Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and... The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Ψ augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuropharmacology Elsevier

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

13 pages
Read Article

Loading next page...
1
 
/lp/elsevier/two-delta-opioid-receptor-subtypes-are-functional-in-single-ventral-l3MtpNse5D
Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Ltd
ISSN
0028-3908
eISSN
1873-7064
D.O.I.
10.1016/j.neuropharm.2017.06.019
Publisher site
See Article on Publisher Site

Abstract

The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Ψ augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling.

Journal

Neuropharmacology – Elsevier

Published: Sep 1, 2017

References

  • Minireview: ubiquitination-regulated G protein-coupled receptor signaling and trafficking
    Alonso, V.; Friedman, P.A.
  • Sodium ions increase the binding of the antagonist peptide ICI 174864 to the delta-opiate receptor
    Appelmans, N.; Carroll, J.A.; Rance, M.J.; Simon, E.J.; Traynor, J.R.
  • Ventral tegmental area opioid mechanisms and modulation of ingestive behavior
    Badiani, A.; Leone, P.; Noel, M.B.; Stewart, J.
  • Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats
    Bals-Kubik, R.; Ableitner, A.; Herz, A.; Shippenberg, T.S.
  • Dopaminergic modulation of axon initial segment calcium channels regulates action potential initiation
    Bender, K.J.; Ford, C.P.; Trussell, L.O.
  • Neuroanatomical boundaries of the reward-relevant opiate-receptor field in the ventral tegmental area as mapped by the conditioned place preference method in rats
    Bozarth, M.A.
  • Opioid delta agonists and endogenous enkephalins induce different emotional reactivity than mu agonists after injection in the rat ventral tegmental area
    Calenco-Choukroun, G.; Daugé, V.; Gacel, G.; Féger, J.; Roques, B.P.
  • The Delta Receptor
    Chang, K.-J.; Porreca, F.; Woods, J.
  • G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats
    Chini, B.; Parenti, M.
  • Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series
    Daniels, D.J.; Lenard, N.R.; Etienne, C.L.; Law, P.Y.; Roerig, S.C.; Portoghese, P.S.
  • Ventral mesencephalic delta opioid receptors are involved in modulation of basal mesolimbic dopamine neurotransmission: an anatomical localization study
    Devine, D.P.; Leone, P.; Carlezon, W.A.; Wise, R.A.
  • Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: in vivo microdialysis studies
    Devine, D.P.; Leone, P.; Pocock, D.; Wise, R.A.
  • Mesolimbic dopamine neurotransmission is increased by administration of mu-opioid receptor antagonists
    Devine, D.P.; Leone, P.; Wise, R.A.
  • Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats
    Devine, D.P.; Wise, R.A.
  • beta-arrestin-biased agonism at the beta2-adrenergic receptor
    Drake, M.T.; Violin, J.D.; Whalen, E.J.; Wisler, J.W.; Shenoy, S.K.; Lefkowitz, R.J.
  • A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks
    Erbs, E.; Faget, L.; Scherrer, G.; Matifas, A.; Filliol, D.; Vonesch, J.L.; Koch, M.; Kessler, P.; Hentsch, D.; Birling, M.C.; Koutsourakis, M.; Vasseur, L.; Veinante, P.; Kieffer, B.L.; Massotte, D.
  • Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites
    Erspamer, V.; Melchiorri, P.; Falconieri-Erspamer, G.; Negri, L.; Corsi, R.; Severini, C.; Barra, D.; Simmaco, M.; Kreil, G.
  • Dynorphin-containing pathways in the substantia nigra and ventral tegmentum: a double labeling study using combined immunofluorescence and retrograde tracing
    Fallon, J.H.; Leslie, F.M.; Cone, R.I.
