Skip to main content
SpringerLink
Log in

Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on κ-opioid agonists in the mouse writhing assay

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

Abstract

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-depend-ently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kgβ-FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone. Hence, SC administered nor-BNI selectively antagonized agonist activity mediated through kappaopioid receptors without differentiating between kappa subtypes. Nor-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured.

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

Similar content being viewed by others

References

  • Birch PJ, Hayes AG, Sheehan MJ, Tyres MB (1987) Norbinaltorphimine: antagonist profile atκ opoid receptors. Eur J Pharmacol 144:405–408

    Article  PubMed  Google Scholar 

  • Butelman ER, Negus SS, Ai Y, deCosta BR, Woods JH (1993)Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys. J Pharmacol Exp Ther 267:1269–1276

    PubMed  Google Scholar 

  • Chang K-J, Rigdon GC, Howard JL, McNutt RW (1993) A novel, potent and selective non-peptidicδ-opioid receptor agonist BW 373U96. J Pharmacol Exp Ther 267:852–857

    PubMed  Google Scholar 

  • Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW (1989) Kappa opiate receptor multiplicity: evidence for two U50,488-sensitiveκ 1 subtypes and a novelκ 3 subtype. J Pharmacol Exp Ther 251:461–468

    PubMed  Google Scholar 

  • Comer SD (1992) BW 373U86: Behavioral pharmacology of a putative non-peptide, systemically-active delta opioid agonist. PhD Thesis, University of Michigan, USA

    Google Scholar 

  • Cooper SJ, Sanger DJ (1984) Endorphinergic mechanisms in food, salt and water intake: an overview. Appetite 5:1–6

    PubMed  Google Scholar 

  • Cooper SJ, Jackson A, Kirkham TC (1985) Endorphins and food intake: kappa opioid receptor agonists and hyperphagia. Pharmacol Biochem Behav 23:889–901

    Google Scholar 

  • Corbett AD, Kosterlitz HW (1986) Bremazocine is an agonist atκ-opiate receptors and an antagonist atμ-opioid receptors in guinea-pig myenteric plexus. Br J Pharmacol 89:245–249

    PubMed  Google Scholar 

  • Devlin T, Shoemaker WJ (1990) Characterization of kappa opioid binding using dynorphin A1–13 and U69,593 in the rat brain. J Pharmacol Exp Ther 253:749–759

    PubMed  Google Scholar 

  • Endoh T, Matsuura H, Tanaka C, Nagase H (1992) Nor-binaltorphimine: a potent and selectiveκ-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn 316:30–42

    PubMed  Google Scholar 

  • Hayes AG, Sheehan MJ, Tyers MB (1987a) Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig toμ andκ-opioid receptor agonists. Br J Pharmacol 91:823–832

    PubMed  Google Scholar 

  • Hayes AG, Skingle M, Tyers MB (1987b) Evaluation of the receptor selectivities of opioid drugs by investigating the block of their effect on urine output byβ-funaltrexamine. J Pharmacol Exp Ther 240:984–988

    PubMed  Google Scholar 

  • Hein DW, Young AM, Herling S, Woods JH (1981) Pharmacological analysis of the discriminative stimulus characteristics of ethylketazocine in the rhesus monkey. J Pharmacol Exp Ther 218:7–15

    PubMed  Google Scholar 

  • Horan P, de Costa BR, Rice KC, Porreca F (1991) Differential antagonism of U69,593- and bremazocine-induced antinociception by (-)-UPHIT: evidence of kappa opioid receptor multiplicity in mice. J Pharmacol Exp Ther 257:1154–1161

    PubMed  Google Scholar 

  • Horan P. Taylor J, Yamamura HI, Porreca F (1992) Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. J Pharmacol Exp Ther 260:1237–1243

    PubMed  Google Scholar 

  • Hunter JC, Leighton GE, Meecham KG, Boyle SJ, Horwell DC, Rees DC, Hughs J (1990) CI-977, a novel and selective agonist for theκ-opioid receptor. Br J Pharmacol 101:183–189

    PubMed  Google Scholar 

  • Iyengar S, Kim HS, Wood PL (1986) Effects of kappa opiate agonists on neurochemical and neuroendocrine indices: evidence for kappa receptor subtypes. Life Sci 39:637–644

    PubMed  Google Scholar 

  • Jiang Q, Takemori AE, Sultana M, Portoghese PS, Bowen WD, Mosberg HI, Porreca F (1991) Differential antagonism of opioid delta antinociception by [D-Ala2, Leu5, Cys6] enkephalin and naltrindole 5′-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol Exp Ther 257:1069–1075

    PubMed  Google Scholar 

  • Jones DNC, Holtzman SG (1992) Long termκ-opioid receptor blockade following nor-binaltorphimine. Eur J Pharmacol 215:345–348

