KEGG   PATHWAY: epz05032
Entry
epz05032                    Pathway                                
Name
Morphine addiction - Equus przewalskii (Przewalski's horse)
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
epz05032  Morphine addiction
epz05032

Other DBs
GO: 0043278
Organism
Equus przewalskii (Przewalski's horse) [GN:epz]
Gene
103556818  OPRM1; opioid receptor mu 1 [KO:K04215]
103565152  DRD1; dopamine receptor D1 [KO:K04144]
103550430  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
103562505  adenylate cyclase type 2-like [KO:K08042] [EC:4.6.1.1]
103547823  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
103561050  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
103563830  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
103563634  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
103556685  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
103565019  adenylate cyclase type 8-like [KO:K08048] [EC:4.6.1.1]
103567623  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
103553014  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
103549241  SLC32A1; solute carrier family 32 member 1 [KO:K15015]
103555321  KCNJ3; potassium voltage-gated channel subfamily J member 3 [KO:K04997]
103564035  KCNJ6; potassium voltage-gated channel subfamily J member 6 [KO:K05000]
103551152  KCNJ9; potassium voltage-gated channel subfamily J member 9 [KO:K05002]
103551404  KCNJ5; potassium voltage-gated channel subfamily J member 5 [KO:K04999]
103566268  CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
103554173  CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
103549065  GABRA6; gamma-aminobutyric acid type A receptor alpha6 subunit [KO:K05175]
103551833  GABRA4; gamma-aminobutyric acid type A receptor alpha4 subunit [KO:K05175]
103557019  GABRA1; gamma-aminobutyric acid type A receptor alpha1 subunit [KO:K05175]
103558116  GABRA2; gamma-aminobutyric acid type A receptor alpha2 subunit [KO:K05175]
103564242  GABRA5; gamma-aminobutyric acid type A receptor alpha5 subunit [KO:K05175]
103549066  GABRB2; gamma-aminobutyric acid type A receptor beta2 subunit [KO:K05181]
103551832  GABRB1; gamma-aminobutyric acid type A receptor beta1 subunit [KO:K05181]
103563988  GABRB3; gamma-aminobutyric acid type A receptor beta3 subunit [KO:K05181]
103557021  GABRG2; gamma-aminobutyric acid type A receptor gamma2 subunit [KO:K05186]
103558118  GABRG1; gamma-aminobutyric acid type A receptor gamma1 subunit [KO:K05186]
103539982  GABRD; gamma-aminobutyric acid type A receptor delta subunit [KO:K05184]
103543435  GABRE; gamma-aminobutyric acid type A receptor epsilon subunit [KO:K05185]
103563105  GABRQ; gamma-aminobutyric acid type A receptor theta subunit [KO:K05192]
103563258  GABRP; gamma-aminobutyric acid type A receptor pi subunit [KO:K05189]
103543831  gamma-aminobutyric acid receptor subunit rho-3-like [KO:K05190]
103567574  GABRR1; gamma-aminobutyric acid type A receptor rho1 subunit [KO:K05190]
103567575  GABRR2; gamma-aminobutyric acid type A receptor rho2 subunit [KO:K05190]
103550239  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
103566021  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
103552141  guanine nucleotide-binding protein G(i) subunit alpha-1-like [KO:K04630]
103553052  GNAI3; G protein subunit alpha i3 [KO:K04630]
103557343  GNAI2; G protein subunit alpha i2 [KO:K04630]
103555391  GNAO1; G protein subunit alpha o1 [KO:K04534]
103567413  GNB1; G protein subunit beta 1 [KO:K04536]
103555641  GNB2; G protein subunit beta 2 [KO:K04537]
103547020  GNB3; G protein subunit beta 3 [KO:K07825]
103551737  GNB4; G protein subunit beta 4 [KO:K04538]
103548465  GNB5; G protein subunit beta 5 [KO:K04539]
103543306  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
103558941  GNG3; G protein subunit gamma 3 [KO:K04540]
103547680  GNG4; G protein subunit gamma 4 [KO:K04541]
103557283  GNG5; G protein subunit gamma 5 [KO:K04542]
103542500  GNG8; G protein subunit gamma 8 [KO:K04544]
103542169  GNG11; G protein subunit gamma 11 [KO:K04546]
103564847  GNG12; G protein subunit gamma 12 [KO:K04347]
103542772  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04347]
103565302  GNG13; G protein subunit gamma 13 [KO:K04547]
103568001  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
103551067  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
103565402  guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
103547036  neuroendocrine secretory protein 55 [KO:K04632]
103559830  GRK2; G protein-coupled receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
103550032  GRK3; G protein-coupled receptor kinase 3 [KO:K00910] [EC:2.7.11.15]
103554506  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
103539972  GRK6; G protein-coupled receptor kinase 6 [KO:K08291] [EC:2.7.11.16]
103558677  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
103560673  ARRB2; arrestin beta 2 [KO:K04439]
103566551  ARRB1; arrestin beta 1 [KO:K04439]
103558165  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
103556196  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
103557289  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103565953  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103552355  PDE1C; phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
103552659  PDE1A; phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
103563243  PDE1B; phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
103549343  PDE2A; phosphodiesterase 2A [KO:K18283] [EC:3.1.4.17]
103546727  PDE3A; phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
103557936  PDE3B; phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
103547349  PDE4D; phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
103550596  PDE4B; phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
103561541  PDE4C; phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
103541710  PDE4A; phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
103552474  PDE7A; phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
103556267  PDE7B; phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
103546227  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
103547094  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
103548407  PDE10A; phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
103565145  PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
103555122  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
epz04727  GABAergic synapse
epz04728  Dopaminergic synapse
KO pathway
ko05032   
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