Psychopharmacology

, Volume 210, Issue 2, pp 161–168

Consequences of opioid receptor mutation on actions of univalent and bivalent kappa and delta ligands

  • Michael A. Ansonoff
  • Philip S. Portoghese
  • John E. Pintar
Original Investigation

Abstract

Introduction

During the past decade, substantial evidence has documented that opioid receptor heterodimers form in cell lines expressing one or more opioid receptors. More recent studies have begun to investigate whether heterodimer formation also occurs in vivo.

Objectives

We have used opioid receptor knockout mice to determine whether the in vivo intrathecal (i.t.) pharmacological potency of delta, kappa, and bivalent kappa/delta ligands is altered in the absence of the KOR-1 and/or DOR-1 genes.

Results

We observe that both NorBNI (a kappa antagonist) and KDN-21 (a kappa/delta bivalent antagonist) specifically inhibit DPDPE but not deltorphin II i.t potency in wild-type mice but that following mutation of KOR-1, the ability of either compound to reduce DPDPE potency is lost. In contrast, knockout of KOR-1 unexpectedly slightly reduces the potency of deltorphin II (delta2) but not DPDPE (delta1). Finally, two compounds with kappa agonist activity, 6′-GNTI (a putative kappa/delta heterodimer selective agonist) and KDAN-18 (kappa agonist/delta antagonist bivalent ligand) show reduced potency in DOR-1 KO mice.

Conclusions

These results show, genetically, that bivalent ligands with kappa agonist activity require delta receptors for maximal potency in vivo, which is consistent with the presence of opioid heterodimer/oligomer complexes in vivo, and also highlight the complexity of delta drug action even when complementary pharmacologic and genetic approaches are used.

