KEGG   PATHWAY: cbai05032
Entry
cbai05032                   Pathway                                
Name
Morphine addiction - Camelus bactrianus (Bactrian camel)
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
cbai05032  Morphine addiction
cbai05032

Other DBs
GO: 0043278
Organism
Camelus bactrianus (Bactrian camel) [GN:cbai]
Gene
105077337  OPRM1; mu-type opioid receptor isoform X1 [KO:K04215]
105062066  DRD1; D(1A) dopamine receptor [KO:K04144]
105080525  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
105081234  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
105063873  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
105068818  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
105081635  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105076187  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
105074271  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
105082946  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
105064797  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
105071951  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
105081914  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
105072485  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
105069587  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
105071238  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
105068402  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
105073404  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
105074918  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
105074920  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
105082620  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
105082621  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
105062095  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
105070071  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
105074917  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
105082619  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
105062094  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 [KO:K05181]
105074922  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
105074773  gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
105082624  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
105071050  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
105070087  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
105070061  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
105082640  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
105077935  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
105064121  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
105064122  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
105084061  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
105067386  GABBR2; LOW QUALITY PROTEIN: gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
105080234  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105062385  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105063651  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105078712  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
105071051  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105067755  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
105071086  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
105063316  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
105080494  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105070137  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
105075111  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
105069319  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4-like [KO:K04541]
105062549  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
105082939  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
105068344  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04347]
105065706  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
105082944  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
105071802  guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
105071803  neuroendocrine secretory protein 55 [KO:K04632]
105070324  ADRBK1; LOW QUALITY PROTEIN: beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
105066103  ADRBK2; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
105080777  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
105062033  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
105072344  GRK4; LOW QUALITY PROTEIN: G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
105083323  ARRB1; beta-arrestin-1 [KO:K04439]
105066402  ARRB2; beta-arrestin-2 [KO:K04439]
105063941  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
105073669  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
105074322  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105075498  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105068302  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
105081806  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
105076318  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
105072897  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
105083343  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [KO:K18283] [EC:3.1.4.17]
105062274  PDE3A; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
105076796  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
105075561  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
105082570  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
105077788  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
105068383  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
105081461  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
105077256  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
105069099  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
105064358  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
105065325  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
105072877  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
105062241  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
cbai04727  GABAergic synapse
cbai04728  Dopaminergic synapse
KO pathway
ko05032   
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