KEGG   PATHWAY: pcoo05032
Entry
pcoo05032                   Pathway                                
Name
Morphine addiction - Puma concolor (puma)
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
pcoo05032  Morphine addiction
pcoo05032

Other DBs
GO: 0043278
Organism
Puma concolor (puma) [GN:pcoo]
Gene
112862076  OPRM1; mu-type opioid receptor isoform X1 [KO:K04215]
112861354  DRD1; D(1A) dopamine receptor [KO:K04144]
112859788  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
112860207  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
112864041  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
112855238  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
112849881  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
112867731  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
112857348  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
112859389  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
112853291  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
112869336  SLC32A1; vesicular inhibitory amino acid transporter [KO:K15015]
112865957  KCNJ3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
112849482  KCNJ6; G protein-activated inward rectifier potassium channel 2 [KO:K05000]
112865404  KCNJ5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
112852304  CACNA1A; LOW QUALITY PROTEIN: voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
112860864  CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
112855891  GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
112858021  GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175]
112858034  GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175]
112871326  GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175]
112860278  GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
112860281  GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175]
112861469  GABRB2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181]
112855888  GABRB3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181]
112858237  GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181]
112855309  GABRG3; gamma-aminobutyric acid receptor subunit gamma-3 isoform X1 [KO:K05186]
112858174  GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
112860212  GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
112848543  GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184]
112871204  GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185]
112871113  GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192]
112861281  GABRP; gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
112862054  GABRR2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
112862086  GABRR1; gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
112850113  GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190]
112852537  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
112853616  GABBR1; LOW QUALITY PROTEIN: gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
112852602  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
112872095  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
112866857  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
112857493  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
112848368  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
112859921  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
112867306  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
112849315  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
112854988  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
112856354  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
112852144  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
112851564  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
112848743  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
112852664  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
112869453  GNG10; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
112866879  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
112848961  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
112852984  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
112866333  guanine nucleotide-binding protein G(T) subunit gamma-T1-like [KO:K04548]
112854055  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
112869078  guanine nucleotide-binding protein G(s) subunit alpha-like [KO:K04632]
112869430  neuroendocrine secretory protein 55 [KO:K04632]
112870399  GRK3; beta-adrenergic receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
112851961  GRK2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
112858238  GRK4; LOW QUALITY PROTEIN: G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
112861006  GRK6; G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
112854769  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
112865543  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
112864470  PRKCA; LOW QUALITY PROTEIN: protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
112853117  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
112850908  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
112852313  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
112871920  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
112848945  PDE1A; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
112866565  PDE1C; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
112867441  PDE1B; calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
112865740  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [KO:K18283] [EC:3.1.4.17]
112867325  PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
112865644  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
112852264  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
112871472  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
112852394  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
112860366  cAMP-specific 3',5'-cyclic phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
112862310  PDE7B; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
112859421  PDE7A; high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A isoform X1 [KO:K18436] [EC:3.1.4.53]
112861466  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
112856477  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
112862202  PDE10A; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
112870381  PDE11A; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
112857717  adenosine receptor A1 [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
pcoo04727  GABAergic synapse
pcoo04728  Dopaminergic synapse
KO pathway
ko05032   
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