KEGG   PATHWAY: mjv05032
Entry
mjv05032                    Pathway                                
Name
Morphine addiction - Manis javanica (Malayan pangolin)
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
mjv05032  Morphine addiction
mjv05032

Other DBs
GO: 0043278
Organism
Manis javanica (Malayan pangolin) [GN:mjv]
Gene
108384659  OPRM1; mu-type opioid receptor [KO:K04215]
108397515  DRD1; D(1A) dopamine receptor [KO:K04144]
108403511  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
108409724  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
108397345  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
108410207  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
108396721  ADCY5; adenylate cyclase type 5 isoform X4 [KO:K08045] [EC:4.6.1.1]
108383520  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
108407296  ADCY7; adenylate cyclase type 7 isoform X2 [KO:K08047] [EC:4.6.1.1]
108397669  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
108388549  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
108402449  SLC32A1; vesicular inhibitory amino acid transporter isoform X1 [KO:K15015]
108405081  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
108407990  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
108402846  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
108408804  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
108399643  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
108404638  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
108408365  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 isoform X1 [KO:K05175]
108408367  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
108399481  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
108405392  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
108391397  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
108401439  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
108406171  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
108392047  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
108408364  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
108402951  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 isoform X1 [KO:K05186]
108384302  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
108402109  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 isoform X1 [KO:K05186]
108390080  GABRD; gamma-aminobutyric acid receptor subunit delta isoform X1 [KO:K05184]
108385508  GABRE; gamma-aminobutyric acid receptor subunit epsilon isoform X1 [KO:K05185]
108387559  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
108403475  gamma-aminobutyric acid receptor subunit pi [KO:K05189]
108384738  gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
108400356  gamma-aminobutyric acid receptor subunit rho-2 isoform X1 [KO:K05190]
108395286  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
108396770  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
108402874  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
108400984  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
108388509  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
108408793  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
108398173  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
108409379  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
108403551  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
108409661  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
108395258  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
108386548  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
108393633  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
108394280  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
108386580  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
108393262  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
108406129  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
108398401  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
108404891  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
108399649  GNG14; LOW QUALITY PROTEIN: putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
108386122  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X5 [KO:K04547]
108398403  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
108391050  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X2 [KO:K04549]
108406177  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
108406179  neuroendocrine secretory protein 55-like [KO:K04632]
118970338  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas-like [KO:K04632]
108393151  GRK2; beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
108387037  GRK3; beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
108406370  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
108396051  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
108385086  ARRB1; beta-arrestin-1 isoform X3 [KO:K04439]
108403336  ARRB2; beta-arrestin-2 isoform X2 [KO:K04439]
108387768  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
108385666  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
108395733  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
108408343  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
108408529  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
108397007  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
108403435  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
108390529  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [KO:K18283] [EC:3.1.4.17]
108402090  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A isoform X1 [KO:K19021] [EC:3.1.4.17]
108396796  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
108386022  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X2 [KO:K13293] [EC:3.1.4.53]
108398780  cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X6 [KO:K13293] [EC:3.1.4.53]
108397111  LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
108390886  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
108409507  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
108393258  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
108393144  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
108409836  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
108401669  ADORA1; adenosine receptor A1 isoform X1 [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
mjv04727  GABAergic synapse
mjv04728  Dopaminergic synapse
KO pathway
ko05032   
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