Keywords

Opioid Dimer Intrathecal Knockout 

References

  1. Ansonoff MA, Zhang J, Czyzyk T, Rothman RB, Stewart J, Xu H, Zjwiony J, Siebert DJ, Yang F, Roth BL, Pintar JE (2006) Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice. J Pharmacol Exp Ther 318:641–648CrossRefPubMedGoogle Scholar
  2. Ansonoff MA, Wen T, Pintar JE (2010) Kappa2 opioid receptor subtype binding requires the presence of the DOR-1 gene. Front Biosci (Schol Ed) 2:772–780CrossRefGoogle Scholar
  3. Ballet S, Pietsch M, Abell AD (2008) Multiple ligands in opioid research. Protein Pept Lett 15:668–682CrossRefPubMedGoogle Scholar
  4. Bhushan RG, Sharma SK, Xie Z, Daniels DJ, Portoghese PS (2004) A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers. J Med Chem 47:2969–2972CrossRefPubMedGoogle Scholar
  5. Daniels DJ, Kulkarni A, Xie Z, Bhushan RG, Portoghese PS (2005) A bivalent ligand (KDAN-18) containing delta-antagonist and kappa-agonist pharmacophores bridges delta2 and kappa1 opioid receptor phenotypes. J Med Chem 48:1713–1716CrossRefPubMedGoogle Scholar
  6. Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG (2009) Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile. Br J Anaesth 103:38–49CrossRefPubMedGoogle Scholar
  7. Ellison NM (1993) Opioid analgesics for cancer pain: toxicities and their treatments. In: Patt RB (ed) Cancer pain. J. P. Lippincott, Philadelphia, pp 185–194Google Scholar
  8. Fowler CJ, Fraser GL (1994) Mu-, delta-, kappa-opioid receptors and their subtypes. A critical review with emphasis on radioligand binding experiments. [comment]. Neurochem Int 24:401–426CrossRefPubMedGoogle Scholar
  9. Gomes I, Filipovska J, Jordan BA, Devi LA (2002) Oligomerization of opioid receptors. Methods 27:358–365CrossRefPubMedGoogle Scholar
  10. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA (2004) A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci U S A 101:5135–5139CrossRefPubMedGoogle Scholar
  11. Goody RJ, Oakley SM, Filliol D, Kieffer BL, Kitchen I (2002) Quantitative autoradiographic mapping of opioid receptors in the brain of delta-opioid receptor gene knockout mice. Brain Research 945:9–19Google Scholar
  12. Hossain SM, Wong BK, Simpson EM (2004) The dark phase improves genetic discrimination for some high throughput mouse behavioral phenotyping. Genes Brain Behav 3:167–177CrossRefPubMedGoogle Scholar
  13. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67:313–316CrossRefPubMedGoogle Scholar
  14. Jordan BA, Devi LA (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399:697–700CrossRefPubMedGoogle Scholar
  15. Jordan BA, Trapaidze N, Gomes I, Nivarthi R, Devi LA (2001) Oligomerization of opioid receptors with beta 2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. Proc Natl Acad Sci USA 98:343–348CrossRefPubMedGoogle Scholar
  16. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dolle P, Tzavara E, Hanoune J, Roques BP, Kieffer BL (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383:819–823CrossRefPubMedGoogle Scholar
  17. Oertel B, Lotsch J (2008) Genetic mutations that prevent pain: implications for future pain medication. Pharmacogenomics 9:179–194CrossRefPubMedGoogle Scholar
  18. Parenty G, Appelbe S, Milligan G (2008) CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2-DOP receptor heterodimer. Biochem J 412:245–256CrossRefPubMedGoogle Scholar
  19. Portoghese PS (2001) From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J Med Chem 44:2259–2269CrossRefPubMedGoogle Scholar
  20. Portoghese PS, Lunzer MM (2003) Identity of the putative 1-opioid receptor as a kappa-delta heteromer in the mouse spinal cord. Eur J Pharmacol 457:233–234CrossRefGoogle Scholar
  21. Rios C, Gomes I, Devi LA (2006) mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol 148:387–395CrossRefPubMedGoogle Scholar
  22. Roy S, Barke RA, Loh HH (1998a) MU-opioid receptor-knockout mice: role of mu-opioid receptor in morphine mediated immune functions. Brain Res Mol Brain Res 61:190–194CrossRefPubMedGoogle Scholar
  23. Roy S, Liu HC, Loh HH (1998b) mu-Opioid receptor-knockout mice: the role of mu-opioid receptor in gastrointestinal transit. Brain Res Mol Brain Res 56:281–283CrossRefPubMedGoogle Scholar
  24. Schuller AG, King MA, Zhang J, Bolan E, Pan YX, Morgan DJ, Chang A, Czick ME, Unterwald EM, Pasternak GW, Pintar JE (1999) Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 2:151–156CrossRefPubMedGoogle Scholar
  25. Simonin F, Slowe S, Becker JA, Matthes HW, Filliol D, Chluba J, Kitchen I, Kieffer BL (2001) Analysis of [3H]bremazocine binding in single and combinatorial opioid receptor knockout mice. Eur J Pharmacol 414:189–195CrossRefPubMedGoogle Scholar
  26. Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, Miner LL, Uhl GR (1997) Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA 94:1544–1549CrossRefPubMedGoogle Scholar
  27. Trescot AM, Datta S, Lee M, Hansen H (2008) Opioid pharmacology. Pain Physician 11:S133–S153PubMedGoogle Scholar
  28. van Rijn RM, Whistler JL (2009) The delta(1) opioid receptor is a heterodimer that opposes the actions of the delta(2) receptor on alcohol intake. Biol Psychiatry 66:777–784CrossRefPubMedGoogle Scholar
  29. Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL (2005) A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA 102:9050–9055CrossRefPubMedGoogle Scholar
  30. Wang D, Sun X, Bohn LM, Sadee W (2005) Opioid receptor homo- and heterodimerization in living cells by quantitative bioluminescence resonance energy transfer. Mol Pharmacol 67:2173–2184CrossRefPubMedGoogle Scholar
  31. Xie Z, Bhushan RG, Daniels DJ, Portoghese PS (2005) Interaction of bivalent ligand KDN21 with heterodimeric delta-kappa opioid receptors in human embryonic kidney 293 cells. Mol Pharmacol 68:1079–1086CrossRefPubMedGoogle Scholar
  32. Zaki PA, Bilsky EJ, Vanderah TW, Lai J, Evans CJ, Porreca F (1996) Opioid receptor types and subtypes: the delta receptor as a model. Annu Rev Pharmacol Toxicol 36:379–401CrossRefPubMedGoogle Scholar
  33. Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP, Unterwald E, Pasternak GW, Pintar JE (1999) Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24:243–252CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Michael A. Ansonoff
    • 1
  • Philip S. Portoghese
    • 2
  • John E. Pintar
    • 1
  1. 1.Department of Neuroscience and Cell BiologyUniversity of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (UMDNJ-RWJMS)PiscatawayUSA
  2. 2.Department of Medicinal Chemistry, College of PharmacyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations