KEGG   PATHWAY: umr05032
Entry
umr05032                    Pathway                                
Name
Morphine addiction - Ursus maritimus (polar bear)
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
umr05032  Morphine addiction
umr05032

Other DBs
GO: 0043278
Organism
Ursus maritimus (polar bear) [GN:umr]
Gene
103656186  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
103657071  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
103657694  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
103657790  ADORA1; adenosine receptor A1 [KO:K04265]
103658167  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
103658168  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
103658731  [KO:K04548]
103658734  [KO:K04546]
103658775  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
103658951  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
103659256  GRK3; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
103659471  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
103659612  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
103659643  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
103659927  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
103659943  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
103660272  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
103660451  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
103660550  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
103660668  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
103660816  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
103660913  OPRM1; LOW QUALITY PROTEIN: mu-type opioid receptor [KO:K04215]
103661704  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
103661898  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
103662017  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
103662972  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
103663028  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
103663044  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
103663109  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
103663139  [KO:K13293] [EC:3.1.4.53]
103663361  [KO:K04545]
103663379  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
103663548  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
103663656  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X2 [KO:K13293] [EC:3.1.4.53]
103664442  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
103664469  DRD1; D(1A) dopamine receptor [KO:K04144]
103664515  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X2 [KO:K05186]
103664516  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
103664517  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
103664518  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
103664783  [KO:K05189]
103665907  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
103668461  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
103668547  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
103668895  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
103669896  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
103670041  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
103670935  [KO:K04632]
103670936  [KO:K04632]
103671685  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
103672699  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
103672700  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X2 [KO:K05175]
103672702  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
103672704  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
103672837  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
103672914  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
103673159  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
103673898  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
103673916  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
103674168  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
103674675  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
103674803  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
103674942  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
103675000  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
103675324  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
103675567  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
103675618  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
103676121  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
103676663  GRK4; G protein-coupled receptor kinase 4 isoform X1 [KO:K08291] [EC:2.7.11.16]
103676755  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
103677084  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X3 [KO:K05181]
103677085  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 isoform X1 [KO:K05175]
103677112  GABRG3; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
103677517  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
103677806  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
103678059  ARRB1; beta-arrestin-1 isoform X2 [KO:K04439]
103678109  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
103678196  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
103678446  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
103678622  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
103678657  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
103678723  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
103678826  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
103679250  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
103679331  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
103679607  GRK2; LOW QUALITY PROTEIN: beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
103681653  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
103681979  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
103682042  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
103682158  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 isoform X1 [KO:K04347]
103682183  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103682191  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
103682384  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
121103962  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
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
umr04727  GABAergic synapse
umr04728  Dopaminergic synapse
KO pathway
ko05032   

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