KEGG   PATHWAY: ncar05032
Entry
ncar05032                   Pathway                                
Name
Morphine addiction - Sciurus carolinensis (gray squirrel)
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
ncar05032  Morphine addiction
ncar05032

Other DBs
GO: 0043278
Organism
Sciurus carolinensis (gray squirrel) [GN:ncar]
Gene
124989714  mu-type opioid receptor [KO:K04215]
124987160  LOW QUALITY PROTEIN: D(1A) dopamine receptor-like [KO:K04144]
124990345  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
124987010  adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
124962927  adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
124978229  LOW QUALITY PROTEIN: adenylate cyclase type 4-like [KO:K08044] [EC:4.6.1.1]
124992559  adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
124983776  adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
124966834  adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
124965096  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
124970113  LOW QUALITY PROTEIN: adenylate cyclase type 9-like [KO:K08049] [EC:4.6.1.1]
124977302  vesicular inhibitory amino acid transporter [KO:K15015]
124980509  G protein-activated inward rectifier potassium channel 1 [KO:K04997]
124993028  G protein-activated inward rectifier potassium channel 2 [KO:K05000]
124990924  G protein-activated inward rectifier potassium channel 3 [KO:K05002]
124960772  G protein-activated inward rectifier potassium channel 4 isoform X1 [KO:K04999]
124969155  LOW QUALITY PROTEIN: voltage-dependent P/Q-type calcium channel subunit alpha-1A-like [KO:K04344]
124964767  voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849]
124987295  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit alpha-6-like [KO:K05175]
124995075  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit alpha-2-like [KO:K05175]
124995083  gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175]
124987552  gamma-aminobutyric acid receptor subunit alpha-1 [KO:K05175]
124976923  gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175]
124971921  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit alpha-3-like [KO:K05175]
124994665  gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181]
124987594  LOW QUALITY PROTEIN: gamma-aminobutyric acid receptor subunit beta-2-like [KO:K05181]
124971099  gamma-aminobutyric acid receptor subunit beta-3 [KO:K05181]
124995100  gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186]
124987599  gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186]
124976856  gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186]
124977995  gamma-aminobutyric acid receptor subunit delta [KO:K05184]
124971915  gamma-aminobutyric acid receptor subunit epsilon isoform X1 [KO:K05185]
124971968  gamma-aminobutyric acid receptor subunit theta-like isoform X1 [KO:K05192]
124986256  gamma-aminobutyric acid receptor subunit pi isoform X1 [KO:K05189]
124993354  gamma-aminobutyric acid receptor subunit rho-3-like [KO:K05190]
124988766  gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190]
124988785  gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190]
124988516  gamma-aminobutyric acid type B receptor subunit 1 isoform X1 [KO:K04615]
124964896  gamma-aminobutyric acid type B receptor subunit 2 [KO:K04615]
124992673  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
124988012  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
124991078  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
124967520  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
124976089  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
124969987  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
124993231  guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
124978030  guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
124960444  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
124961969  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
124978139  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
124961463  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
124961876  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
124965653  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
124968657  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
124967414  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
124970655  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
124964520  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
124975713  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
124991054  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
124993726  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
124969192  putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
124990131  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
124980134  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X1 [KO:K04549]
124978161  neuroendocrine secretory protein 55 [KO:K04632]
124975134  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
124990808  beta-adrenergic receptor kinase 2 isoform X1 [KO:K00910] [EC:2.7.11.15]
124960255  beta-adrenergic receptor kinase 1 isoform X1 [KO:K00910] [EC:2.7.11.15]
124986734  G protein-coupled receptor kinase 6 isoform X1 [KO:K08291] [EC:2.7.11.16]
124994901  G protein-coupled receptor kinase 4-like isoform X1 [KO:K08291] [EC:2.7.11.16]
124984553  G protein-coupled receptor kinase 5 isoform X1 [KO:K08291] [EC:2.7.11.16]
124958432  beta-arrestin-1 isoform X1 [KO:K04439]
124979615  beta-arrestin-2 isoform X1 [KO:K04439]
124979014  protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
124970211  LOW QUALITY PROTEIN: protein kinase C beta type-like [KO:K19662] [EC:2.7.11.13]
124967611  protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
124985819  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
124969119  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
124990587  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C isoform X1 [KO:K13755] [EC:3.1.4.17]
124978816  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A isoform X1 [KO:K13755] [EC:3.1.4.17]
124983446  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B isoform X1 [KO:K13755] [EC:3.1.4.17]
124959840  cGMP-dependent 3',5'-cyclic phosphodiesterase isoform X1 [KO:K18283] [EC:3.1.4.17]
124982565  cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17]
124958301  cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
124961340  LOW QUALITY PROTEIN: uncharacterized protein LOC124961340 [KO:K13296] [EC:3.1.4.17]
124986645  LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4D-like [KO:K13293] [EC:3.1.4.53]
124968763  LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4A-like [KO:K13293] [EC:3.1.4.53]
124968827  cAMP-specific 3',5'-cyclic phosphodiesterase 4C isoform X1 [KO:K13293] [EC:3.1.4.53]
124979707  cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
124988194  cAMP-specific 3',5'-cyclic phosphodiesterase 7B isoform X1 [KO:K18436] [EC:3.1.4.53]
124977300  high affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
124987575  high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
124973659  high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
124989090  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform X1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
124980034  dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]
124962441  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
ncar04727  GABAergic synapse
ncar04728  Dopaminergic synapse
KO pathway
ko05032   
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