Skip to main content

Advertisement

SpringerLink
Log in

The role of regulator of G protein signaling 4 in delta-opioid receptor-mediated behaviors

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Regulator of G protein signaling (RGS) proteins act as negative modulators of G protein signaling. RGS4 has been shown to negatively modulate G protein signaling mediated by the delta opioid receptor (DOPr) in vitro. However, the role of RGS4 in modulating DOPr-mediated behaviors in vivo has not been elucidated.

Objective

The aim of this study was to compare the ability of the DOPr agonist SNC80 to induce DOPr-mediated antinociception, antihyperalgesia, antidepressant-like effects, and convulsions in wild-type and RGS4 knockout mice.

Methods

Antinociception was assessed in the acetic acid stretch assay. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. Antidepressant-like effects were evaluated in the forced swim and tail suspension tests. Mice were also observed for convulsive activity post-SNC80 treatment. SNC80-induced phosphorylation of MAP kinase in striatal tissue from RGS4 wild-type and knockout mice was quantified by Western blot. DOPr number from forebrain tissue was measured using [3H]DPDPE saturation binding.

Results

Elimination of RGS4 potentiated SNC80-induced antinociception and antihyperalgesia. SNC80-induced antidepressant-like effects were potentiated in RGS4 knockout mice in the forced swim test but not in the tail suspension test. Additionally, RGS4 knockout did not alter SNC80-induced convulsions. SNC80-induced phosphorylation of MAP kinase was potentiated in striatum from RGS4 knockout mice. Loss of RGS4 did not affect total DOPr number.

Conclusions

Overall, these findings demonstrate that reduction of RGS4 functionally may increase the therapeutic index of SNC80. These results provide the first evidence of differential regulation of DOPr-mediated behaviors by RGS proteins and G protein signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI, Ptáček AAH (2010) Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 30:170–178. doi:10.1111/j.1468-2982.2009.01864

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blazer LL, Storaska AJ, Jutkiewicz EM, Turner EM, Calcagno M, Wade SM, Wang Q, Huang XP, Traynor JR, Husbands SM, Morari M, Neubig RR (2015) Selectivity and anti-Parkinson’s potential of thiadiazolidinone RGS4 inhibitors. ACS Chem Neurosci 6:911–919. doi:10.1021/acschemneuro.5b00063

    Article  CAS  PubMed  Google Scholar 

  • Bradbury FA, Zelnik JC, Traynor JR (2009) G protein independent phosphorylation and internalization of the delta-opioid receptor. J Neurochem 109:1526–1535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods JH (2002a) Nonpeptidic delta-opioid receptor agonists reduce immobility in the forced swim assay in rats. Neuropsychopharmacology 26:744–755. doi:10.1038/S0893-133X(01)00413-4

    Article  CAS  PubMed  Google Scholar 

  • Broom DC, Nitsche JF, Pintar JE, Rice KC, Woods JH, Traynor JR (2002b) Comparison of receptor mechanisms and efficacy requirements for delta-agonist-induced convulsive activity and antinociception in mice. J Pharmacol Exp Ther 303:723–729. doi:10.1124/jpet.102.036525

    Article  CAS  PubMed  Google Scholar 

  • Broom DC, Guo L, Copp A, Husbands SM, Lewis JW, Woods JH, Traynor JR (2000) BU:48 a novel buprenorphine analog that exhibits δ-opioid-mediated convulsions but not δ-opioid- mediated antinociception in mice. J Pharmacol Exp Ther 294:1195–1200

    CAS  PubMed  Google Scholar 

  • Charfi L, Audet N, Bagheri Tudashki H, Pineyro G (2015) Identifying ligand-specific signaling within biased responses: focus on d opioid receptor ligands. Br J Pharmacol 172:435–448

    Article  CAS  PubMed  Google Scholar 

  • Charfi I, Nagi K, Mnie-Filali O, Thibault D, Balboni G, Schiller PW, Trudeau LE, Pineyro G (2014) Ligand- and cell-dependent determinants of internalization and cAMP modulation by delta opioid receptor (DOR) agonists. Cell Mol Life Sci 71:1529–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiang T, Sansuk K, van Rijn RM (2016) β-Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake. Br J Pharmacol 173:332–343. doi:10.1111/bph.13374

