KEGG   PATHWAY: pps05032
Entry
pps05032                    Pathway                                
Name
Morphine addiction - Pan paniscus (bonobo)
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
pps05032  Morphine addiction
pps05032

Other DBs
GO: 0043278
Organism
Pan paniscus (bonobo) [GN:pps]
Gene
100975162  OPRM1; mu-type opioid receptor isoform X3 [KO:K04215]
100988335  DRD1; D(1A) dopamine receptor [KO:K04144]
100984585  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
100992014  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100995134  ADCY3; adenylate cyclase type 3 isoform X4 [KO:K08043] [EC:4.6.1.1]
100978200  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
100989177  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
100991116  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100984225  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100994715  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100972356  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
100990783  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
100972367  KCNJ3; G protein-activated inward rectifier potassium channel 1 isoform X1 [KO:K04997]
100975815  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
100969260  KCNJ9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
100969758  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
100971898  CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X4 [KO:K04344]
100979369  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B isoform X6 [KO:K04849]
100971836  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
100974376  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175]
100976047  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 isoform X2 [KO:K05175]
100981073  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
100982741  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X3 [KO:K05175]
100970387  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
100976384  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X2 [KO:K05181]
100980522  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
100970969  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
100973578  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
100983533  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
100977311  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 isoform X1 [KO:K05186]
100980099  GABRD; gamma-aminobutyric acid receptor subunit delta isoform X1 [KO:K05184]
100972727  GABRE; gamma-aminobutyric acid receptor subunit epsilon isoform X1 [KO:K05185]
100971149  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
100977971  GABRP; gamma-aminobutyric acid receptor subunit pi [KO:K05189]
100970587  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
100967706  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190]
100968735  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
100983001  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
100974195  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 isoform X2 [KO:K04615]
100968961  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100974334  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
100985590  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X3 [KO:K04630]
100991540  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100978523  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100982509  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100968267  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
100967770  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100990010  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100970547  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100995028  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
100980807  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100973322  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
117975026  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
100983091  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
100987458  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
112437196  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100978647  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 isoform X2 [KO:K04545]
100976735  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100992242  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
112437428  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100977074  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
100994102  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100990650  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X2 [KO:K04632]
117974231  neuroendocrine secretory protein 55 [KO:K04632]
100984800  GRK3; G protein-coupled receptor kinase 3 isoform X1 [KO:K00910] [EC:2.7.11.15]
100991802  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
100972921  GRK4; G protein-coupled receptor kinase 4 isoform X2 [KO:K08291] [EC:2.7.11.16]
100975050  GRK5; G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
100972068  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
100988967  ARRB2; beta-arrestin-2 isoform X3 [KO:K04439]
100984768  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
100967981  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100970296  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
100990245  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100982589  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
100970917  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100968237  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100995565  PDE1B; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X3 [KO:K13755] [EC:3.1.4.17]
100989825  PDE1C; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X5 [KO:K13755] [EC:3.1.4.17]
100981582  PDE1A; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X10 [KO:K13755] [EC:3.1.4.17]
100989932  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
100991054  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A isoform X1 [KO:K19021] [EC:3.1.4.17]
100972602  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
100976153  PDE4B; 3',5'-cyclic-AMP phosphodiesterase 4B isoform X2 [KO:K13293] [EC:3.1.4.53]
100971074  PDE4D; 3',5'-cyclic-AMP phosphodiesterase 4D isoform X5 [KO:K13293] [EC:3.1.4.53]
100978147  PDE4C; 3',5'-cyclic-AMP phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
100995931  PDE4A; 3',5'-cyclic-AMP phosphodiesterase 4A isoform X1 [KO:K13293] [EC:3.1.4.53]
100988314  PDE7B; 3',5'-cyclic-AMP phosphodiesterase 7B isoform X2 [KO:K18436] [EC:3.1.4.53]
100993464  PDE7A; high affinity 3',5'-cyclic-AMP phosphodiesterase 7A isoform X2 [KO:K18436] [EC:3.1.4.53]
100972757  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
100973493  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X4 [KO:K18437] [EC:3.1.4.53]
100975452  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
100982736  dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
100993503  ADORA1; adenosine receptor A1 isoform X1 [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
pps04727  GABAergic synapse
pps04728  Dopaminergic synapse
KO pathway
ko05032   
LinkDB

DBGET integrated database retrieval system