KEGG   PATHWAY: bacu05032
Entry
bacu05032                   Pathway                                
Name
Morphine addiction - Balaenoptera acutorostrata scammoni (minke whale)
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
bacu05032  Morphine addiction
bacu05032

Other DBs
GO: 0043278
Organism
Balaenoptera acutorostrata scammoni (minke whale) [GN:bacu]
Gene
103020254  OPRM1; opioid receptor mu 1 [KO:K04215]
103009568  DRD1; dopamine receptor D1 [KO:K04144]
102998650  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
103020085  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
103020845  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
103005549  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
103006764  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
103014094  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
102997912  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
103019172  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
103016058  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
103019095  SLC32A1; solute carrier family 32 member 1 [KO:K15015]
103017653  KCNJ3; potassium voltage-gated channel subfamily J member 3 [KO:K04997]
103014208  KCNJ6; potassium voltage-gated channel subfamily J member 6 [KO:K05000]
103007029  KCNJ9; potassium voltage-gated channel subfamily J member 9 [KO:K05002]
103005183  KCNJ5; potassium voltage-gated channel subfamily J member 5 [KO:K04999]
103007483  CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
103004988  CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
103011249  GABRA2; gamma-aminobutyric acid type A receptor alpha2 subunit [KO:K05175]
103012320  GABRA4; gamma-aminobutyric acid type A receptor alpha4 subunit [KO:K05175]
103003955  GABRA3; gamma-aminobutyric acid type A receptor alpha3 subunit [KO:K05175]
103011733  GABRA5; gamma-aminobutyric acid type A receptor alpha5 subunit [KO:K05175]
102999330  GABRA1; gamma-aminobutyric acid type A receptor alpha1 subunit [KO:K05175]
102999781  GABRA6; gamma-aminobutyric acid type A receptor alpha6 subunit [KO:K05175]
103012600  GABRB1; gamma-aminobutyric acid type A receptor beta1 subunit [KO:K05181]
103011442  GABRB3; gamma-aminobutyric acid type A receptor beta3 subunit [KO:K05181]
103001353  GABRB2; gamma-aminobutyric acid type A receptor beta2 subunit [KO:K05181]
103010962  GABRG1; gamma-aminobutyric acid type A receptor gamma1 subunit [KO:K05186]
103014923  GABRG3; gamma-aminobutyric acid type A receptor gamma3 subunit [KO:K05186]
102998856  GABRG2; gamma-aminobutyric acid type A receptor gamma2 subunit [KO:K05186]
103005575  GABRD; gamma-aminobutyric acid type A receptor delta subunit [KO:K05184]
103006106  GABRE; gamma-aminobutyric acid type A receptor epsilon subunit [KO:K05185]
103001582  GABRQ; gamma-aminobutyric acid (GABA) A receptor, theta [KO:K05192]
103008888  GABRP; gamma-aminobutyric acid type A receptor pi subunit [KO:K05189]
103005557  GABRR3; gamma-aminobutyric acid type A receptor rho3 subunit [KO:K05190]
103014826  GABRR1; gamma-aminobutyric acid type A receptor rho1 subunit [KO:K05190]
103015463  GABRR2; gamma-aminobutyric acid type A receptor rho2 subunit [KO:K05190]
102997684  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
103016984  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
103017385  GNAI1; G protein subunit alpha i1 [KO:K04630]
103010531  GNAI2; G protein subunit alpha i2 [KO:K04630]
103008589  GNAI3; G protein subunit alpha i3 [KO:K04630]
103011674  GNAO1; G protein subunit alpha o1 [KO:K04534]
103006513  GNB1; G protein subunit beta 1 [KO:K04536]
103000308  GNB2; G protein subunit beta 2 [KO:K04537]
103008105  GNB3; G protein subunit beta 3 [KO:K07825]
103001811  GNB4; G protein subunit beta 4 [KO:K04538]
103000160  GNB5; G protein subunit beta 5 [KO:K04539]
103004854  GNG2; G protein subunit gamma 2 [KO:K07826]
103019275  GNG4; G protein subunit gamma 4 [KO:K04541]
103017244  GNG7; G protein subunit gamma 7 [KO:K04543]
102997635  GNG8; G protein subunit gamma 8 [KO:K04544]
103007358  GNG11; G protein subunit gamma 11 [KO:K04546]
103016707  GNG13; G protein subunit gamma 13 [KO:K04547]
103007657  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
103004432  GNAS; GNAS complex locus [KO:K04632]
103004158  neuroendocrine secretory protein 55-like [KO:K04632]
103005732  GRK3; G protein-coupled receptor kinase 3 [KO:K00910] [EC:2.7.11.15]
103019615  GRK2; G protein-coupled receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
103017883  GRK6; G protein-coupled receptor kinase 6 [KO:K08291] [EC:2.7.11.16]
103011898  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
103005786  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
103021082  ARRB2; arrestin beta 2 [KO:K04439]
103017343  ARRB1; arrestin beta 1 [KO:K04439]
103004532  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
103012542  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
103017540  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
103000011  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103008319  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103015373  PDE1C; phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
103007918  PDE1A; phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
103006648  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B-like [KO:K13755] [EC:3.1.4.17]
103009980  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B-like [KO:K13755] [EC:3.1.4.17]
103005086  PDE1B; phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
103008978  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B-like [KO:K13755] [EC:3.1.4.17]
103000616  PDE2A; phosphodiesterase 2A [KO:K18283] [EC:3.1.4.17]
103004781  PDE3A; phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
103008332  PDE3B; phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
103017037  PDE4A; phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
103000561  PDE4B; phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
103008716  PDE4C; phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
103002367  PDE4D; phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
102999187  PDE7A; phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
103020746  PDE7B; phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
103004118  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
103013331  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
103003425  PDE10A; phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
103017485  PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
103010703  ADORA1; adenosine A1 receptor [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
bacu04727  GABAergic synapse
bacu04728  Dopaminergic synapse
KO pathway
ko05032   
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