KEGG   PATHWAY: mlk05032
Entry
mlk05032                    Pathway                                
Name
Morphine addiction - Mustela lutreola (European mink)
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
mlk05032  Morphine addiction
mlk05032

Other DBs
GO: 0043278
Organism
Mustela lutreola (European mink) [GN:mlk]
Gene
131833440  OPRM1; mu-type opioid receptor [KO:K04215]
131831933  DRD1; D(1A) dopamine receptor [KO:K04144]
131829179  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
131831568  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
131807291  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
131836404  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
131824632  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
131838820  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
131818734  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
131826395  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
131819927  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
131807660  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
131827207  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
131825372  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
131815351  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
131838542  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
131823608  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
131812571  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
131835729  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
131821743  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
131824394  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
131824405  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
131831866  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 isoform X1 [KO:K05175]
131831867  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
131835727  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
131824389  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
131831865  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
131825006  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit beta-3-like [KO:K05181]
131835730  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
131824416  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 isoform X1 [KO:K05186]
131831868  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
131810395  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
131821298  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
131821977  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
131831903  GABRP; gamma-aminobutyric acid receptor subunit pi [KO:K05189]
131825945  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
131833122  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
131833123  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
131834858  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
131812836  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
131829305  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
131823969  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
131810079  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
131818465  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
131808851  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
131819170  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
131838470  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
131824844  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
131836300  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
131836560  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
131814104  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
131829051  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
131828138  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
131810292  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
131823267  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
131818745  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
131812092  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
131829388  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
131838003  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12-like [KO:K04347]
131823580  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
131820002  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
131829387  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
131815902  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
131840487  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas-like [KO:K04632]
131840488  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
131807579  neuroendocrine secretory protein 55 [KO:K04632]
131811921  GRK3; beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
131816253  GRK2; beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
131826899  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
131830625  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
131831978  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
131840630  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
131815763  ARRB2; beta-arrestin-2 [KO:K04439]
131815964  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
131819600  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
131818861  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
131823635  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
131808844  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
131838653  PDE1B; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
131827015  PDE1A; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
131829591  PDE1C; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
131807824  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
131838983  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
131809644  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
131823518  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
131823761  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
131808908  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
131832260  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
131826772  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
131833768  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
131835551  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
131832380  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
131833379  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
131827927  dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
131815141  ADORA1; adenosine receptor A1 isoform X1 [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
mlk04727  GABAergic synapse
mlk04728  Dopaminergic synapse
KO pathway
ko05032   
LinkDB

DBGET integrated database retrieval system