KEGG   PATHWAY: hsa05032Help
Entry
hsa05032                    Pathway                                
Name
Morphine addiction - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Morphine addiction
hsa05032

All organismsOrtholog table
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
4988  
OPRM1; opioid receptor, mu 1 [KO:K04215]
1812  
DRD1; dopamine receptor D1 [KO:K04144]
107  
ADCY1; adenylate cyclase 1 (brain) [KO:K08041] [EC:4.6.1.1]
108  
ADCY2; adenylate cyclase 2 (brain) [KO:K08042] [EC:4.6.1.1]
109  
ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
196883  
ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
111  
ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  
ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  
ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  
ADCY8; adenylate cyclase 8 (brain) [KO:K08048] [EC:4.6.1.1]
115  
ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
140679  
SLC32A1; solute carrier family 32 (GABA vesicular transporter), member 1 [KO:K15015]
3760  
KCNJ3; potassium inwardly-rectifying channel, subfamily J, member 3 [KO:K04997]
3763  
KCNJ6; potassium inwardly-rectifying channel, subfamily J, member 6 [KO:K05000]
3765  
KCNJ9; potassium inwardly-rectifying channel, subfamily J, member 9 [KO:K05002]
3762  
KCNJ5; potassium inwardly-rectifying channel, subfamily J, member 5 [KO:K04999]
773  
CACNA1A; calcium channel, voltage-dependent, P/Q type, alpha 1A subunit [KO:K04344]
774  
CACNA1B; calcium channel, voltage-dependent, N type, alpha 1B subunit [KO:K04849]
2554  
GABRA1; gamma-aminobutyric acid (GABA) A receptor, alpha 1 [KO:K05175]
2555  
GABRA2; gamma-aminobutyric acid (GABA) A receptor, alpha 2 [KO:K05175]
2556  
GABRA3; gamma-aminobutyric acid (GABA) A receptor, alpha 3 [KO:K05175]
2557  
GABRA4; gamma-aminobutyric acid (GABA) A receptor, alpha 4 [KO:K05175]
2558  
GABRA5; gamma-aminobutyric acid (GABA) A receptor, alpha 5 [KO:K05175]
2559  
GABRA6; gamma-aminobutyric acid (GABA) A receptor, alpha 6 [KO:K05175]
2560  
GABRB1; gamma-aminobutyric acid (GABA) A receptor, beta 1 [KO:K05181]
2562  
GABRB3; gamma-aminobutyric acid (GABA) A receptor, beta 3 [KO:K05181]
2561  
GABRB2; gamma-aminobutyric acid (GABA) A receptor, beta 2 [KO:K05181]
2565  
GABRG1; gamma-aminobutyric acid (GABA) A receptor, gamma 1 [KO:K05186]
2566  
GABRG2; gamma-aminobutyric acid (GABA) A receptor, gamma 2 [KO:K05186]
2567  
GABRG3; gamma-aminobutyric acid (GABA) A receptor, gamma 3 [KO:K05186]
2563  
GABRD; gamma-aminobutyric acid (GABA) A receptor, delta [KO:K05184]
2564  
GABRE; gamma-aminobutyric acid (GABA) A receptor, epsilon [KO:K05185]
55879  
GABRQ; gamma-aminobutyric acid (GABA) A receptor, theta [KO:K05192]
2568  
GABRP; gamma-aminobutyric acid (GABA) A receptor, pi [KO:K05189]
2569  
GABRR1; gamma-aminobutyric acid (GABA) A receptor, rho 1 [KO:K05190]
2570  
GABRR2; gamma-aminobutyric acid (GABA) A receptor, rho 2 [KO:K05190]
200959  
GABRR3; gamma-aminobutyric acid (GABA) A receptor, rho 3 [KO:K05190]
2550  
GABBR1; gamma-aminobutyric acid (GABA) B receptor, 1 [KO:K04615]
9568  
GABBR2; gamma-aminobutyric acid (GABA) B receptor, 2 [KO:K04615]
2770  
GNAI1; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 [KO:K04630]
2773  
GNAI3; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 [KO:K04630]
2771  
GNAI2; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2 [KO:K04630]
2775  
GNAO1; guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O [KO:K04534]
2782  
GNB1; guanine nucleotide binding protein (G protein), beta polypeptide 1 [KO:K04536]
2783  
GNB2; guanine nucleotide binding protein (G protein), beta polypeptide 2 [KO:K04537]
2784  
GNB3; guanine nucleotide binding protein (G protein), beta polypeptide 3 [KO:K07825]
59345  
GNB4; guanine nucleotide binding protein (G protein), beta polypeptide 4 [KO:K04538]
10681  
GNB5; guanine nucleotide binding protein (G protein), beta 5 [KO:K04539]
54331  
GNG2; guanine nucleotide binding protein (G protein), gamma 2 [KO:K07826]
2785  
GNG3; guanine nucleotide binding protein (G protein), gamma 3 [KO:K04540]
2786  
GNG4; guanine nucleotide binding protein (G protein), gamma 4 [KO:K04541]
2787  
GNG5; guanine nucleotide binding protein (G protein), gamma 5 [KO:K04542]
2788  
GNG7; guanine nucleotide binding protein (G protein), gamma 7 [KO:K04543]
94235  
GNG8; guanine nucleotide binding protein (G protein), gamma 8 [KO:K04544]
2790  
GNG10; guanine nucleotide binding protein (G protein), gamma 10 [KO:K04545]