    Article  CAS  PubMed  Google Scholar 

  • Chu Sin Chung P, Kieffer BL (2013) Delta opioid receptors in brain function and disease. Pharmacol Ther 140:112–120. doi:10.1016/j.pharmthera.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  • Chu Sin Chung P, Keyworth HL, Martin-Garcia E, Charbogne P, Darcq E, Bailey A, Filliol D, Matifas A, Scherrer G, Ouagazzal AM, Gaveriaux-Ruff C, Befort K, Maldonado R, Kitchen I, Kieffer BL (2015) A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons. Biol Psychiatry 77:404–415. doi:10.1016/j.biopsych.2014.07.033

    Article  CAS  PubMed  Google Scholar 

  • Chung PC, Boehrer A, Stephan A, Matifas A, Scherrer G, Darcq E, Befort K, Kieffer BL (2015) Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures. Behav Brain Res 278:429–434. doi:10.1016/j.bbr.2014.10.029

    Article  PubMed  Google Scholar 

  • Cifelli C, Rose RA, Zhang H, Voigtlaender-Bolz J, Bolz SS, Backx PH, Heximer SP (2008) RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circ Res 103:527–535. doi:10.1161/CIRCRESAHA.108.180984

    Article  CAS  PubMed  Google Scholar 

  • Comer SD, Hoenicke EM, Sable AI, McNutt RW, Chang KJ, De Costa BR, Mosberg HI, Woods JH (1993) Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice. J Pharmacol Exp Ther 267:888–895

    CAS  PubMed  Google Scholar 

  • Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci and. Biobehav Rev 29:571–625

    Article  CAS  Google Scholar 

  • Gallantine EL, Meert TF (2005) A comparison of the antinociceptive and adverse effects of mu-opioid agonist morphine and the delta-opioid agonist SNC80. Basic Clin Pharmacol Toxicol 97:39–51. doi:10.1111/j.1742-7843.2005.pto_97107

    Article  CAS  PubMed  Google Scholar 

  • Gu Z, Jiang Q, Yan Z (2007) RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. Mol Pharmacol 71:1030–1039. doi:10.1124/mol.106.032490

    Article  CAS  PubMed  Google Scholar 

  • Han MH, Renthal W, Ring RH, Rahman Z, Psifogeorgou K, Howland D, Birnbaum S, Young K, Neve R, Nestler EJ, Zachariou V (2010) Brain region specific actions of regulator G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biol Psychiatry 67:761–769

    Article  CAS  PubMed  Google Scholar 

  • Hollinger S, Hepler JR (2002) Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev 54:527–559

    Article  CAS  PubMed  Google Scholar 

  • Hong EJ, Rice KC, Calderon SN, Woods JH, Traynor JR (1998) Convulsive behavior of nonpeptide δ-opioid ligands: comparison of SNC80 and BW373U86 in mice. Analgesia 3:269–276

    CAS  Google Scholar 

  • Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (2006) The convulsive and electroencephalographic changes produced by nonpeptidic δ-opioid agonists in rats: comparison with pentylenetetrazol. J Pharmacol Exp Ther 317:1337–1348

    Article  CAS  PubMed  Google Scholar 

  • Leontiadis LJ, Papakonstantinou MP, Georgoussi Z (2009) Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate mu- and delta-opioid receptor signaling. Cell Signal 21:1218–1228. doi:10.1016/j.cellsig.2009.03.013

  • Lutz PE, Kieffer BL (2013) Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36:195–206. doi:10.1016/j.tins.2012.11.002

    Article  CAS  PubMed  Google Scholar 

  • Naidu PS, Lichtman AH, Archer CC, May EL, Harris LS, Aceto MD (2007) NIH 11082 produces antidepressant-like activity in the mouse tail-suspension through a delta opioid receptor mechanism of action. Eur J Pharmacol 566:132–136. doi:10.1016/j.ejphar.2007.03.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Negus SS, Rosenberg MB, Altarifi AA, O’Connell RH, Folk JE, Rice KC (2012) Effects of the δ opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats. J Pain 13:317–327. doi:10.1016/j.jpain.2011.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nomoto S, Adachi K, Yang LX, Hirata Y, Muragachi S, Kiuchi K (1997) Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization. Biochem Biophys Res Commun 241:281–287

