Effector | Observed Response after DOR Activation | Cell Type/Structure in Which Response Was Observed | Possible In Vivo Response or Established by the Study | G Protein/Reported Signaling Cascade Involved | Reference |
---|---|---|---|---|---|
G protein | GTP hydrolysis | HEK293 cells | — | Gαi1 is more effective turnover than Gαo | Moon et al. (2001) |
Conformational rearrangement within heterotrimeric G protein subunits | HEK293 cells | — | Gαi1β1γ2 activation | Audet et al. (2008) | |
Photoaffinity labeling | NG108-15 hybrid; SK-N-BE cells | — | Gαi2, Gαi3, Gαo | Offermanns et al. (1991), Prather et al. (1994), Allouche et al. (2000) | |
Immunoreactivity active G protein conformation | Murine PAG membranes | — | Gαi2, Gαz | Garzón et al. (1997) | |
GTPγS35 incorporation | Rat striatum, rat hippocampus | Movement, reward, mood, anxiety, cognition | Gαi3, Gαz | Kabli et al. (2014) | |
Loss of spinal analgesia by G protein knockdown | Intrathecal injection of antisense nucleotides and DOPr agonists (mice) | Analgesiaa (thermal; tail-flick test) | Gαi1, Gαi2, Gαi3, Gαo, Gαx/z, Gαq | Standifer et al. (1996) | |
Loss of supraspinal analgesia by G protein knockdown | Intracerebroventricular injection of antisense nucleotides and DOPr agonists (mice) | Analgesiaa (thermal; tail-flick test) | Gαi2, Gαi3, Gαo, Gα11, Gαq, Gαz | Garzón and Sánchez-Blázquez (1995), Sánchez-Blázquez and Garzón (1998) | |
AC | cAMP inhibition | COS and CHO cells | — | Gαz, Gαi3 | George et al. (2000), Fan et al. (2005) |
cAMP inhibition | HEK293 cells; NG108-15 and neuro 2A cells | — | Gαi2, Gαz | McKenzie and Milligan (1990), Tsu et al. (1997), Ho and Wong (2000), Megaritis et al. (2000), Zhang et al. (2006) | |
cAMP inhibition superactivation cAMP production | HEK293 cells | Cellular tolerance | Gαi/o; Gαz Gαi/o (not Gαz) | Tso et al. (2000) | |
cAMP inhibition | SK-N-BE | — | Gαi1, Gαi2, Gαi3, Gαo | Allouche et al. (1999) | |
cAMP inhibition superactivation cAMP production | Neuro 2A cells | Cellular tolerance | Gαi2 | Zhang et al. (2006) | |
cAMP inhibition | Rat frontal cortex | — | Not assessed | Perrine et al. (2008) | |
cAMP inhibition | Homogenates of rat olfactory bulb (external plexiform and granule cell layers) | Limbic circuit; emotions, depression | Not assessed | Onali and Olianas (2004) | |
cAMP inhibition | Rat striatum and nucleaus accumbens membranes | Movement, reward, anxiety, predictive- associative learning/decision making | Gαi/o | Unterwald and Cuntapay (2000), Perrine et al. (2008) | |
cAMP inhibition (striatopallidal and striatonigral pathway) | Rat caudate-putamen nucleaus and accumbens membranes | Movement, reward, anxiety, predictive-associative learning/decision making | Not assessed | Noble and Cox (1997) | |
cAMP inhibition | Murine nucleus accumbens membranes | Movement, reward, anxiety, predictive-associative learning/decision making | Not assessed | McCarthy et al. (2011) | |
cAMP inhibition | WT and AC5−/− mice striatal membranes | Psycholocomotiona | Gαi/o | Kim et al. (2006) | |
cAMP inhibition | Murine striatal membranes | Movement, reward, anxiety, predictive- associative learning/decision making | Gαi/o | Olianas et al. (2012) | |
Inhibition DARP32 phosphorylation by adenosine (striatopallidal pathway) | Rat striatal homogenates | Movement, reward, anxiety, predictive- associative learning/decision making | not assessed | Lindskog et al. (1999) | |
Superactivation cAMP production | CHO cells | Cellular tolerance | Gαi/o → Gβγ → PLCβ3 → IP3 → PKC → Raf1 → ACV/VI | Rubenzik et al. (2001), Varga (2003) | |
