KEGG   PATHWAY: ptg05032
Entry
ptg05032                    Pathway                                
Name
Morphine addiction - Panthera tigris altaica (Amur tiger)
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
ptg05032  Morphine addiction
ptg05032

Other DBs
GO: 0043278
Organism
Panthera tigris altaica (Amur tiger) [GN:ptg]
Gene
102954234  OPRM1; opioid receptor mu 1 [KO:K04215]
102959390  DRD1; dopamine receptor D1 [KO:K04144]
102961712  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
102949732  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
102965866  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
102969833  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
102949044  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
102972917  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
102948581  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
102969003  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
102950064  SLC32A1; solute carrier family 32 member 1 [KO:K15015]
102959759  G protein-activated inward rectifier potassium channel 1 [KO:K04997]
102966763  G protein-activated inward rectifier potassium channel 2 [KO:K05000]
102965302  KCNJ5; potassium voltage-gated channel subfamily J member 5 [KO:K04999]
102962991  CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
102954775  CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
102967192  GABRA1; gamma-aminobutyric acid type A receptor alpha1 subunit [KO:K05175]
102966903  GABRA6; gamma-aminobutyric acid type A receptor alpha6 subunit [KO:K05175]
102954929  GABRA5; gamma-aminobutyric acid type A receptor alpha5 subunit [KO:K05175]
102969994  GABRA4; gamma-aminobutyric acid type A receptor alpha4 subunit [KO:K05175]
102970774  GABRA2; gamma-aminobutyric acid type A receptor alpha2 subunit [KO:K05175]
102960080  GABRA3; gamma-aminobutyric acid type A receptor alpha3 subunit [KO:K05175]
102966235  GABRB2; gamma-aminobutyric acid type A receptor beta2 subunit [KO:K05181]
102969531  GABRB1; gamma-aminobutyric acid type A receptor beta1 subunit [KO:K05181]
102961197  GABRB3; gamma-aminobutyric acid type A receptor beta3 subunit [KO:K05181]
102967474  GABRG2; gamma-aminobutyric acid type A receptor gamma2 subunit [KO:K05186]
102971068  GABRG1; gamma-aminobutyric acid type A receptor gamma1 subunit [KO:K05186]
102960394  GABRD; gamma-aminobutyric acid type A receptor delta subunit [KO:K05184]
102956001  GABRE; gamma-aminobutyric acid type A receptor epsilon subunit [KO:K05185]
102960652  GABRQ; gamma-aminobutyric acid type A receptor theta subunit [KO:K05192]
102963248  GABRP; gamma-aminobutyric acid type A receptor pi subunit [KO:K05189]
102960223  GABRR1; gamma-aminobutyric acid type A receptor rho1 subunit [KO:K05190]
102960494  GABRR2; gamma-aminobutyric acid type A receptor rho2 subunit [KO:K05190]
102948508  GABRR3; gamma-aminobutyric acid type A receptor rho3 subunit [KO:K05190]
102966499  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
102951005  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
102954501  GNAI1; G protein subunit alpha i1 [KO:K04630]
102951159  GNAI3; G protein subunit alpha i3 [KO:K04630]
102962946  GNAI2; G protein subunit alpha i2 [KO:K04630]
102958483  GNAO1; G protein subunit alpha o1 [KO:K04534]
102950533  GNB1; G protein subunit beta 1 [KO:K04536]
102955271  GNB2; G protein subunit beta 2 [KO:K04537]
102953535  GNB3; G protein subunit beta 3 [KO:K07825]
102963895  GNB4; G protein subunit beta 4 [KO:K04538]
102954935  GNB5; G protein subunit beta 5 [KO:K04539]
102962902  GNG2; G protein subunit gamma 2 [KO:K07826]
102968307  GNG3; G protein subunit gamma 3 [KO:K04540]
102953604  GNG4; G protein subunit gamma 4 [KO:K04541]
102963799  GNG7; G protein subunit gamma 7 [KO:K04543]
102956095  GNG10; G protein subunit gamma 10 [KO:K04545]
102972135  GNG11; G protein subunit gamma 11 [KO:K04546]
102951416  GNG12; G protein subunit gamma 12 [KO:K04347]
102949358  GNG13; G protein subunit gamma 13 [KO:K04547]
102972425  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
102967045  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
102964541  GNAS; GNAS complex locus [KO:K04632]
102957039  GRK3; G protein-coupled receptor kinase 3 [KO:K00910] [EC:2.7.11.15]
102970752  GRK2; G protein-coupled receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
102962153  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
102968971  GRK6; G protein-coupled receptor kinase 6 [KO:K08291] [EC:2.7.11.16]
102955344  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
102950573  ARRB1; arrestin beta 1 [KO:K04439]
102970356  ARRB2; arrestin beta 2 [KO:K04439]
102968590  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
102952814  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
102956490  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
102948983  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102972158  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
102969061  PDE1B; phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
102951670  PDE1A; phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
102968598  PDE1C; phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
102955891  PDE2A; phosphodiesterase 2A [KO:K18283] [EC:3.1.4.17]
102969601  PDE3A; phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
102966458  PDE3B; phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
102964227  PDE4D; phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
102952909  PDE4A; phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
102957916  PDE4B; phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
102958950  PDE4C; phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
107180324  cAMP-specific 3',5'-cyclic phosphodiesterase 4B-like [KO:K13293] [EC:3.1.4.53]
102964441  PDE7A; phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
102960891  PDE7B; phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
102964515  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
102953863  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
102966722  PDE10A; phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
102961308  PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
102954668  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
ptg04727  GABAergic synapse
ptg04728  Dopaminergic synapse
KO pathway
ko05032   
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