KEGG   PATHWAY: ko05032
Entry
ko05032                     Pathway                                
Name
Morphine addiction
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
ko05032  Morphine addiction
ko05032

Other DBs
GO: 0043278
Orthology
K00910  ADRBK, GRK; beta-adrenergic-receptor kinase [EC:2.7.11.15]
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K04144  DRD1; dopamine receptor D1
K04215  OPRM1; mu-type opioid receptor
K04265  ADORA1; adenosine receptor A1
K04344  CACNA1A, CAV2.1; voltage-dependent calcium channel P/Q type alpha-1A
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04347  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04439  ARRB; beta-arrestin
K04534  GNAO, G-ALPHA-O; guanine nucleotide-binding protein G(o) subunit alpha
K04536  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K04538  GNB4; guanine nucleotide-binding protein subunit beta-4
K04539  GNB5; guanine nucleotide-binding protein subunit beta-5
K04540  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04547  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K04615  GABBR; gamma-aminobutyric acid type B receptor
K04630  GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04849  CACNA1B, CAV2.2; voltage-dependent calcium channel N type alpha-1B
K04997  KCNJ3, KIR3.1; potassium inwardly-rectifying channel subfamily J member 3
K04999  KCNJ5, KIR3.4; potassium inwardly-rectifying channel subfamily J member 5
K05000  KCNJ6, KIR3.2; potassium inwardly-rectifying channel subfamily J member 6
K05002  KCNJ9, KIR3.3; potassium inwardly-rectifying channel subfamily J member 9
K05175  GABRA; gamma-aminobutyric acid receptor subunit alpha
K05181  GABRB; gamma-aminobutyric acid receptor subunit beta
K05184  GABRD; gamma-aminobutyric acid receptor subunit delta
K05185  GABRE; gamma-aminobutyric acid receptor subunit epsilon
K05186  GABRG; gamma-aminobutyric acid receptor subunit gamma
K05189  GABRP; gamma-aminobutyric acid receptor subunit pi
K05190  GABRR; gamma-aminobutyric acid receptor subunit rho
K05192  GABRQ; gamma-aminobutyric acid receptor subunit theta
K07825  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K07826  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K08291  GRK4_5_6; G protein-coupled receptor kinase [EC:2.7.11.16]
K13293  PDE4; cAMP-specific phosphodiesterase 4 [EC:3.1.4.53]
K13296  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17]
K13298  PDE11; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11 [EC:3.1.4.17 3.1.4.35]
K13755  PDE1; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase [EC:3.1.4.17]
K15015  SLC32A, VGAT; solute carrier family 32 (vesicular inhibitory amino acid transporter)
K18283  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [EC:3.1.4.17]
K18436  PDE7; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7 [EC:3.1.4.53]
K18437  PDE8; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8 [EC:3.1.4.53]
K18438  PDE10; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10 [EC:3.1.4.17 3.1.4.35]
K19021  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [EC:3.1.4.17]
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
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
ko04727  GABAergic synapse
ko04728  Dopaminergic synapse

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