Increase cAMP production | HEK293 cells | — | Gαi2; Gαz → Gβγ → ACII | McKenzie and Milligan (1990), Tsu et al. (1997), Ho and Wong (2000), Megaritis et al. (2000), Zhang et al. (2006) | |
Increased AC activity | Homogenates of rat olfactory bulb (granule cell layer) | Limbic circuit; emotions, depression | Not assessed | Onali and Olianas (2004) | |
Increase cAMP production synergism D2R | Hippocampal neuron cultures newborn rats | — | Gαi/o → Gβγ → AC → PKA → CREB | Yao et al. (2003) | |
Increase cAMP production synergism D1R | Murine PFC membranes | Reward-motivated attentional processing, mood, anxiety | Gαi/o → GβγAC → PKA → 1) CREB; 2) pNR; 3) pGluR1 | Olianas et al. (2012) | |
Increase cAMP production synergism VIPR | Rat spinal cord (slices) | Visceral analgesia | Gαi/o... → PLCβ → IP3 →... → AC | Liu and Gintzler (2003) | |
Kinase cascade | |||||
ERK | ERK1/2 activation | CHO cells | — | 1) Gαi/o → Gβγ → Src → Raf/MEK/ERK1/2; 2) βarr1/2 → Raf/MEK/ERK1/2 | Xu et al. (2010) |
ERK1/2 activation | HEK293 cells | — | Gαi/o → PLC → Integrin a5b1 → PKCδ → EGFR → MEK/ERK1/2 | Eisinger and Ammer (2008a, 2009) | |
ERK1/2 activation | COS-7 cells | — | Gαi/o → Gβγ → Ras → Raf/MEK/ERK1/2 | Belcheva et al. (1998) | |
ERK1/2 activation | Jurkat human T lymphocyte cell line | Modulation cytokine secretion | Gαi/o → ?→ MEK/ERK1/2 (Gβγ/PI3K independent) | Hedin et al. (1999) | |
ERK1/2 activation | NG108-15 hybrid cells | — | Gαi/o → ? → MEK/ERK1/2 (Gβγ/PI3K independent) | Zhang et al. (2003) | |
ERK1/2 activation | NG108-15 hybrid cells | — | Gαi/o → PLC → Integrin a5b1 → PKCδ → TrkA → MEK/ERK1/2 | Eisinger and Ammer (2008a,b) | |
ERK1/2 activation evidence of neuroprotection | PC12 cells | Prosurvival/antiapoptotic effects upon serum deprivationa (measured as reduced LDH release and DNA fragmentation) | MEK → ERK1/2 → increased survival | Hayashi et al. (2002) | |
ERK1/2 activation evidence of neuroprotection | Pluripotent murine stem cell line differentiated to neurons | Neuroprotection after exposure to ROSa (measured as reduced caspase 3 activation) | Trk → reduced caspase 3 immunoreactivity | Narita et al. (2006) | |
ERK1/2 activation evidence of neuroprotection | Embryonic rat cortical rat neuron cultures | Prosurvival/antiapoptotic actions during severe hypoxiaa (measured as reduced LDH release and DNA fragmentation); response requires hypoxic preconditioning | MEK → ERK1/2 → Bcl2 → increased survival | Ma et al. (2005) | |
ERK1/2 activation evidence of neuroprotection | Embryonic rat cortical neuron cultures | Increased survival after oxygen glucose deprivationa (as measured by levels) | MEK → ERK1/2 → increased survival | Ke et al. (2009) | |
ERK1/2 activation | Embryonic murine astrocyte-enriched cultures | Increased expression of EAAT1 and EAAT2 and of glutamate uptakea | MEK → ERK1/2 → increased EAAT1 and EAAT2 expression | Liang et al. (2014) | |
ERK1/2 activation evidence of neuroprotection | Rat cortical slices | Prosurvival actions during glucose deprivationa (measured as reduced LDH release and DNA fragmentation) | MEK → ERK1/2 → Bcl2 → increased survival | Zheng et al. (2012) | |
ERK1/2 activation evidence of neuroprotection | Rat cortical and striatal homogenates | Downregulation of FADDa; possible offset of proapoptotic caspase 3/8 activity | MEK → ERK1/2 → reduced FADD | García-Fuster et al. (2007) | |
