KEGG   PATHWAY: phas05032
Entry
phas05032                   Pathway                                
Name
Morphine addiction - Phyllostomus hastatus (greater spear-nosed bat)
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
phas05032  Morphine addiction
phas05032

Other DBs
GO: 0043278
Organism
Phyllostomus hastatus (greater spear-nosed bat) [GN:phas]
Gene
123821727  OPRM1; mu-type opioid receptor [KO:K04215]
123806765  DRD1; D(1A) dopamine receptor [KO:K04144]
123811468  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
123824963  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
123822448  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
123820487  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
123826843  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
123812947  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
123805699  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
123833093  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
123807136  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
123815086  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
123813422  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
123827899  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
123820554  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
123832480  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
123828203  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
123823376  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
123812481  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175]
123807070  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 isoform X1 [KO:K05175]
123815735  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
123815902  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
123809224  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
123809740  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
123811578  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 [KO:K05181]
123815946  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
123809739  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
123812734  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
123815966  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 isoform X1 [KO:K05186]
123809745  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
123832013  GABRD; gamma-aminobutyric acid receptor subunit delta isoform X1 [KO:K05184]
123807064  GABRE; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
123807057  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
123805929  gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
123827404  GABRR3; LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
123821660  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
123821668  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
123820195  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
123810346  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
123804401  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
123811789  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
123830671  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
123805731  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
123832310  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
123806391  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
123810635  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
123827153  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
123808220  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
123808681  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
123829444  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
123804859  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
123821983  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
123822119  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
123816473  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
123825297  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
123825413  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
123826542  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
123813731  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
123823052  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
123812121  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
123819929  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
123821470  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
123811727  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
123828441  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
123816445  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
123825394  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X1 [KO:K04547]
123811087  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
123817087  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
123815116  neuroendocrine secretory protein 55-like [KO:K04632]
123815292  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
123820806  GRK3; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
123829489  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
123828954  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
123808059  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
123815942  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
123805290  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
123809193  ARRB2; beta-arrestin-2 [KO:K04439]
123817558  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
123825494  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
123824140  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
123828245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
123816440  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
123811380  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
123812987  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
123808500  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
123805421  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
123812393  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A isoform X1 [KO:K19021] [EC:3.1.4.17]
123810006  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
123828247  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
123828274  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
123816451  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
123824671  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X1 [KO:K13293] [EC:3.1.4.53]
123833078  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
123821947  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
123809613  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
123824590  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
123822225  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
123815099  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A isoform X1 [KO:K13298] [EC:3.1.4.17 3.1.4.35]
123832995  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
phas04727  GABAergic synapse
phas04728  Dopaminergic synapse
KO pathway
ko05032   
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