KEGG   PATHWAY: pvp05032
Entry
pvp05032                    Pathway                                
Name
Morphine addiction - Pteropus vampyrus (large flying fox)
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
pvp05032  Morphine addiction
pvp05032

Other DBs
GO: 0043278
Organism
Pteropus vampyrus (large flying fox) [GN:pvp]
Gene
105293834  OPRM1; mu-type opioid receptor isoform X2 [KO:K04215]
105307882  DRD1; D(1A) dopamine receptor [KO:K04144]
105308299  adenylate cyclase type 1-like [KO:K08041] [EC:4.6.1.1]
105299581  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
105289813  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
105309400  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
105288850  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105297518  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
105292087  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
105301250  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
105303095  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
105296495  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
105291464  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
105295807  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
105300718  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
105306042  KCNJ5; G protein-activated inward rectifier potassium channel 4 isoform X2 [KO:K04999]
105307194  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
105298593  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
105289891  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175]
105289892  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
105305784  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
105293915  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
105308191  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
105293917  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
105289947  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 [KO:K05181]
105306170  gamma-aminobutyric acid receptor subunit beta-3-like [KO:K05181]
105293898  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
105310026  gamma-aminobutyric acid receptor subunit beta-3-like [KO:K05181]
105305788  gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
105289890  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
105293897  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
105303608  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
105308189  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
105308196  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
105299316  GABRP; gamma-aminobutyric acid receptor subunit pi [KO:K05189]
105296979  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
105289631  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
105296978  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 isoform X1 [KO:K05190]
105296286  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
105308164  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X2 [KO:K04615]
105297202  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105295155  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105295517  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105292074  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
105303584  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105299738  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
105295952  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
105307521  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
105288758  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105309385  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
105297807  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X2 [KO:K04540]
105302718  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 isoform X1 [KO:K04541]
105289068  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
105310269  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
111744611  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
105307968  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105294373  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
105307158  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
105295886  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
105303281  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X4 [KO:K04547]
105294383  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
105307274  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
105296083  neuroendocrine secretory protein 55-like [KO:K04632]
105309917  GRK2; beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
105301826  GRK3; beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
105291448  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
105293506  GRK6; G protein-coupled receptor kinase 6 isoform X3 [KO:K08291] [EC:2.7.11.16]
105301218  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
105297636  ARRB1; beta-arrestin-1 isoform X2 [KO:K04439]
105291748  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
105297702  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105308818  protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
105309462  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105289063  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105308501  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
105289761  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
105293685  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
105302622  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
105303688  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [KO:K18283] [EC:3.1.4.17]
105306548  cGMP-inhibited 3',5'-cyclic phosphodiesterase A isoform X1 [KO:K19021] [EC:3.1.4.17]
105301483  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
105296601  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
105305599  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
105298365  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
105299350  cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
105289524  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
105295066  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
105302190  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
105302891  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
105302218  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
105289998  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
105296923  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
pvp04727  GABAergic synapse
pvp04728  Dopaminergic synapse
KO pathway
ko05032   
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