KEGG   PATHWAY: psiu05032
Entry
psiu05032                   Pathway                                
Name
Morphine addiction - Phocoena sinus (vaquita)
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
psiu05032  Morphine addiction
psiu05032

Other DBs
GO: 0043278
Organism
Phocoena sinus (vaquita) [GN:psiu]
Gene
116763263  OPRM1; mu-type opioid receptor isoform X1 [KO:K04215]
116750400  DRD1; D(1A) dopamine receptor [KO:K04144]
116759445  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
116752275  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
116764233  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
116749116  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
116753224  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
116760787  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
116744731  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
116742406  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
116740403  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
116740842  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
116756285  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
116752719  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
116761814  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
116758063  KCNJ5; G protein-activated inward rectifier potassium channel 4 isoform X1 [KO:K04999]
116751638  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
116755421  CACNA1B; LOW QUALITY PROTEIN: voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
116747461  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
116754229  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
116754263  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
116749073  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
116741222  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit alpha-5-like [KO:K05175]
116751345  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175]
116751396  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
116754137  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
116750004  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
116751382  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
116754257  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
116749807  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
116751267  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
116763887  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
116747809  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
116747990  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
116751761  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
116753391  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
116763181  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
116763512  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
116755193  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
116762593  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
116761812  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
116749946  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
116759318  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
116744142  guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
116764574  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
116739605  GNB2; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
116760197  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
116753308  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
116748817  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
116748861  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X1 [KO:K07826]
116758798  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
116742043  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
116753058  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
116763781  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
116743126  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
116752047  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
116743417  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
116744006  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
116755457  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
116759883  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 isoform X1 [KO:K04546]
116756875  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
116740969  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
116759589  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
116745853  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
116740990  neuroendocrine secretory protein 55-like [KO:K04632]
116740988  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
116738732  GRK3; LOW QUALITY PROTEIN: beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
116757833  GRK2; beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
116750668  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
116741728  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
116746086  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
116757726  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
116745476  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
116739537  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
116743766  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
116754197  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
116751566  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
116759999  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
116756887  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
116759526  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
116758120  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
116760961  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A isoform X1 [KO:K19021] [EC:3.1.4.17]
116758554  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
116750878  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
116751251  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
116751469  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
116752088  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
116763611  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
116742396  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
116746651  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
116740856  LOW QUALITY PROTEIN: high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A-like [KO:K18437] [EC:3.1.4.53]
116750827  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
116763464  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
116756698  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
116741695  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
psiu04727  GABAergic synapse
psiu04728  Dopaminergic synapse
KO pathway
ko05032   
LinkDB

DBGET integrated database retrieval system