  • Cardiac enkephalins interrupt vagal bradycardia via delta 2-opioid receptors in sinoatrial node
    Farias, M.; Jackson, K.E.; Yoshishige, D.; Caffrey, J.L.
  • Molecular control of δ-opioid receptor signalling
    Fenalti, G.; Giguere, P.M.; Katritch, V.; Huang, X.P.; Thompson, A.A.; Cherezov, V.; Roth, B.L.; Stevens, R.C.
  • Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location
    Ford, C.P.; Mark, G.P.; Williams, J.T.
  • Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities
    Fujita, W.; Gomes, I.; Devi, L.A.
  • Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers
    Fujita, W.; Gomes, I.; Dove, L.S.; Prohaska, D.; McIntyre, G.; Devi, L.A.
  • Membrane-mediated Oligomerization of G Protein coupled receptors and its implications for GPCR function
    Gahbauer, S.; Böckmann, R.A.
  • Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity
    Gomes, I.; Fujita, W.; Gupta, A.; Saldanha, S.A.; Saldanha, A.S.; Negri, A.; Pinello, C.E.; Eberhart, C.; Roberts, E.; Filizola, M.; Hodder, P.; Devi, L.A.
  • A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia
    Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H.H.; Pintar, J.E.; Devi, L.A.
  • G protein-coupled receptor heteromerization: a role in allosteric modulation of ligand binding
    Gomes, I.; Ijzerman, A.P.; Ye, K.; Maillet, E.L.; Devi, L.A.
  • Heterodimerization of mu and delta opioid receptors: a role in opiate synergy
    Gomes, I.; Jordan, B.A.; Gupta, A.; Trapaidze, N.; Nagy, V.; Devi, L.A.
  • Increased abundance of opioid receptor heteromers after chronic morphine administration
    Gupta, A.; Mulder, J.; Gomes, I.; Rozenfeld, R.; Bushlin, I.; Ong, E.; Lim, M.; Maillet, E.; Junek, M.; Cahill, C.M.; Harkany, T.; Devi, L.A.
  • Morphine acutely regulates opioid receptor trafficking selectively in dendrites of nucleus accumbens neurons
    Haberstock-Debic, H.; Wein, M.; Barrot, M.; Colago, E.E.; Rahman, Z.; Neve, R.L.; Pickel, V.M.; Nestler, E.J.; von Zastrow, M.; Svingos, A.L.
  • Differential effects of intrathecally administered delta and mu opioid receptor agonists on formalin-evoked nociception and on the expression of Fos-like immunoreactivity in the spinal cord of the rat
    Hammond, D.L.; Wang, H.; Nakashima, N.; Basbaum, A.I.
  • Trafficking of preassembled opioid mu-delta heterooligomer-Gz signaling complexes to the plasma membrane: coregulation by agonists
    Hasbi, A.; Nguyen, T.; Fan, T.; Cheng, R.; Rashid, A.; Alijaniaram, M.; Rasenick, M.M.; O'Dowd, B.F.; George, S.R.
  • G-protein-independent modulation of P-type calcium channels by mu-opioids in Purkinje neurons of rat
    Iegorova, O.; Fisyunov, A.; Krishtal, O.
  • Regional difference of high voltage-activated Ca2+ channels in rat CNS neurones
    Ishibashi, H.; Rhee, J.S.; Akaike, N.
  • Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5'-isothiocyanate: evidence for delta receptor subtypes
    Jiang, Q.; Takemori, A.E.; Sultana, M.; Portoghese, P.S.; Bowen, W.D.; Mosberg, H.I.; Porreca, F.
  • Opioids excite dopamine neurons by hyperpolarization of local interneurons
    Johnson, S.W.; North, R.A.
  • Two types of neurone in the rat ventral tegmental area and their synaptic inputs
    Johnson, S.W.; North, R.A.
  • GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral tegmental area
    Kalivas, P.W.; Churchill, L.; Klitenick, M.A.
  • Opioid receptor subtype antagonists differentially alter GABA agonist-induced feeding elicited from either the nucleus accumbens shell or ventral tegmental area regions in rats
    Khaimova, E.; Kandov, Y.; Israel, Y.; Cataldo, G.; Hadjimarkou, M.M.; Bodnar, R.J.
  • Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat
    Korotkova, T.M.; Brown, R.E.; Sergeeva, O.A.; Ponomarenko, A.A.; Haas, H.L.
  • Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins
    Korotkova, T.M.; Sergeeva, O.A.; Eriksson, K.S.; Haas, H.L.; Brown, R.E.
  • Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for delta opioid receptors
    Kreil, G.; Barra, D.; Simmaco, M.; Erspamer, V.; Erspamer, G.F.; Negri, L.; Severini, C.; Corsi, R.; Melchiorri, P.
  • GABAergic neurons in the ventral tegmental area receive dual GABA/enkephalin-mediated inhibitory inputs from the bed nucleus of the stria terminalis
    Kudo, T.; Konno, K.; Uchigashima, M.; Yanagawa, Y.; Sora, I.; Minami, M.; Watanabe, M.
  • Analysis of opioid receptor subtype antagonist effects upon mu opioid agonist-induced feeding elicited from the ventral tegmental area of rats
    Lamonte, N.; Echo, J.A.; Ackerman, T.F.; Christian, G.; Bodnar, R.J.
  • Glutamate receptor modulation is restricted to synaptic microdomains
    Lur, G.; Higley, M.J.
  • Crystal structure of the μ-opioid receptor bound to a morphinan antagonist
    Manglik, A.; Kruse, A.C.; Kobilka, T.S.; Thian, F.S.; Mathiesen, J.M.; Sunahara, R.K.; Pardo, L.; Weis, W.I.; Kobilka, B.K.; Granier, S.
  • The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores
    Mansour, A.; Hoversten, M.T.; Taylor, L.P.; Watson, S.J.; Akil, H.
  • Reliability in the identification of midbrain dopamine neurons
    Margolis, E.B.; Coker, A.R.; Driscoll, J.R.; Lemaître, A.I.; Fields, H.L.
  • Delta-opioid receptor expression in the ventral tegmental area protects against elevated alcohol consumption
    Margolis, E.B.; Fields, H.L.; Hjelmstad, G.O.; Mitchell, J.M.
  • Direct bidirectional μ-opioid control of midbrain dopamine neurons
    Margolis, E.B.; Hjelmstad, G.O.; Fujita, W.; Fields, H.L.
  • Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex
    Margolis, E.B.; Lock, H.; Chefer, V.I.; Shippenberg, T.S.; Hjelmstad, G.O.; Fields, H.L.
  • The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?
    Margolis, E.B.; Lock, H.; Hjelmstad, G.O.; Fields, H.L.
  • Midbrain dopamine neurons: projection target determines action potential duration and dopamine D(2) receptor inhibition
    Margolis, E.B.; Mitchell, J.M.; Ishikawa, J.; Hjelmstad, G.O.; Fields, H.L.
  • Identification of rat ventral tegmental area GABAergic neurons
    Margolis, E.B.; Toy, B.; Himmels, P.; Morales, M.; Fields, H.L.
  • Lack of antinociceptive cross-tolerance between [D-Pen2, D-Pen5]enkephalin and [D-Ala2]deltorphin II in mice: evidence for delta receptor subtypes
    Mattia, A.; Vanderah, T.; Mosberg, H.I.; Porreca, F.
  • Intra-VTA deltorphin, but not DPDPE, induces place preference in ethanol-drinking rats: distinct DOR-1 and DOR-2 mechanisms control ethanol consumption and reward
    Mitchell, J.M.; Margolis, E.B.; Coker, A.R.; Allen, D.C.; Fields, H.L.
  • Cyclic penicillamine containing enkephalin analogs display profound delta receptor selectivities
    Mosberg, H.I.; Hurst, R.; Hruby, V.J.; Gee, K.; Akiyama, K.; Yamamura, H.I.; Galligan, J.J.; Burks, T.F.
  • Deprivation state switches the neurobiological substrates mediating opiate reward in the ventral tegmental area
    Nader, K.; van der Kooy, D.
  • Incomplete cross tolerance and multiple mu opioid peptide receptors
    Pasternak, G.W.
  • Differential somatic Ca2+ channel profile in midbrain dopaminergic neurons
    Philippart, F.; Destreel, G.; Merino-Sepúlveda, P.; Henny, P.; Engel, D.; Seutin, V.
  • Role of spacer and address components in peptidomimetic delta opioid receptor antagonists related to naltrindole