2791  
GNG11; guanine nucleotide binding protein (G protein), gamma 11 [KO:K04546]
55970  
GNG12; guanine nucleotide binding protein (G protein), gamma 12 [KO:K04347]
648044  
guanine nucleotide binding protein (G protein); K04347 guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
51764  
GNG13; guanine nucleotide binding protein (G protein), gamma 13 [KO:K04547]
2792  
GNGT1; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 [KO:K04548]
2793  
GNGT2; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 2 [KO:K04549]
2778  
GNAS; GNAS complex locus [KO:K04632]
156  
ADRBK1; adrenergic, beta, receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
157  
ADRBK2; adrenergic, beta, receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
2868  
GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
2869  
GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
2870  
GRK6; G protein-coupled receptor kinase 6 [KO:K08291] [EC:2.7.11.16]
408  
ARRB1; arrestin, beta 1 [KO:K04439]
409  
ARRB2; arrestin, beta 2 [KO:K04439]
5578  
PRKCA; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C, beta [KO:K02677] [EC:2.7.11.13]
5582  
PRKCG; protein kinase C, gamma [KO:K02677] [EC:2.7.11.13]
5566  
PRKACA; protein kinase, cAMP-dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
5567  
PRKACB; protein kinase, cAMP-dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
5568  
PRKACG; protein kinase, cAMP-dependent, catalytic, gamma [KO:K04345] [EC:2.7.11.11]
5613  
PRKX; protein kinase, X-linked [KO:K04345] [EC:2.7.11.11]
5136  
PDE1A; phosphodiesterase 1A, calmodulin-dependent [KO:K13755] [EC:3.1.4.17]
5153  
PDE1B; phosphodiesterase 1B, calmodulin-dependent [KO:K13755] [EC:3.1.4.17]
5137  
PDE1C; phosphodiesterase 1C, calmodulin-dependent 70kDa [KO:K13755] [EC:3.1.4.17]
5139  
PDE3A; phosphodiesterase 3A, cGMP-inhibited [KO:K13296] [EC:3.1.4.17]
5140  
PDE3B; phosphodiesterase 3B, cGMP-inhibited [KO:K13296] [EC:3.1.4.17]
50940  
PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.35 3.1.4.17]
8622  
PDE8B; phosphodiesterase 8B [KO:K01120] [EC:3.1.4.17]
5150  
PDE7A; phosphodiesterase 7A [KO:K01120] [EC:3.1.4.17]
5151  
PDE8A; phosphodiesterase 8A [KO:K01120] [EC:3.1.4.17]
10846  
PDE10A; phosphodiesterase 10A [KO:K01120] [EC:3.1.4.17]
27115  
PDE7B; phosphodiesterase 7B [KO:K01120] [EC:3.1.4.17]
5138  
PDE2A; phosphodiesterase 2A, cGMP-stimulated [KO:K01120] [EC:3.1.4.17]
5144  
PDE4D; phosphodiesterase 4D, cAMP-specific [KO:K01120] [EC:3.1.4.17]
5142  
PDE4B; phosphodiesterase 4B, cAMP-specific [KO:K01120] [EC:3.1.4.17]
5143  
PDE4C; phosphodiesterase 4C, cAMP-specific [KO:K01120] [EC:3.1.4.17]
5141  
PDE4A; phosphodiesterase 4A, cAMP-specific [KO:K01120] [EC:3.1.4.17]
134  
ADORA1; adenosine A1 receptor [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 hydrate (JP16)
D02271  
Morphine hydrochloride hydrate (JP16)
D08233  
Morphine (BAN)
D08234  
Morphine tartrate
Reference
  Authors
Bailey CP, Connor M
  Title
Opioids: cellular mechanisms of tolerance and physical dependence.
  Journal
Curr Opin Pharmacol 5:60-8 (2005)
Reference
  Authors
Williams JT, Christie MJ, Manzoni O
  Title
Cellular and synaptic adaptations mediating opioid dependence.
  Journal
Physiol Rev 81:299-343 (2001)
Reference
  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)
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)
Reference
  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)
Reference
  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)
Reference
  Authors
Zhang Y, Chen Q, Yu LC
  Title
Morphine: a protective or destructive role in neurons?
  Journal
Neuroscientist 14:561-70 (2008)
Reference
  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)
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)
Reference
  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)
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)
Reference
  Authors
Morikawa H, Paladini CA
  Title
Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms.
  Journal
Neuroscience 198:95-111 (2011)
Reference
  Authors
Xi ZX, Stein EA
  Title
GABAergic mechanisms of opiate reinforcement .
  Journal
Alcohol Alcohol 37:485-94 (2002)
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)
Reference
  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)
Reference
  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)
Reference
  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)
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