ERK1/2 activation; evidence of cardioprotection | Neonatal rat cardiomyocytes | Ultrastructural features of apoptosis upon serum glucose deprivation | MEK → ERK1/2-PI3K → increased survivin expression → reduced apoptosis | Yao et al. (2007) | |
ERK1/2 activation; evidence of cardioprotection | Neonatal rat cardiomyocytes | Prosurvival/antiapoptotic actions upon serum deprivationa (measured as reduced IDH release, caspase 3 activation and DNA fragmentation) | MEK → ERK1/2 → reduced apoptosis / increased survival | Shen et al. (2012) | |
ERK1/2 activation; evidence of cardioprotection | Neonatal rat cardiomyocytes | Increased survival after serum deprivationa (as measured by MTT levels) | PKC/MEK → ERK1/2 → reduced apoptosis / increased survival | Suo et al. (2014) | |
ERK1/2 activation; evidence of cardioprotection | Rat hearts | Reduction in infarct see at reperfusion after coronary ligationa | MEK → ERK1/2 activation and calcineurin suppression → reduced infarct size | Ikeda et al. (2006) | |
AKT | Akt activation | CHO cells | — | Gαi/o → Src/PDGFR/IGFR1/AMPK → PI3K → Akt → GSK3 inhibition | Olianas et al. (2011) |
Akt activation; evidence of neuroprotection | NG108-15 hybrid cells | Caspase 3 and GSK3 inhibitiona in serum deprived cells (prosurvival, antiapopototic actions) | Gαi/o → Trk → PI3K → Akt → caspase; GSK3 inhibition | Heiss et al. (2009) | |
Akt and ERK1/2 activation; evidence of cardioprotection | Adult rabbit cardiomyocytes | Ischemic preconditioning (measured by mitochondrial membrane integrity/ROS production) | Metalloproteinase → Src/HB-EGF shedding → EGFR → PI3K/PKC → Akt/ERK1/2 → cardioprotection | Philipp et al. (2006), Cohen et al. (2007), Förster et al. (2007) | |
Rabbit isolated hearts | Reduced infarct size upon reperfusion | ||||
p38 | p38 activation | NG108-15 hybrid cells | — | Gαi/o → p38 | Zhang et al. (1999b) |
p38 activation evidence of cardioprotection | Murine hearts | Protection from functional consequences of ischemia/reperfusion as evidenced by contractile recovery | Not assessed | Peart et al. (2007) | |
p38 inhibition evidence of neuroprotection | Embryonic rat cortical neuron cultures | Prosurvival/antiapoptotic actions during severe hypoxiaa (measured as reduced IDH release and DNA fragmentation) Response requires hypoxic preconditioning | MEK → ERK1/2 → p38 → increased survival | Ma et al. (2005), Hong et al. (2007) | |
p38 inhibition evidence of neuroprotection | Embryonic rat DRG neuron cultures | Blocked increase in Nav.1 expression after exposure to hyperglycemic culture mediuma | Not assessed | Chattopadhyay et al. (2008) | |
p38 inhibition counters proinlfammatory response | Murine macrophage cell line (RAW 264.7) | Limited proinflammatory responsea measured as reduced production of proinflammatory cytokine (TNFα) and of neutrophil attaracting chemokine (MIP-2) after exposure to lipopolysaccharide | Not assessed | Husted et al. (2005) | |
JNK | JNK activation | COS-7 cells | — | Gαi/o → Gβγ → Src → Rac + Cdc42 → p-JNK | Kam et al. (2003) |
JNK activation ATF-2 activation | CD3-activated splenic T cells; Jurkat human T lymphocyte cell line | Cytokine gene transcription | JNK → pJNK → JNK-ATF-2 complex → p-ATF-2 → transcription | Shahabi et al. (2003) | |
JNK activation c-Jun activation | CD3-activated splenic T cells | Cytokine gene transcription | Gαi/o → pJNK → PI3K → pAkt → p-c-Jun → transcription | Shahabi et al. (2006) | |
Phospholipase | |||||
PLCβ | PLCβ1 activation | COS-7 cells | — | Gα14 → PLCβ1 → IP formation | Ho et al. (2001) |
PLCβ1 activation | COS-7 cells | — | Gα16 → PLCβ1 → IP formation | Lee et al. (1998), Chan (2003) | |
