KEGG   PATHWAY: oga05032
Entry
oga05032                    Pathway                                
Name
Morphine addiction - Otolemur garnettii (small-eared galago)
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
oga05032  Morphine addiction
oga05032

Other DBs
GO: 0043278
Organism
Otolemur garnettii (small-eared galago) [GN:oga]
Gene
100952218  OPRM1; mu-type opioid receptor isoform X1 [KO:K04215]
100967027  DRD1; D(1A) dopamine receptor [KO:K04144]
100955472  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100941250  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100942592  ADCY3; LOW QUALITY PROTEIN: adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100949638  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
100942320  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100963748  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
100956925  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
100952034  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100943767  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
100945983  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
100963121  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
100954049  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
100954733  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
100945700  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
100940437  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
100957337  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
100941086  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
100954326  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X2 [KO:K05175]
100961059  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
100957365  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175]
100958314  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
100954634  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
100941625  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
100958637  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X3 [KO:K05181]
100954948  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
100945525  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
100956855  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
100954017  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
100965004  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
100961382  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
100960738  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
100949613  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
100958621  gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
100940751  gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
100965775  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
100944506  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
100966327  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
100962114  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100945007  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100962000  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X2 [KO:K04630]
100966468  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100964694  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100940763  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100950950  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
100961335  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100954252  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
111726116  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100947073  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
100967014  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
111723289  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
111724938  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
111728356  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
111723667  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
100954553  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100950477  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
111727847  GNG14; LOW QUALITY PROTEIN: putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
111725594  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100954240  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
111724020  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100966244  neuroendocrine secretory protein 55 [KO:K04632]
100966563  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
100943694  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
100966357  GRK3; beta-adrenergic receptor kinase 2 isoform X4 [KO:K00910] [EC:2.7.11.15]
100946468  GRK4; G protein-coupled receptor kinase 4 isoform X1 [KO:K08291] [EC:2.7.11.16]
100954169  GRK6; G protein-coupled receptor kinase 6 isoform X3 [KO:K08291] [EC:2.7.11.16]
100956889  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
100946246  ARRB1; beta-arrestin-1 [KO:K04439]
100954933  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
100965377  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100943579  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
100956877  PRKCG; protein kinase C gamma type isoform X2 [KO:K19663] [EC:2.7.11.13]
100964083  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100966533  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100960156  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X3 [KO:K13755] [EC:3.1.4.17]
100952295  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X2 [KO:K13755] [EC:3.1.4.17]
100953359  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
100942013  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
100965949  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
100961357  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
100957460  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
100961249  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
100954042  cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X2 [KO:K13293] [EC:3.1.4.53]
100953521  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
100962167  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
100946021  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
100960650  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
100956143  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
100963741  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
100951251  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
100957132  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
oga04727  GABAergic synapse
oga04728  Dopaminergic synapse
KO pathway
ko05032   
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