KEGG   PATHWAY: vpc05032
Entry
vpc05032                    Pathway                                
Name
Morphine addiction - Vicugna pacos (alpaca)
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
vpc05032  Morphine addiction
vpc05032

Other DBs
GO: 0043278
Organism
Vicugna pacos (alpaca) [GN:vpc]
Gene
102527342  OPRM1; mu-type opioid receptor [KO:K04215]
102535792  DRD1; D(1A) dopamine receptor [KO:K04144]
102538400  ADCY1; LOW QUALITY PROTEIN: adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
102539698  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
102536207  ADCY3; adenylate cyclase type 3 isoform X5 [KO:K08043] [EC:4.6.1.1]
102544207  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
102534219  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102532587  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
102529498  ADCY7; adenylate cyclase type 7 isoform X2 [KO:K08047] [EC:4.6.1.1]
102543885  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
102535401  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
102544383  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
102532045  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
102537978  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
102542515  KCNJ9; G protein-activated inward rectifier potassium channel 3 isoform X3 [KO:K05002]
102534532  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
102529757  CACNA1A; LOW QUALITY PROTEIN: voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
102539072  CACNA1B; LOW QUALITY PROTEIN: voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
102529360  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
102531410  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 isoform X1 [KO:K05175]
102524989  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
102525239  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
102540847  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
102540354  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X2 [KO:K05175]
102531167  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 [KO:K05181]
102541512  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X2 [KO:K05181]
102539453  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 [KO:K05181]
102535641  gamma-aminobutyric acid receptor subunit gamma-3-like [KO:K05186]
102540108  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
102545921  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
102537249  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
102532236  GABRE; gamma-aminobutyric acid receptor subunit epsilon isoform X1 [KO:K05185]
102532978  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
102540674  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X2 [KO:K05189]
102538425  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
102536789  GABRR2; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
102537030  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
102531423  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X5 [KO:K04615]
102526877  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 isoform X3 [KO:K04615]
102543440  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
102541755  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102525399  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
102532808  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
102537006  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
102534586  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
102530911  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
102544072  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
102533271  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
102537024  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
102538024  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
102545167  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
102526370  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
116280345  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
102536904  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
107033627  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
107033717  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
102538587  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
102537146  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
107034536  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X1 [KO:K04549]
102528916  GNAS; LOW QUALITY PROTEIN: neuroendocrine secretory protein 55 [KO:K04632]
102533381  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas [KO:K04632]
102543317  GRK2; beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
102536025  GRK3; beta-adrenergic receptor kinase 2 isoform X2 [KO:K00910] [EC:2.7.11.15]
102533153  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
102539850  GRK4; G protein-coupled receptor kinase 4 isoform X1 [KO:K08291] [EC:2.7.11.16]
102528313  GRK6; LOW QUALITY PROTEIN: G protein-coupled receptor kinase 6 [KO:K08291] [EC:2.7.11.16]
102536324  ARRB2; beta-arrestin-2 [KO:K04439]
102545544  ARRB1; beta-arrestin-1 isoform X3 [KO:K04439]
102541926  PRKCA; protein kinase C alpha type isoform X2 [KO:K02677] [EC:2.7.11.13]
102526158  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
102542323  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
102528179  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102534902  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102541146  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
102525353  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X7 [KO:K13755] [EC:3.1.4.17]
102530617  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
102533320  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X2 [KO:K18283] [EC:3.1.4.17]
102544834  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A isoform X1 [KO:K19021] [EC:3.1.4.17]
102541993  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
102540080  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
102529494  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X4 [KO:K13293] [EC:3.1.4.53]
102535549  PDE4C; LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
102534504  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
102528767  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
102543603  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X4 [KO:K18436] [EC:3.1.4.53]
102537603  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
102541913  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
102544279  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X7 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
102535177  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
102538982  ADORA1; adenosine receptor A1 isoform X2 [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
vpc04727  GABAergic synapse
vpc04728  Dopaminergic synapse
KO pathway
ko05032   
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