KEGG   PATHWAY: hsa05032
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
Pathway map
hsa05032  Morphine addiction
hsa05032

Drug
D01340  Naloxone hydrochloride (JP18/USP)
D01383  Meperidine hydrochloride (USP)
D02095  Naltrexone hydrochloride (USP)
D04716  Levomethadyl acetate (USAN)
D04973  Methadyl acetate (USAN)
D05113  Naltrexone (USAN/INN)
D08249  Naloxone (INN)
D08343  Pethidine (INN)
D10478  Naldemedine tosylate (JAN/USAN)
D10612  Benzhydrocodone (USAN/INN)
D10692  Benzhydrocodone hydrochloride (USAN)
D10812  Nalmefene hydrochloride hydrate (JAN)
D11620  Naloxone hydrochloride dihydrate
D12660  Alphacetylmethadol (INN)
D12661  Betacetylmethadol (INN)
D12662  Allylprodine (INN)
D12666  Alphameprodine (INN)
D12667  Betameprodine (INN)
D12668  Clonitazene (INN)
D12669  Etonitazene (INN)
D12674  Alphamethadol (INN)
D12675  Betamethadol (INN)
D12676  Isomethadone (INN)
D12678  Alphaprodine (INN)
D12679  Betaprodine (INN)
D12680  Etoxeridine (INN)
D12681  Hydroxypethidine (INN)
D12682  Furethidine (INN)
D12683  Piminodine (INN)
D12685  Benzethidine (INN)
D12686  Hydromorphinol (INN)
D12693  Phenampromide (INN)
D12694  Diampromide (INN)
D12697  Morpheridin (INN)
D13025  Properidine (INN)
Other DBs
GO: 0043278
Organism
Homo sapiens (human) [GN:hsa]
Gene
10681  GNB5; G protein subunit beta 5 [KO:K04539]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
10846  PDE10A; phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [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 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
134  ADORA1; adenosine A1 receptor [KO:K04265]
140679  SLC32A1; solute carrier family 32 member 1 [KO:K15015]
156  GRK2; G protein-coupled receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
157  GRK3; G protein-coupled receptor kinase 3 [KO:K00910] [EC:2.7.11.15]
1812  DRD1; dopamine receptor D1 [KO:K04144]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
200959  GABRR3; gamma-aminobutyric acid type A receptor subunit rho3 [KO:K05190]
2550  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
2554  GABRA1; gamma-aminobutyric acid type A receptor subunit alpha1 [KO:K05175]
2555  GABRA2; gamma-aminobutyric acid type A receptor subunit alpha2 [KO:K05175]
2556  GABRA3; gamma-aminobutyric acid type A receptor subunit alpha3 [KO:K05175]
2557  GABRA4; gamma-aminobutyric acid type A receptor subunit alpha4 [KO:K05175]
2558  GABRA5; gamma-aminobutyric acid type A receptor subunit alpha5 [KO:K05175]
2559  GABRA6; gamma-aminobutyric acid type A receptor subunit alpha6 [KO:K05175]
2560  GABRB1; gamma-aminobutyric acid type A receptor subunit beta1 [KO:K05181]
2561  GABRB2; gamma-aminobutyric acid type A receptor subunit beta2 [KO:K05181]
2562  GABRB3; gamma-aminobutyric acid type A receptor subunit beta3 [KO:K05181]
2563  GABRD; gamma-aminobutyric acid type A receptor subunit delta [KO:K05184]
2564  GABRE; gamma-aminobutyric acid type A receptor subunit epsilon [KO:K05185]
2565  GABRG1; gamma-aminobutyric acid type A receptor subunit gamma1 [KO:K05186]
2566  GABRG2; gamma-aminobutyric acid type A receptor subunit gamma2 [KO:K05186]
2567  GABRG3; gamma-aminobutyric acid type A receptor subunit gamma3 [KO:K05186]
2568  GABRP; gamma-aminobutyric acid type A receptor subunit pi [KO:K05189]
2569  GABRR1; gamma-aminobutyric acid type A receptor subunit rho1 [KO:K05190]
2570  GABRR2; gamma-aminobutyric acid type A receptor subunit rho2 [KO:K05190]
27115  PDE7B; phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2775  GNAO1; G protein subunit alpha o1 [KO:K04534]
2778  GNAS; GNAS complex locus [KO:K04632]
2782  GNB1; G protein subunit beta 1 [KO:K04536]
2783  GNB2; G protein subunit beta 2 [KO:K04537]
2784  GNB3; G protein subunit beta 3 [KO:K07825]
2785  GNG3; G protein subunit gamma 3 [KO:K04540]
2786  GNG4; G protein subunit gamma 4 [KO:K04541]
2787  GNG5; G protein subunit gamma 5 [KO:K04542]
2788  GNG7; G protein subunit gamma 7 [KO:K04543]
2790  GNG10; G protein subunit gamma 10 [KO:K04545]
2791  GNG11; G protein subunit gamma 11 [KO:K04546]
2792  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
2793  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
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]
3760  KCNJ3; potassium inwardly rectifying channel subfamily J member 3 [KO:K04997]
3762  KCNJ5; potassium inwardly rectifying channel subfamily J member 5 [KO:K04999]
3763  KCNJ6; potassium inwardly rectifying channel subfamily J member 6 [KO:K05000]
3765  KCNJ9; potassium inwardly rectifying channel subfamily J member 9 [KO:K05002]
408  ARRB1; arrestin beta 1 [KO:K04439]
409  ARRB2; arrestin beta 2 [KO:K04439]
4988  OPRM1; opioid receptor mu 1 [KO:K04215]
50940  PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
5136  PDE1A; phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
5137  PDE1C; phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
5138  PDE2A; phosphodiesterase 2A [KO:K18283] [EC:3.1.4.17]
5139  PDE3A; phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
5140  PDE3B; phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
5141  PDE4A; phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
5142  PDE4B; phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
5143  PDE4C; phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
5144  PDE4D; phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
5150  PDE7A; phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
5151  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
5153  PDE1B; phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
51764  GNG13; G protein subunit gamma 13 [KO:K04547]
54331  GNG2; G protein subunit gamma 2 [KO:K07826]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
55879  GABRQ; gamma-aminobutyric acid type A receptor subunit theta [KO:K05192]
55970  GNG12; G protein subunit gamma 12 [KO:K04347]
59345  GNB4; G protein subunit beta 4 [KO:K04538]
773  CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
774  CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
8622  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
94235  GNG8; G protein subunit gamma 8 [KO:K04544]
9568  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
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
hsa04727  GABAergic synapse
hsa04728  Dopaminergic synapse
KO pathway
ko05032   

DBGET integrated database retrieval system