KEGG   PATHWAY: csyr05032
Entry
csyr05032                   Pathway                                
Name
Morphine addiction - Carlito syrichta (Philippine tarsier)
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
csyr05032  Morphine addiction
csyr05032

Other DBs
GO: 0043278
Organism
Carlito syrichta (Philippine tarsier) [GN:csyr]
Gene
103251814  OPRM1; mu-type opioid receptor isoform X1 [KO:K04215]
103254801  DRD1; D(1A) dopamine receptor [KO:K04144]
103252919  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
103262642  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
103272228  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
103254816  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
103273462  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
103259338  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
103267869  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
103273680  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
103258846  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
103262382  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
103275832  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
103261119  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
103276788  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
103251529  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
103260517  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
103262510  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
103262518  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
103262519  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
103266463  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
103267421  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
103249586  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X2 [KO:K05181]
103267422  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
103267553  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
103272396  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
103256756  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
103266464  gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
103249452  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
103269295  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
103250335  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
103263387  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
103252739  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
103263699  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
103263752  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
103255483  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 isoform X2 [KO:K04615]
103277075  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
103263431  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
103255466  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
103264772  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
103253155  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
103251518  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform X1 [KO:K04536]
103255674  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 isoform X3 [KO:K04537]
103265017  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
103262814  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
103275187  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
103273050  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X1 [KO:K07826]
103255636  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
103254833  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
110594660  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
110594775  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
110594710  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
110595842  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
103268263  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
103271375  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
110595573  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
110596243  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
103271374  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
110596118  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
103251768  neuroendocrine secretory protein 55 [KO:K04632]
103255823  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
103258733  GRK2; LOW QUALITY PROTEIN: beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
103265957  GRK3; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
103269522  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
103275859  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
103258067  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
103254000  ARRB1; beta-arrestin-1 [KO:K04439]
103276546  ARRB2; beta-arrestin-2 isoform X2 [KO:K04439]
103269994  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
103251444  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
103276479  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
103253311  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
103266092  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103256541  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
103267670  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X2 [KO:K13755] [EC:3.1.4.17]
103272564  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
103258180  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
103270415  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
103250949  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
103261301  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X2 [KO:K13293] [EC:3.1.4.53]
103261890  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
103269300  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
103256322  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
103264425  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
103255592  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
103276594  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
103260608  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A isoform X1 [KO:K13298] [EC:3.1.4.17 3.1.4.35]
103262817  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
csyr04727  GABAergic synapse
csyr04728  Dopaminergic synapse
KO pathway
ko05032   
LinkDB

DBGET integrated database retrieval system