KEGG   PATHWAY: setr05032
Entry
setr05032                   Pathway                                
Name
Morphine addiction - Suncus etruscus (white-toothed pygmy shrew)
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
setr05032  Morphine addiction
setr05032

Other DBs
GO: 0043278
Organism
Suncus etruscus (white-toothed pygmy shrew) [GN:setr]
Gene
125996440  OPRM1; mu-type opioid receptor [KO:K04215]
126012227  DRD1; D(1A) dopamine receptor [KO:K04144]
126029834  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
126000769  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
126024026  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
126001049  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
126026247  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
126022668  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
126027080  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
125997104  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
126001221  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
126017336  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
126008767  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
126025599  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
126013957  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
126015697  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
126030243  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
126020490  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
126012225  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
126012226  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
126021832  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 isoform X1 [KO:K05175]
126032455  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
126032458  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
125999440  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
126012223  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
126021830  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 [KO:K05181]
126032460  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
126011917  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 [KO:K05186]
126021831  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
126032121  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
126007243  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit gamma-1-like [KO:K05186]
126011537  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
125998944  GABRE; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
125998946  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
126012230  GABRP; gamma-aminobutyric acid receptor subunit pi [KO:K05189]
126006726  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit rho-2-like [KO:K05190]
126006733  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit rho-1-like [KO:K05190]
125996385  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
126023323  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
126014071  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
126022872  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
125997317  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
126027101  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
126011605  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
126031035  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
126006589  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
126012077  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
126002081  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
125999572  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
126017910  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
126030791  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
126005956  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
126026239  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
126031195  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
126028279  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
126020263  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
126003829  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126023960  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126024701  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126033760  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
125999484  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126000312  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
126010869  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126010895  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
126020118  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126024681  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
126030830  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
126010822  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
126001569  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
126024671  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
126020139  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
126013317  GNAS; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
126013337  neuroendocrine secretory protein 55-like [KO:K04632]
126030572  GRK3; beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
126018096  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
126011942  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
125994907  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
126032241  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
126018158  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
126011248  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
126017297  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
126030861  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
126027978  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
126030328  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
126005939  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
126022490  PDE1B; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
126025476  PDE1C; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
126009193  PDE1A; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
126018133  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [KO:K18283] [EC:3.1.4.17]
126022025  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
126018893  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
126030199  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
126030284  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
126010827  PDE4B; LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
126001492  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
126020360  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
126029706  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
126022366  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
125997756  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
125996205  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A-like [KO:K18438] [EC:3.1.4.17 3.1.4.35]
125996554  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
126009051  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
126004205  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
setr04727  GABAergic synapse
setr04728  Dopaminergic synapse
KO pathway
ko05032   
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