KEGG   PATHWAY: myd05032
Entry
myd05032                    Pathway                                
Name
Morphine addiction - Myotis davidii (David's myotis)
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
myd05032  Morphine addiction
myd05032

Other DBs
GO: 0043278
Organism
Myotis davidii (David's myotis) [GN:myd]
Gene
102768707  OPRM1; opioid receptor mu 1 [KO:K04215]
102762916  DRD1; dopamine receptor D1 [KO:K04144]
102759978  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
102774384  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
102757252  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
102762536  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
102760678  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
102766123  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
102764043  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
102765722  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
102760324  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
102754201  SLC32A1; solute carrier family 32 member 1 [KO:K15015]
102764090  KCNJ3; potassium voltage-gated channel subfamily J member 3 [KO:K04997]
102767915  KCNJ6; potassium voltage-gated channel subfamily J member 6 [KO:K05000]
102760671  KCNJ9; potassium voltage-gated channel subfamily J member 9 [KO:K05002]
102758324  KCNJ5; potassium voltage-gated channel subfamily J member 5 [KO:K04999]
102771143  CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
102756826  CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
102757080  GABRA5; gamma-aminobutyric acid type A receptor alpha5 subunit [KO:K05175]
102754510  GABRA2; gamma-aminobutyric acid type A receptor alpha2 subunit [KO:K05175]
102770847  GABRA4; gamma-aminobutyric acid type A receptor alpha4 subunit [KO:K05175]
102752852  GABRA3; gamma-aminobutyric acid type A receptor alpha3 subunit [KO:K05175]
102761323  GABRA6; gamma-aminobutyric acid type A receptor alpha6 subunit [KO:K05175]
102761607  GABRA1; gamma-aminobutyric acid type A receptor alpha1 subunit [KO:K05175]
102754847  GABRB3; gamma-aminobutyric acid type A receptor beta3 subunit [KO:K05181]
102771136  GABRB1; gamma-aminobutyric acid type A receptor beta1 subunit [KO:K05181]
102760653  GABRB2; gamma-aminobutyric acid type A receptor beta2 subunit [KO:K05181]
102756795  GABRG3; gamma-aminobutyric acid type A receptor gamma3 subunit [KO:K05186]
102770263  GABRG1; gamma-aminobutyric acid type A receptor gamma1 subunit [KO:K05186]
102762362  GABRG2; gamma-aminobutyric acid type A receptor gamma2 subunit [KO:K05186]
102773668  GABRD; gamma-aminobutyric acid type A receptor delta subunit [KO:K05184]
102754936  GABRE; gamma-aminobutyric acid type A receptor epsilon subunit [KO:K05185]
102764604  GABRQ; gamma-aminobutyric acid type A receptor theta subunit [KO:K05192]
102758269  GABRP; gamma-aminobutyric acid type A receptor pi subunit [KO:K05189]
102768224  GABRR2; gamma-aminobutyric acid type A receptor rho2 subunit [KO:K05190]
102768512  GABRR1; gamma-aminobutyric acid type A receptor rho1 subunit [KO:K05190]
102766042  GABBR2; gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
102753947  GABBR1; gamma-aminobutyric acid type B receptor subunit 1 [KO:K04615]
102765504  GNAI3; G protein subunit alpha i3 [KO:K04630]
102766400  GNAI1; G protein subunit alpha i1 [KO:K04630]
102754275  GNAI2; G protein subunit alpha i2 [KO:K04630]
102765603  GNAO1; G protein subunit alpha o1 [KO:K04534]
102764577  GNB1; G protein subunit beta 1 [KO:K04536]
102762354  GNB2; G protein subunit beta 2 [KO:K04537]
102759440  GNB3; G protein subunit beta 3 [KO:K07825]
102761136  GNB4; G protein subunit beta 4 [KO:K04538]
102765079  GNB5; G protein subunit beta 5 [KO:K04539]
102771107  GNG2; G protein subunit gamma 2 [KO:K07826]
107182728  GNG4; G protein subunit gamma 4 [KO:K04541]
102759351  GNG5; G protein subunit gamma 5 [KO:K04542]
102774762  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
102751276  GNG7; G protein subunit gamma 7 [KO:K04543]
102769875  GNG10; G protein subunit gamma 10 [KO:K04545]
102753337  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
102769983  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
102752682  GNG12; G protein subunit gamma 12 [KO:K04347]
102773554  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04347]
102770191  GNG13; G protein subunit gamma 13 [KO:K04547]
102754858  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
102774843  guanine nucleotide-binding protein G(s) subunit alpha isoforms short [KO:K04632]
102775507  neuroendocrine secretory protein 55 [KO:K04632]
102764962  GRK2; G protein-coupled receptor kinase 2 [KO:K00910] [EC:2.7.11.15]
102761774  GRK3; G protein-coupled receptor kinase 3 [KO:K00910] [EC:2.7.11.15]
102758601  GRK5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
102762532  GRK4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
102757801  GRK6; G protein-coupled receptor kinase 6 [KO:K08291] [EC:2.7.11.16]
102754944  G protein-coupled receptor kinase 5-like [KO:K08291] [EC:2.7.11.16]
102770259  ARRB1; arrestin beta 1 [KO:K04439]
102765545  ARRB2; arrestin beta 2 [KO:K04439]
102765661  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
102757004  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
102756030  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
102759840  cGMP-dependent protein kinase 1 [KO:K04345] [EC:2.7.11.11]
102772218  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102773780  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
102757771  PDE1B; phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
102767547  PDE1C; phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
102772289  PDE1A; phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
102773138  PDE2A; phosphodiesterase 2A [KO:K18283] [EC:3.1.4.17]
102751922  PDE3A; phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
102765733  PDE3B; phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
102752957  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
102766717  cAMP-specific 3',5'-cyclic phosphodiesterase 4B-like [KO:K13293] [EC:3.1.4.53]
102771187  cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
102763684  PDE4D; phosphodiesterase 4D [KO:K13293] [EC:3.1.4.53]
102771836  PDE4B; phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
102762522  PDE4C; phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
102761512  high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A-like [KO:K18436] [EC:3.1.4.53]
102767506  PDE7A; phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
102771886  PDE7B; phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
102775210  high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
102756083  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
102767862  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
102754239  ODF4; outer dense fiber of sperm tails 4 [KO:K18437] [EC:3.1.4.53]
102758421  PDE10A; phosphodiesterase 10A [KO:K18438] [EC:3.1.4.17 3.1.4.35]
102756021  PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
102757676  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 (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
myd04727  GABAergic synapse
myd04728  Dopaminergic synapse
KO pathway
ko05032   
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