KEGG   PATHWAY: mmur05032
Entry
mmur05032                   Pathway                                
Name
Morphine addiction - Microcebus murinus (gray mouse lemur)
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
mmur05032  Morphine addiction
mmur05032

Other DBs
GO: 0043278
Organism
Microcebus murinus (gray mouse lemur) [GN:mmur]
Gene
105862109  mu-type opioid receptor isoform X1 [KO:K04215]
105870100  mu-type opioid receptor-like [KO:K04215]
105880477  DRD1; D(1A) dopamine receptor [KO:K04144]
105870668  ADCY1; LOW QUALITY PROTEIN: adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
105859934  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
105884349  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
105866617  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
105879870  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105867497  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
105884745  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
105882731  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
105859653  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
105866042  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
105859138  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
105881285  KCNJ6; G protein-activated inward rectifier potassium channel 2 isoform X2 [KO:K05000]
105862704  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
105875338  KCNJ5; LOW QUALITY PROTEIN: G protein-activated inward rectifier potassium channel 4 [KO:K04999]
105885431  CACNA1A; LOW QUALITY PROTEIN: voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
105882232  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
105859333  GABRA2; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit alpha-2 [KO:K05175]
105859338  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
105868903  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
105864847  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
105857924  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
105865773  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
105859330  GABRB1; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
105868828  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
109730325  gamma-aminobutyric acid receptor subunit beta-1-like [KO:K05181]
105857935  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
105859331  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 isoform X1 [KO:K05186]
105868811  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 isoform X1 [KO:K05186]
105864846  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
105877683  GABRD; gamma-aminobutyric acid receptor subunit delta isoform X1 [KO:K05184]
105855139  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
105869850  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
105867180  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
105863610  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
105863620  gamma-aminobutyric acid receptor subunit rho-2 isoform X1 [KO:K05190]
105872743  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
105868940  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
105873786  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
105874990  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105864008  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105879338  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105866545  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
105877661  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105868427  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 isoform X1 [KO:K04537]
105869000  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
105855818  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
105870695  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105867677  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
105878586  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
105856485  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
105861782  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
105873983  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
109729970  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
109731176  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105885526  LOW QUALITY PROTEIN: uncharacterized LOC105372280 homolog [KO:K04347]
105872857  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
109729570  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
105867248  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
109729475  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
105874518  guanine nucleotide-binding protein G(s) subunit alpha isoforms short isoform X1 [KO:K04632]
105874520  neuroendocrine secretory protein 55-like [KO:K04632]
105866915  GRK3; beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
105867521  GRK2; beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
105883855  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
105856035  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
105857047  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
105860366  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
105879284  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
105861618  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105879718  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
105874723  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105867963  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
105861780  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
105883000  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
105871274  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
105879047  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
105858269  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
105860371  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
105882816  PDE3A; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
105879994  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
105854983  PDE4C; LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
105877318  PDE4D; LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
105885589  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
105872832  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
105855920  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
105857235  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
105870579  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
105856524  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
105877849  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
105883021  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A isoform X1 [KO:K13298] [EC:3.1.4.17 3.1.4.35]
105868113  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
mmur04727  GABAergic synapse
mmur04728  Dopaminergic synapse
KO pathway
ko05032   
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