    Portoghese, P.S.; Nagase, H.; MaloneyHuss, K.E.; Lin, C.E.; Takemori, A.E.
  • Preferred supramolecular organization and dimer interfaces of opioid receptors from simulated self-association
    Provasi, D.; Boz, M.B.; Johnston, J.M.; Filizola, M.
  • Evaluation of opioid receptor subtype antagonist effects in the ventral tegmental area upon food intake under deprivation, glucoprivic and palatable conditions
    Ragnauth, A.; Ruegg, H.; Bodnar, R.J.
  • Receptor heterodimerization leads to a switch in signaling: beta-arrestin2-mediated ERK activation by mu-delta opioid receptor heterodimers
    Rozenfeld, R.; Devi, L.A.
  • TIPP[psi]: a highly potent and stable pseudopeptide delta opioid receptor antagonist with extraordinary delta selectivity
    Schiller, P.W.; Weltrowska, G.; Nguyen, T.M.; Wilkes, B.C.; Chung, N.N.; Lemieux, C.
  • Dual ultrastructural localization of enkephalin and tyrosine hydroxylase immunoreactivity in the rat ventral tegmental area: multiple substrates for opiate-dopamine interactions
    Sesack, S.R.; Pickel, V.M.
  • Involvement of the mesolimbic dopamine system in mediating the aversive effects of opioid antagonists in the rat
    Shippenberg, T.S.; Bals-Kubik, R.
  • Place preference conditioning reveals the involvement of D1-dopamine receptors in the motivational properties of mu- and kappa-opioid agonists
    Shippenberg, T.S.; Herz, A.
  • Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for delta opioid receptor subtypes
    Sofuoglu, M.; Portoghese, P.S.; Takemori, A.E.
  • 7-Benzylidenenaltrexone (BNTX): a selective delta 1 opioid receptor antagonist in the mouse spinal cord
    Sofuoglu, M.; Portoghese, P.S.; Takemori, A.E.
  • Modulation of GPCRs by monovalent cations and anions
    Strasser, A.; Wittmann, H.J.; Schneider, E.H.; Seifert, R.
  • The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat
    Swanson, L.W.
  • The delta(1) opioid receptor is a heterodimer that opposes the actions of the delta(2) receptor on alcohol intake
    van Rijn, R.M.; Whistler, J.L.
  • Structural mechanisms of voltage Sensing in G Protein-coupled receptors
    Vickery, O.N.; Machtens, J.P.; Tamburrino, G.; Seeliger, D.; Zachariae, U.
  • The influence of monovalent cations on trimeric G protein G(i)1α activity in HEK293 cells stably expressing DOR-G(i)1α (Cys(351)-Ile(351)) fusion protein
    Vošahlíková, M.; Svoboda, P.
  • Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih
    Wanat, M.J.; Hopf, F.W.; Stuber, G.D.; Phillips, P.E.; Bonci, A.
  • CRF-R2 and the heterosynaptic regulation of VTA glutamate during reinstatement of cocaine seeking
    Williams, C.L.; Buchta, W.C.; Riegel, A.C.
  • Cellular and synaptic adaptations mediating opioid dependence
    Williams, J.T.; Christie, M.J.; Manzoni, O.
  • Recent developments in biased agonism
    Wisler, J.W.; Xiao, K.; Thomsen, A.R.; Lefkowitz, R.J.
  • Opioid receptor types and subtypes: the delta receptor as a model
    Zaki, P.A.; Bilsky, E.J.; Vanderah, T.W.; Lai, J.; Evans, C.J.; Porreca, F.
  • In vitro identification and electrophysiological characterization of dopamine neurons in the ventral tegmental area
    Zhang, T.A.; Placzek, A.N.; Dani, J.A.
  • Posttranslation modification of G protein-coupled receptor in relationship to biased agonism
    Zheng, H.; Loh, H.H.; Law, P.Y.

You’re reading a free preview. Subscribe to read the entire article.

Try 2 weeks free now

DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

or browse the journals available

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off

Sign up
for free
Start 14 day
Free Trial