KEGG   PATHWAY: oro05032
Entry
oro05032                    Pathway                                
Name
Morphine addiction - Odobenus rosmarus divergens (Pacific walrus)
Description
Morphine is an alkaloid from the plant extracts of opium poppy. Although morphine is highly effective for the treatment of pain, it is also known to be intensely addictive. We now know that the most important brain-reward circuit involves dopamine (DA) -containing neurons in the ventral tegmental area (VTA) of the midbrain and their target areas in the limbic forebrain, in particular, the nucleus accumbens (NAc) and frontal regions of cerebral cortex. Morphine can cause indirect excitation of VTA dopamine neurons by reducing inhibitory synaptic transmission mediated by GABAergic neurons. The chronic use of morphine is characterized by adaptive changes in neurons and neuronal communication; such adaptations (e.g., 'superactivation' of adenylyl cyclase) must underlie altered behaviour associated with morphine dependence and withdrawal syndrome, as well as drug-induced craving and relapse to drug use.
Class
Human Diseases; Substance dependence
Pathway map
oro05032  Morphine addiction
oro05032

Other DBs
GO: 0043278
Organism
Odobenus rosmarus divergens (Pacific walrus) [GN:oro]
Gene
101380732  OPRM1; mu-type opioid receptor isoform X2 [KO:K04215]
101368015  DRD1; D(1A) dopamine receptor [KO:K04144]
101379158  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101365382  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101368682  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101374313  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
101380824  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101373816  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
101377421  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101370350  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101364108  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101368793  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
101383826  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
101366647  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
101378770  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
101370849  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
101378448  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
105758129  voltage-dependent N-type calcium channel subunit alpha-1B-like [KO:K04849]
101367195  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
101367694  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
101383169  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
101384124  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 [KO:K05175]
101384663  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
101374508  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 isoform X2 [KO:K05175]
101375620  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 [KO:K05181]
101367987  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
101382692  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X2 [KO:K05181]
101366419  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
101374799  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
101384321  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
101381192  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
101373634  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
101376482  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
101381014  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
101362961  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
101371998  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
101372494  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
101374451  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
101378598  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
101376186  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
101367568  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101367936  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
101376297  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
101381482  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform X1 [KO:K04536]
101378633  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 isoform X1 [KO:K04537]
101371845  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
101369300  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
101362117  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
101366315  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
101376879  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
101369684  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
101365462  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
101363588  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
101371482  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
101370001  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
101375712  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
101379027  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
101374080  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
101368814  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7-like [KO:K04347]
101382152  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
101375999  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 isoform X1 [KO:K04548]
101386155  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
101364060  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
105757053  neuroendocrine secretory protein 55 [KO:K04632]
101384757  ADRBK1; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
101385645  ADRBK2; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
101385208  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
101366445  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
101377206  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
101382651  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
101380767  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
101386060  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101380879  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101363254  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101367408  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
101383001  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101365244  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
101380225  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
101363002  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
101368284  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
105757534  LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase A-like [KO:K19021] [EC:3.1.4.17]
101384884  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
101371957  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
101383319  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
101372982  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
101367993  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
101367053  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
101367755  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
101382648  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
101367637  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
101377436  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
101372969  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
101386595  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
101374348  ADORA1; adenosine receptor A1 [KO:K04265]
Compound
C00020  AMP
C00076  Calcium cation
C00212  Adenosine
C00238  Potassium cation
C00334  4-Aminobutanoate
C00575  3',5'-Cyclic AMP
C00698  Cl-
C03758  Dopamine
D00842  Morphine sulfate (USP)
D02271  Morphine hydrochloride hydrate (JP18)
D08233  Morphine (BAN)
D08234  Morphine tartrate
Reference
PMID:15661627
  Authors
Bailey CP, Connor M
  Title
Opioids: cellular mechanisms of tolerance and physical dependence.
  Journal
Curr Opin Pharmacol 5:60-8 (2005)
DOI:10.1016/j.coph.2004.08.012
Reference
PMID:11152760
  Authors
Williams JT, Christie MJ, Manzoni O
  Title
Cellular and synaptic adaptations mediating opioid dependence.
  Journal
Physiol Rev 81:299-343 (2001)
DOI:10.1152/physrev.2001.81.1.299
Reference
PMID:16581089
  Authors
Gintzler AR, Chakrabarti S
  Title
Post-opioid receptor adaptations to chronic morphine; altered functionality and associations of signaling molecules.