PLCβ2/β3 activation mobilization intracellular Ca+2 stores | NG108-15 hybrid cells | — | Gαi/o → PLCβ → IP3 → intracellular Ca+2 stores | Jin et al. (1994), Smart and Lambert (1996), Yoon et al. (1999) | |
Mobilization intracellular Ca+2 stores | SH-SY5Y cells | — | Gαi/o → Gβγ → intracellular Ca+2 stores; requires concomitant Gq activation | Chen et al. (2000), Yeo et al. (2001) | |
PLCβ2/β3 activation mobilization intracellular Ca+2 stores | Rabbit iris-ciliary body | Reduction in acqueous flow rate and intraocular pressure | Gαi/o → Gβγ → PLCβ → IP3 → intracellular Ca+2 stores | Dortch-Carnes and Potter (2003) | |
PLCβ3 activation muscle contraction | Dispersed intestinal muscle cells guinea pig intestine | Intestinal smooth muscle contraction | Gαi2/Gαo → Gβγ → PLCβ3 → IP3 → intracellular Ca+2 stores | Murthy and Mahklouf (1996) | |
Synergistic peripheral analgesia | Hind paw injection of agonists (rats) | Analgesiaa (thermal, paw withdrawl) | Priming by BK/PKC/AA necessary for DOPr analgesia | Rowan et al. (2009) | |
Spinal analgesia inhibition NT release from primary afferents | Intrathecal injection of agonist (rats) | Analgesiaa (thermal, tail-immersion) | Coactivation of PKC by α2ADR necessay for analgesic synergism; DOPr analgesia requires PKC activity | Overland et al. (2009) | |
Spinal analgesia | Intrathecal injection of agonist (mice) | Analgesiaa (thermal, tail-flick) | DOPr analgesia requires PIC activity; PKC inhibition enhances analgesia | Narita et al. (2000) | |
PLA2 | Arachidonate release | CHO cells | — | Gαi/o → intracellular Ca+2 stores → PKC → ERK1/2 → PLA2 → AA | Fukuda et al. (1996) |
Inhibition GABAergic currents supraspinal analgesia | NRM slices (rats), intracerebral injection of agonist into NRM (rats) | AA release/HPETEs production in NRM; analgesia (thermal; tail-flick test) | PLA2 → AA → 12-LOX → HPETEs → ? → reduced GABA release | Zhang and Pan (2010, 2012) | |
PLD2 | PLD2 activation | HEK293; SHSY-5Y cells | DOPr endocytosis | DOPr/ARF interaction (?) → PLD2 → PA → DAG → p38 → EEA-1 | Koch et al. (2006), Yang et al. (2010) |
Channel | |||||
Kir3 | Ba+2-sensitive, K+ current with inward rectification | Xenopus oocytes | — | Gαi/o → Gβγ → Kir3 channel | Ikeda et al. (1995), Kovoor et al. (1997), Kobayashi et al. (1998), Zhao et al. (2006) |
Spinal analgesia | Intrathecal injection | Analgesiaa (thermal, tail-flick test) | Analgesia lost in Kir3.1 or Kir3.2 knockout mice or in mice that received tertiapin Q intrathecally | Marker et al. (2005) | |
Peripheral analgesia | intra-masseter injection | Analgesiaa (noxious mechanical, chemical stimuli) | Analgesia lost by intramasseter injection of tertiapin Q | Chung et al. (2014) | |
Outward currents in local and projection neurons of RVM | Rostral-ventro-medial-medulla slices (rats) | Regulation of local and projection neurons pro or antinociceptive (?) | Outward current presumably Kir3-mediated | Marinelli et al. (2005) | |
Outward currents in local GABAergic neurons of RVM | Rostral-ventro-medial-medulla slices (mice) | Disinhibition of descending antinociceptive pathway | Outward current presumably Kir3-mediated | Pedersen et al. (2011) | |
Outward (inhibitory) currents in PAG | Periaqueductal gray slices (mice) | Disinhibition of the descending antinociceptive pathway by inhibiting GABAergic interneurons | Current produced by inward rectifying channel | Vaughan et al. (2003) | |
