 30 6 6 5 20 4 4 3 TREMOR PAW TREMOR TEETH CHATTERING 10 2 2 1 0 0 0 SALINE MORPHINE SALINE MORPHINE SALINE MORPHINE MUTANT WILD-TYPE MORPHINE PHYSICAL DEPENDENCE IS PRESERVED IN DOR & KOR KNOCKOUT MICE

  13. agonist opioid receptor G Protein B/g a * GTP Adenylyl cyclase LOCUS COERULEUS Other brain structures (Mesolimbic system, Striatum, Cortex, PAG) Protein Kinase A Phosphoproteins CREB Nucleus

  14.  ACUTE MORPHINE TREATMENT CORTEX HIPOCAMPO LOCUS COERULEUS Noradrenergic neuron Opioid neuron  NA release  Enkephalins MORPHINE

  15. CHRONIC MORPHINE TREATMENT CORTEX HIPOCAMPO LOCUS COERULEUS Noradrenergic neuron Opioid neuron  Normal NA release PKA Up-regulation  Enkephalins MORPHINE

  16. MORPHINE WITHDRAWAL CORTEX HIPOCAMPO LOCUS COERULEUS Noradrenergic neuron Opioid neuron  NA release PKA Up-regulation Enkephalins 

  17. Mechanisms involved in opioid-induced rewarding effects

  18. MORPHINE-INDUCED PLACE CONDITIONINGIN MOR KNOCKOUT MICE 500 400 300 WILD-TYPE Score (s) 200 MUTANT 100 0 -100 MORPHINE SALINE MORPHINE REWARDING EFFECTS ARE PRESERVED IN DOR & KOR KNOCKOUT MICE

  19. MORPHINE CONDITIONED PLACE PREFERENCE IN D2 DOPAMINERGIC RECEPTOR KNOCKOUT MICE 150 100 50 Score (Sec) 0 -50 -100 SALINE MORPHINE 3 mg/kg Wild -type mice D2 Knockout mice

  20. Common Neural Substrate for Drug Addiction From: Nestler, Nature Rev Neurosci, 2:119, 2001

  21. Opioid GABA Nucleus Accumbens Psychostimulants Dopamine Ventral Tegmental Area Opioids Cannabinoids Alcohol Nicotine

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