  Journal
Life Sci 79:717-22 (2006)
DOI:10.1016/j.lfs.2006.02.016
Reference
PMID:8785060
  Authors
Bonci A, Williams JT
  Title
A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine.
  Journal
Neuron 16:631-9 (1996)
DOI:10.1016/S0896-6273(00)80082-3
Reference
PMID:11750924
  Authors
Liu JG, Anand KJ
  Title
Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence.
  Journal
Brain Res Brain Res Rev 38:1-19 (2001)
DOI:10.1016/S0165-0173(01)00057-1
Reference
PMID:10066284
  Authors
Shoji Y, Delfs J, Williams JT
  Title
Presynaptic inhibition of GABA(B)-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal.
  Journal
J Neurosci 19:2347-55 (1999)
DOI:10.1523/JNEUROSCI.19-06-02347.1999
Reference
PMID:18349442
  Authors
Zhang Y, Chen Q, Yu LC
  Title
Morphine: a protective or destructive role in neurons?
  Journal
Neuroscientist 14:561-70 (2008)
DOI:10.1177/1073858408314434
Reference
PMID:12859419
  Authors
Tso PH, Wong YH
  Title
Molecular basis of opioid dependence: role of signal regulation by G-proteins.
  Journal
Clin Exp Pharmacol Physiol 30:307-16 (2003)
DOI:10.1046/j.1440-1681.2003.03835.x
Reference
PMID:1346804
  Authors
Johnson SW, North RA
  Title
Opioids excite dopamine neurons by hyperpolarization of local interneurons.
  Journal
J Neurosci 12:483-8 (1992)
DOI:10.1523/JNEUROSCI.12-02-00483.1992
Reference
PMID:20962224
  Authors
Madhavan A, Bonci A, Whistler JL
  Title
Opioid-Induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area.
  Journal
J Neurosci 30:14029-35 (2010)
DOI:10.1523/JNEUROSCI.3366-10.2010
Reference
PMID:8987801
  Authors
Bonci A, Williams JT
  Title
Increased probability of GABA release during withdrawal from morphine.
  Journal
J Neurosci 17:796-803 (1997)
DOI:10.1523/JNEUROSCI.17-02-00796.1997
Reference
PMID:21872647
  Authors
Morikawa H, Paladini CA
  Title
Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms.
  Journal
Neuroscience 198:95-111 (2011)
DOI:10.1016/j.neuroscience.2011.08.023
Reference
PMID:12217944
  Authors
Xi ZX, Stein EA
  Title
GABAergic mechanisms of opiate reinforcement .
  Journal
Alcohol Alcohol 37:485-94 (2002)
DOI:10.1093/alcalc/37.5.485
Reference
PMID:8096779
  Authors
Kalivas PW
  Title
Neurotransmitter regulation of dopamine neurons in the ventral tegmental area.
  Journal
Brain Res Brain Res Rev 18:75-113 (1993)
DOI:10.1016/0165-0173(93)90008-N
Reference
PMID:21930931
  Authors
Jalabert M, Bourdy R, Courtin J, Veinante P, Manzoni OJ, Barrot M, Georges F
  Title
Neuronal circuits underlying acute morphine action on dopamine neurons.
  Journal
Proc Natl Acad Sci U S A 108:16446-50 (2011)
DOI:10.1073/pnas.1105418108
Reference
PMID:14625081
  Authors
Chakrabarti S, Gintzler AR
  Title
Phosphorylation of Gbeta is augmented by chronic morphine and enhances Gbetagamma stimulation of adenylyl cyclase activity.
  Journal
Brain Res Mol Brain Res 119:144-51 (2003)
DOI:10.1016/j.molbrainres.2003.09.002
Reference
PMID:14969742
  Authors
Ferrer-Alcon M, La Harpe R, Garcia-Sevilla JA
  Title
Decreased immunodensities of micro-opioid receptors, receptor kinases GRK 2/6 and beta-arrestin-2 in postmortem brains of opiate addicts.
  Journal
Brain Res Mol Brain Res 121:114-22 (2004)
DOI:10.1016/j.molbrainres.2003.11.009
Related
pathway
oro04727  GABAergic synapse
oro04728  Dopaminergic synapse
KO pathway
ko05032   
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