KEGG   PATHWAY: bta05032
Entry
bta05032                    Pathway                                
Name
Morphine addiction - Bos taurus (cow)
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
bta05032  Morphine addiction
bta05032

Other DBs
GO: 0043278
Organism
Bos taurus (cow) [GN:bta]
Gene
100124505  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
100125276  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100301361  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
100849042  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
104968964  [KO:K04542]
107131388  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
281125  DRD1; D(1A) dopamine receptor [KO:K04144]
281201  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
281202  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
281203  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
281204  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
281601  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
281603  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
281637  ARRB1; beta-arrestin-1 [KO:K04439]
281638  ARRB2; beta-arrestin-2 [KO:K04439]
281790  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
281791  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
281792  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
281793  GNAS; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
281796  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
281797  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
281801  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
281958  OPRM1; mu-type opioid receptor [KO:K04215]
281969  PDE1A; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
281970  PDE1B; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
281971  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform PDE2A1 [KO:K18283] [EC:3.1.4.17]
282001  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
282002  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
282133  ADORA1; adenosine receptor A1 [KO:K04265]
282136  GRK3; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
282236  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 precursor [KO:K05175]
282237  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 precursor [KO:K05175]
282238  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 precursor [KO:K05175]
282239  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 precursor [KO:K05181]
282240  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 precursor [KO:K05186]
282322  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
282323  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
282325  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
282410  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
282648  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
282682  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
286850  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
287018  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
505740  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
506061  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
506787  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
508711  GABRD; gamma-aminobutyric acid receptor subunit delta precursor [KO:K05184]
509936  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
510708  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
511812  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
512222  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
512489  GRK4; G protein-coupled receptor kinase 4 isoform X3 [KO:K08291] [EC:2.7.11.16]
513340  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
513785  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform 2 precursor [KO:K04615]
517006  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
517040  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
517459  GABRP; gamma-aminobutyric acid receptor subunit pi precursor [KO:K05189]
520166  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 precursor [KO:K05190]
520743  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
521180  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
521413  GRK6; G protein-coupled receptor kinase 6 isoform 1 [KO:K08291] [EC:2.7.11.16]
522099  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 precursor [KO:K05190]
522509  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
523515  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 precursor [KO:K05175]
524115  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
524446  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
524624  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
525482  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
525962  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
526088  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
526211  PDE1C; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X6 [KO:K13755] [EC:3.1.4.17]
527180  GABRQ; gamma-aminobutyric acid receptor subunit theta precursor [KO:K05192]
529425  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
529593  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 precursor [KO:K05181]
533323  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
535017  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
535365  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
535603  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
536636  PDE3A; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
539194  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
539521  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
539556  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X4 [KO:K13293] [EC:3.1.4.53]
539844  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
540657  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 precursor [KO:K05181]
613670  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 isoform X1 [KO:K05186]
613930  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
614969  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
615885  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 precursor [KO:K05186]
618399  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
618470  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
780973  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 precursor [KO:K05175]
788151  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
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
bta04727  GABAergic synapse
bta04728  Dopaminergic synapse
KO pathway
ko05032   

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