Outward (inhibitory) currents in low threshold bursting GABAergic neurons of central amygdala projecting to PAG | Amygdala slices (rats) | Inhibition of GABA release in PAG | Current produced by inward rectifying channel; effect remarkably increased by morphine pretreatment | Chieng and Christie (2009) | |
Inhibition of IPSCs recorded from pyramidal hippocampal neurons (CA1) | Hipppocampal slices (mice) | Enhanced pyramidal neuron excitability via presynaptic desinhibitiona; learning and memory | Not assessed; presumably Kir3 | Rezai et al. (2013) | |
Outward (inhibitory) currents in GABAergic interneurons stratum oriens (CA1) | Hipppocampal slices (rats) | Inhibition of GABAergic interneurons desinhibition of pyramidal cellsa; learning and memory | Current is only partly due to inward rectifying channel; part is due to Ih inactivation | Svoboda and Lupica (1998), Svoboda et al. (1999) | |
Cav2 | Inhibition of membrane currents mediated by voltage-operated Ca+2 channels | Human small-cell lung carcinoma cells | — | Gαi/o → VOCC undistinguished; revesible by hyperpolareation | Sher et al. (1996) |
Inhibition N-type Ca+2 channel currents | NG108-15 hybrid cells | — | PTX-sensitive, Cav2.2 modulation reversible by hyperpolaization | Morikawa et al. (1999), Toselli et al. (1999) | |
Inhibition Cav2.2 channel currents | DRG small and medium neurons (rat 7–11 days old) | Inhibition neurotransmitter releasea; analgesia | DOPrs also inhibited Cav2.1 channel currents | Acosta and López (1999) | |
Inhibition of depolarization driven increase in intracellular Ca+2; reduction in CGRP release | Dissociated DRG neurons (adult rats) | Inhibition CGRP release; analgesia | DOPrs also inhibited Cav2.1 channel permeability to Ca+2 | Khasabova et al. (2004) | |
Inhibition Cav2.2 channel currents | DRG small neurons (rat 5 to 6 weeks old) | Inhibition neurotransmitter release; analgesia | DOPrs also inhibited Cav2.1 channel currents inhibition of all Cav2 channels was more effective in isolectin IB4 negative neurons | Wu et al. (2008) | |
Inhibition Cav2.2 channel currents analgesia in chronic pain model | Medium-large neurons; DRGs from 8- to 14-week-old mice | Inhibition neurotransmitter release; analgesiaa (mechanical allodynia) | Cav2.2 responses to DOPr agonists were observed in 33% of neurons from naïve mice and 100% of CFA- treated mice | Mittal et al. (2013), Pradhan et al. (2013) | |
Inhibition Cav2.2 channel currents | Neurons in TG and DRGs from 7-day-old rats transfected with DOPr-GFP exposed or not to BK | Inhibition neurotransmitter releasea; analgesia | Cav2.2 responses to DOPr agonists were observed in 23% of control neurons and 54% of neurons exposed to BK; greater CGRP release after BK | Pettinger et al. (2013) |
ATF, activating transcription factor; CFA, complete-Freund's-adjuvant; CREB, cAMP response element binding; DARP32, dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa; D1R, dopamine 1 receptor; D2R, dopamine 2 receptor; EAAT, excitatory amino acid transporter; FADD, Fas-associated death domain; HB-EGF, heparin-binding EGF-like growth factor; IDH, isocitrate dehydrogenase; IGFR, insulin-like growth factor 1 receptor; LDH, lactic dehydrogenase; MEK, mitogen-activated protein kinase kinase; MIP, macrophage inflammatory protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; NRM, nucleus raphé magnus; PDGFR, platelet-derived growth factor receptor; PFC, prefrontal cortex; ROS, reactive oxygen species; RVM, rostroventromedial medulla; TNF, tumor necrosis factor; VIPR, vasointestinal polypeptide receptor; VOCC, voltage operated calcium channel; WT, wild type.
↵a Established by the study.