KEGG   PATHWAY: rno05032
Entry
rno05032                    Pathway                                
Name
Morphine addiction - Rattus norvegicus (rat)
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
rno05032  Morphine addiction
rno05032

Other DBs
GO: 0043278
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
25601  Oprm1; mu-type opioid receptor isoform 1 [KO:K04215]
24316  Drd1; D(1A) dopamine receptor [KO:K04144]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
83612  Slc32a1; vesicular inhibitory amino acid transporter [KO:K15015]
50599  Kcnj3; G protein-activated inward rectifier potassium channel 1 [KO:K04997]
25743  Kcnj6; G protein-activated inward rectifier potassium channel 2 isoform 1 [KO:K05000]
116560  Kcnj9; G protein-activated inward rectifier potassium channel 3 [KO:K05002]
29713  Kcnj5; G protein-activated inward rectifier potassium channel 4 [KO:K04999]
25398  Cacna1a; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
257648  Cacna1b; voltage-dependent N-type calcium channel subunit alpha-1B isoform 1 [KO:K04849]
29705  Gabra1; gamma-aminobutyric acid receptor subunit alpha-1 precursor [KO:K05175]
289606  Gabra2; gamma-aminobutyric acid receptor subunit alpha-2 precursor [KO:K05175]
24947  Gabra3; gamma-aminobutyric acid receptor subunit alpha-3 precursor [KO:K05175]
140675  Gabra4; gamma-aminobutyric acid receptor subunit alpha-4 precursor [KO:K05175]
29707  Gabra5; gamma-aminobutyric acid receptor subunit alpha-5 precursor [KO:K05175]
29708  Gabra6; gamma-aminobutyric acid receptor subunit alpha-6 precursor [KO:K05175]
25450  Gabrb1; gamma-aminobutyric acid receptor subunit beta-1 precursor [KO:K05181]
24922  Gabrb3; gamma-aminobutyric acid receptor subunit beta-3 precursor [KO:K05181]
25451  Gabrb2; gamma-aminobutyric acid receptor subunit beta-2 precursor [KO:K05181]
140674  Gabrg1; gamma-aminobutyric acid receptor subunit gamma-1 precursor [KO:K05186]
29709  Gabrg2; gamma-aminobutyric acid receptor subunit gamma-2 isoform 2 precursor [KO:K05186]
79211  Gabrg3; gamma-aminobutyric acid receptor subunit gamma-3 precursor [KO:K05186]
29689  Gabrd; gamma-aminobutyric acid receptor subunit delta precursor [KO:K05184]
65191  Gabre; gamma-aminobutyric acid receptor subunit epsilon precursor [KO:K05185]
65187  Gabrq; gamma-aminobutyric acid receptor subunit theta precursor [KO:K05192]
81658  Gabrp; gamma-aminobutyric acid receptor subunit pi precursor [KO:K05189]
29694  Gabrr1; gamma-aminobutyric acid receptor subunit rho-1 precursor [KO:K05190]
29695  Gabrr2; gamma-aminobutyric acid receptor subunit rho-2 precursor [KO:K05190]
192258  Gabrr3; gamma-aminobutyric acid receptor subunit rho-3 precursor [KO:K05190]
81657  Gabbr1; gamma-aminobutyric acid type B receptor subunit 1 precursor [KO:K04615]
83633  Gabbr2; gamma-aminobutyric acid type B receptor subunit 2 precursor [KO:K04615]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
50664  Gnao1; guanine nucleotide-binding protein G(o) subunit alpha isoform B [KO:K04534]
24400  Gnb1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
81667  Gnb2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
60449  Gnb3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
294962  Gnb4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
83579  Gnb5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
80850  Gng2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
114117  Gng3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
114118  Gng4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
79218  Gng5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
58979  Gng7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
245986  Gng8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
114119  Gng10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
64199  Gng11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
114120  Gng12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
685513  Gng14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
685451  Gng13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
680149  Gngt1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
690825  Gngt2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
25238  Grk2; beta-adrenergic receptor kinase 1 [KO:K00910] [EC:2.7.11.15]
25372  Grk3; G protein-coupled receptor kinase 3 [KO:K00910] [EC:2.7.11.15]
59075  Grk5; G protein-coupled receptor kinase 5 [KO:K08291] [EC:2.7.11.16]
59076  Grk6; G protein-coupled receptor kinase 6 isoform c [KO:K08291] [EC:2.7.11.16]
59077  Grk4; G protein-coupled receptor kinase 4 [KO:K08291] [EC:2.7.11.16]
25387  Arrb1; beta-arrestin-1 [KO:K04439]
25388  Arrb2; beta-arrestin-2 [KO:K04439]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
81529  Pde1a; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A [KO:K13755] [EC:3.1.4.17]
29691  Pde1b; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B [KO:K13755] [EC:3.1.4.17]
81742  Pde1c; dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C [KO:K13755] [EC:3.1.4.17]
81743  Pde2a; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform PDE2A2 precursor [KO:K18283] [EC:3.1.4.17]
50678  Pde3a; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A [KO:K19021] [EC:3.1.4.17]
29516  Pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
25638  Pde4a; 3',5'-cyclic-AMP phosphodiesterase 4A isoform 1 [KO:K13293] [EC:3.1.4.53]
24626  Pde4b; 3',5'-cyclic-AMP phosphodiesterase 4B isoform 2 [KO:K13293] [EC:3.1.4.53]
290646  Pde4c; 3',5'-cyclic-AMP phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
24627  Pde4d; 3',5'-cyclic-AMP phosphodiesterase 4D isoform 1 [KO:K13293] [EC:3.1.4.53]
81744  Pde7a; high affinity 3',5'-cyclic-AMP phosphodiesterase 7A [KO:K18436] [EC:3.1.4.53]
140929  Pde7b; cAMP-specific 3',5'-cyclic phosphodiesterase 7B [KO:K18436] [EC:3.1.4.53]
309962  Pde8b; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
308776  Pde8a; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
63885  Pde10a; cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A isoform 1 [KO:K18438] [EC:3.1.4.17 3.1.4.35]
140928  Pde11a; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A isoform 4 [KO:K13298] [EC:3.1.4.17 3.1.4.35]
29290  Adora1; 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
rno04727  GABAergic synapse
rno04728  Dopaminergic synapse
KO pathway
ko05032   
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