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Mu opioid receptor Chen et al Thompson et al Seven

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Mu opioid receptor Chen et al Thompson et al Seven Powered By Docstoc
					    NEUROBIOLOGICAL
MECHANISMS INVOLVED IN
OPIOID PHARMACOLOGICAL
           EFFECTS
           Rafael MALDONADO

        Laboratory of Neuropharmacology
            University Pompeu Fabra
                Barcelona, Spain
       Mu-opioid receptor
   1993. Chen et al., Thompson et al.
Seven transmembrane domains (398 AA)
        CNS & peripheral tissues

      Delta-opioid receptor
    1992. Evans et al., Kieffer et al.
Seven transmembrane domains (372 AA)
       CNS & peripheral tissues

     Kappa-opioid receptor
    1993. Meng et al., Yasuda et al.
Seven transmembrane domains (380 AA)
       CNS & peripheral tissues
Neuroanatomical distribution
 of the mu-opioid receptors




               from Mansour, TINS, 1995
                          agonist

                  opioid receptor

                          G Protein
Ca++   K+
                      a* GTP            B/g


       Protein Kinase A      Protein Kinase C   MAP Kinases
   PROOPIO-
                      PRODYNORPHIN
MELANOCORTIN
                       Dynorphin A (k)
b-endorphin (m , d)
                       Dynorphin B (k)
                      a-neoendorphin (k)
                      b-neoendorphin (k)
                      Leu-enkephalin (d)

PROENKEPHALIN
                      (ENDOMORPHINS)
Leu-enkephalin (d)         ????
Met-enkephalin (d)
                                                MU-OPIOID
                               RELEASE
                                                DELTA-OPIOID
SYNTHESIS   AXONIC TRANSPORT
                                                KAPPA-OPIOID




                                  ENZYMATIC
                                  DEGRADATION
Mechanisms involved in
opioid-induced analgesia
Neural pathways involved in pain transmission and integration


                                            CORTEX
                                                                       BRAIN
                                          THALAMUS

                                            HIPOTHALAMUS    BRAIN
                       LIMBIC
                       SYSTEM
                                               PAG
                                                         BRAIN STEM
                                                             BRAIN STEM



                          SPINOTHALAMIC
                                                     LOCUS
                                                     COERULEUS

                                                              BRAIN STEM
                          PATHWAY


                                              N. RAPHE
                                              MAGNUS



                                                                 SPINAL CORD
Pharmacological activation of the endogenous opioid system
                produces antinociception

                       1                            3
                                                                BRAIN
                                           CORTEX
            3                     THALAMUS                  BRAIN
                    LIMBIC                 HYPOTHALAMUS
                    SYSTEM                                      BRAIN STEM
                                           PAG          2
                                                            BRAIN STEM

                                                            2
                           SPINOTHALAMIC            LOCUS COERULEUS
                           PATHWAY
                                                             BRAIN STEM
                                            N. RAPHE
                                            MAGNUS
                                                                2

                                                             SPINAL CORD


                                            1                       1
             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
Mechanisms involved in
opioid-induced physical
     dependence
  NALOXONE-PRECIPITATED SOMATIC SIGNS OF
MORPHINE WITHDRAWAL IN MOR KNOCKOUT MICE




                                       WET DOG SHAKES
                                                          8                                  40
              10
 JUMPPIMNG




                                                                                  SNIFFING
               8                                          6                                  30
               6                                          4                                  20
               4
                                                          2                                  10
               2
                                                          0                                  0
               0                                                                                     SALINE    MORPHINE
                   SALINE   MORPHINE                          SALINE   MORPHINE




                                       TEETH CHATTERING
              30                                          6                                      6
 PAW TREMOR




                                                                                                 5




                                                                                        TREMOR
              20                                          4                                      4
                                                                                                 3
              10                                          2                                      2
                                                                                                 1
               0                                          0                                      0
                   SALINE   MORPHINE                          SALINE   MORPHINE                       SALINE   MORPHINE




                                              WILD-TYPE                           MUTANT

   MORPHINE PHYSICAL DEPENDENCE IS
 PRESERVED IN DOR & KOR KNOCKOUT MICE
                         agonist

                      opioid receptor

                         G Protein

                        a* GTP       B/g

Adenylyl cyclase
                            LOCUS COERULEUS
Protein Kinase A
                            Other brain structures
Phosphoproteins
                   (Mesolimbic system, Striatum, Cortex, PAG)




                     CREB                         Nucleus
                              ACUTE MORPHINE TREATMENT

     LOCUS COERULEUS                                   CORTEX
                                                       HIPOCAMPO
                                Noradrenergic neuron
Opioid neuron

                                  m                                b
                Enkephalins




                                                          NA
                                                         release
                                  m                                b




      MORPHINE
                              CHRONIC MORPHINE TREATMENT

                                                       CORTEX
   LOCUS COERULEUS                                     HIPOCAMPO

                                Noradrenergic neuron
Opioid neuron
                                 m




                                                                   Up-regulation
                Enkephalins




                                                        Normal
                                                        NA
                                 m    PKA               release




    MORPHINE
                              MORPHINE WITHDRAWAL

                                                      CORTEX
  LOCUS COERULEUS                                     HIPOCAMPO


                               Noradrenergic neuron
Opioid neuron

                               m




                                                                  Up-regulation
                Enkephalins




                                                         NA
                                     PKA                release
                               m
 Mechanisms involved in
opioid-induced rewarding
        effects
MORPHINE-INDUCED PLACE CONDITIONING IN
         MOR KNOCKOUT MICE

              500
              400
  Score (s)

              300
                                         WILD-TYPE
              200
              100                        MUTANT
                 0
              -100

                     SALINE   MORPHINE




  MORPHINE REWARDING EFFECTS ARE
PRESERVED IN DOR & KOR KNOCKOUT MICE
MORPHINE CONDITIONED PLACE PREFERENCE IN
D2 DOPAMINERGIC RECEPTOR KNOCKOUT MICE


                    150

                    100
      Score (Sec)

                     50

                      0

                    -50

                    -100
                           SALINE           MORPHINE
                                             3 mg/kg

                           Wild-type mice
                           D2 Knockout mice
Common Neural Substrate for Drug Addiction




   From: Nestler, Nature Rev Neurosci, 2:119, 2001
                                      Nucleus
                                    Accumbens
Psychostimulants




               Dopamine

                            Ventral Tegmental
                                   Area   Opioids
                          Opioid          Cannabinoids
                                          Alcohol
                                          Nicotine

				
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