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    CAS  PubMed  Google Scholar 

  • Pradhan AA, Perro J, Walwyn WM, Smith ML, Vicente-Sanchez A, Segura L, Bana A, Keiffer BL, Evans CJ (2016) Agonist-specific recruitment of arrestin isforms differentially modify delta opioid receptor function. J Neurosci 36:3541–3551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pradhan AA, Smith ML, Zyuzin J, Charles A (2014) δ-opioid receptor agonists inhibit migraine related hyperalgesia, aversive state, and cortical spreading depression in mice. Br J Pharmacol 171:2375–2384. doi:10.1111/bph.12591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saitoh A, Sugiyama A, Nemoto T, Fujii H, Wada K, Oka J, Nagase H, Yamada M (2011) The novel δ opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions. Behav Brain Res 223:271–279. doi:10.1016/j.bbr.2011.04.041

    Article  CAS  PubMed  Google Scholar 

  • Simmons ML, Chavkin C (1996) Endogenous opioid regulation of hippocampal function. Int Rev Neurobiol 39:145–196

    Article  CAS  PubMed  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    Article  CAS  PubMed  Google Scholar 

  • Stratinaki M, Varidaki A, Mitsi V, Ghose S, Magida J, Dias C, Russo SJ, Vialou V, Caldarone BJ, Tamminga CA, Nestler EJ, Zachariou V (2013) RGS4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models. Proc Natl Acad Sci U S A 110:8254–8259. doi:10.1073/pnas.1214696110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Talbot JN, Roman DL, Clark MJ, Roof RA, Tesmer JJ, Neubig RR, Traynor JR (2010) Differential modulation of my-oioid receptor signaling to adenylyl cyclase by regulators of G proteins 4 or 8 and 7 in permeabilised C6 cells is Galpha subtype dependent. J Neurochem 112:1026–1034

    Article  CAS  PubMed  Google Scholar 

  • Turner EM, Blazer LL, Neubig RR, Husbands SM (2012) Small molecule inhibitors of regulator of G protein signalling (RGS) proteins. ACS Med Chem Lett 9:146–150. doi:10.1021/ml200263y

    Article  Google Scholar 

  • Violin JD (2014) Biased ligands at mu and delta opioid receptors: targeting selective signalling to develop improved therapeutics. International Narcotic Research Conference 2014, pp22.

  • Wang Q, Liu-Chen LY, Traynor JR (2009) Differential modulation of mu- and delta-opioid receptor agonists by endogenous RGS4 protein in SH-SY5Y cells. J Biol Chem 284:18357–18367. doi:10.1074/jbc.M109.015453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Isaac J. Dripps, Qin Wang, John R. Traynor & Emily M. Jutkiewicz

  2. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA

    Richard R. Neubig

  3. Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Rockville, MD, USA

    Kenner C. Rice

Authors
  1. Isaac J. Dripps
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard R. Neubig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenner C. Rice
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John R. Traynor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emily M. Jutkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emily M. Jutkiewicz.

Ethics declarations

All animal use procedures complied with the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health and were approved by the University of Michigan Institutional Committee on the Use and Care of Animals.

Funding and disclosure

Part of this work was funded by a PhRMA Foundation Research Starter Grant awarded to EMJ and funds from the University of Michigan Medical School. She has consulted for Trevena, Inc., in 2011–2012 with compensation. JRT has no conflicts and is supported by the National Institute on Drug Abuse grant DA 035316. This study was also supported in part by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism and by the National Institute on Drug Abuse (KCR). RRN is founder and owner of Argessin LLC which holds a license for small-molecule RGS inhibitors and is supported by NIH DA RO1 023252.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dripps, I.J., Wang, Q., Neubig, R.R. et al. The role of regulator of G protein signaling 4 in delta-opioid receptor-mediated behaviors. Psychopharmacology 234, 29–39 (2017). https://doi.org/10.1007/s00213-016-4432-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4432-5

Keywords

Search

Navigation