KEGG   PATHWAY: efus05032
Entry
efus05032                   Pathway                                
Name
Morphine addiction - Eptesicus fuscus (big brown bat)
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
efus05032  Morphine addiction
efus05032

Other DBs
GO: 0043278
Organism
Eptesicus fuscus (big brown bat) [GN:efus]
Gene
103297947  OPRM1; mu-type opioid receptor [KO:K04215]
103291538  DRD1; D(1A) dopamine receptor [KO:K04144]
103303616  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
103305103  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
103305553  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
103301470  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
103298761  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
103285248  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
103295862  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
103302409  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
103286155  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
103301439  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
103283400  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
103289816  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
103297575  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
103286923  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
103301061  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
103296121  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
103284938  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
103284941  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
103291583  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
103291584  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
103303651  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
129148330  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
103284942  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
103291585  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
103304508  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
103284937  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
103291581  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X2 [KO:K05186]
103304007  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
103295367  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
103301700  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
103303652  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
103291558  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
103292550  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
103292732  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
103300738  GABRR3; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
103286397  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
103300502  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
103291154  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
103293295  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
103298642  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
103295848  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X3 [KO:K04534]
103295279  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform X3 [KO:K04536]
103285992  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
103289027  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
103286752  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
103287561  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
103283745  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
103303734  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X1 [KO:K04540]
103293513  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
103284162  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
103286474  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103299657  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103297851  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103292609  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
129150929  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103294263  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
114227350  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
103286557  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
103292756  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
103301022  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
103284108  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
103300750  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
114234933  guanine nucleotide-binding protein G(T) subunit gamma-T1-like [KO:K04548]
103297082  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
103285782  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X4 [KO:K04632]
103285922  neuroendocrine secretory protein 55-like [KO:K04632]
103290933  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
103286887  GRK3; beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
103287374  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
103288601  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
103294565  GRK4; G protein-coupled receptor kinase 4 isoform X1 [KO:K08291] [EC:2.7.11.16]
103293603  ARRB1; beta-arrestin-1 [KO:K04439]
103299847  ARRB2; beta-arrestin-2 [KO:K04439]
103293119  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
103296210  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
103303678  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
103300989  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X2 [KO:K04345] [EC:2.7.11.11]
103284158  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103285376  PDE1B; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
103291430  PDE1C; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
103283469  PDE1A; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
103293571  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [KO:K18283] [EC:3.1.4.17]
103285137  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A isoform X1 [KO:K19021] [EC:3.1.4.17]
103294603  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
103284098  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X2 [KO:K13293] [EC:3.1.4.53]
103301131  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
103299577  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X2 [KO:K13293] [EC:3.1.4.53]
103305134  cAMP-specific 3',5'-cyclic phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
103293975  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
103305374  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
103302997  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
103305209  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
103299830  high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A-like [KO:K18437] [EC:3.1.4.53]
103299822  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
103283477  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A isoform X1 [KO:K13298] [EC:3.1.4.17 3.1.4.35]
103302922  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
efus04727  GABAergic synapse
efus04728  Dopaminergic synapse
KO pathway
ko05032   
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