    Article  PubMed  Google Scholar 

  • Koster R, Anderson M, deBeer EJ (1959) Acetic acid for analgesic screening. Fed Proc 18:412

    Google Scholar 

  • Lahti RA, Mickekson MM, McCall JM, Von Voigtlander PF (1985) [3H]-U-69593 a highly selective ligand for the opioidκ receptor. Eur J Pharmacol 109:281–284

    Article  PubMed  Google Scholar 

  • Leander JD (1984) Kappa opioid agonists and antagonists: effects on drinking and urinary output. Appetite 5:7–14

    PubMed  Google Scholar 

  • Lord JAH, Waterfield AA, Hughs J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499

    Article  PubMed  Google Scholar 

  • Magnan J, Paterson SJ, Tavani A, Kosterlitz HW (1982) The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn-Schmiedeberg's Arch Pharmacol 319:197–205

    Article  Google Scholar 

  • Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1988) Anatomy of CNS opioid receptors. Trends Neurosci 11:308–314

    Article  PubMed  Google Scholar 

  • Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine-and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532

    PubMed  Google Scholar 

  • Merz H, Stockhaus K, Wick H (1975) Stereoisomeric 5,9-dimethyl-2′-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with non-morphine-like action profiles. J Med Chem 18:996–1000

    Article  PubMed  Google Scholar 

  • Negus SS, Picker MJ, Dykstra LA (1990) Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure. Psychopharmacology 102:465–473

    PubMed  Google Scholar 

  • Pasternak GW (1986) Multiple mu opiate receptors: biochemical and pharmacological evidence for multiplicity. Biochem Pharmacol 35:361–364

    PubMed  Google Scholar 

  • Petrillo P, Gambino MC, Tavini A (1984) Bremazocine induces antinociception, but prevents opioid-induced constipation and catatonia in rats and precipitates withdrawal in morphine-dependent rats. Life Sci 35:917–927

    Article  PubMed  Google Scholar 

  • Portoghese PS, Larson DL, Sayre LM, Fries DS, Takemori AE (1980) A novel opioid receptor site alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities. J. Med Chem 24:233–234

    Google Scholar 

  • Portoghese PS, Lipkowski AW, Takemori AE (1987) Binaltorphimine and nor-binaltorphimine, potent and selectiveκ-opioid receptor antagonists. Life Sci 40:1287–1292

    Article  PubMed  Google Scholar 

  • Portoghese PS, Sultana M. Takemori AE (1988) Naltrindole, a highly selective and potent non-peptide δ opioid receptor antagonist. Eur J Pharmacol 146:185–186

    Article  PubMed  Google Scholar 

  • Robson LE, Gillan MGC, Kosterlitz HW (1985) Species differences in the concentrations and distributions of opioid binding sites. Eur J Pharmacol 112:65–71

    PubMed  Google Scholar 

  • Romer D, Buscher H, Hill RC, Maurer R, Petcher TJ, Welle HBA, Bakel HCCK, Akkerman AM (1980) Bremazocine: a potent, long-acting opiate kappa antagonist. Life Sci 27:971–978

    Article  PubMed  Google Scholar 

  • Rothman RB, Bykov V, Reid A, DeCosta BR, Newman A-H, Jacobson AE, Rice KC (1988) A brief study of the selectivity of norbinaltorphimine, (−)-cyclofoxy, and (+)-cyclofoxy among opioid receptor subtypes in vitro. Neuropeptides 12:181–187

    PubMed  Google Scholar 

  • Rothman RB, Bykov V, DeCosta BR, Jacobson AE, Rice KC, Brady LS (1990) Interaction of endogenous opioid peptides and other drugs with four kappa opioid binding sites in guinea peg brain. Peptides 11:311–331

    Article  PubMed  Google Scholar 

  • Rothman RB, Bykov V, Mahboubi A. Long JB, Jiang Q, Porreca F, De Costa BR, Jacobson AE, Rice KC, Holaday JW (1991) Interaction ofβ-funaltrexamine with [3H] cyclofoxy binding in rat brain: further evidence thatβ-FNA alkylates the opioid receptor complex. Synapse 8:86–99

    PubMed  Google Scholar 

  • Schmauss C, Yaksh TL (1984) In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat. J Pharmacol Exp Ther 228:1–12

    PubMed  Google Scholar 

  • Sharif NA, Durie E, Michel AD, Whiting RL (1990) Dog cerebral cortex contiansμ-,φ- andκ- -opioid receptors at different densities: apparent lack of evidence for subtypes of theκ-receptor using selective radioligands. Brain Res 510:108–114

    PubMed  Google Scholar 

  • Sofuoglu M, Portoghese PS, Takemori AE (1991) Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for deltra opioid receptor subtypes. J Pharmacol Exp Ther 257:676–680

    PubMed  Google Scholar 

  • Takemori AE, Ho BY, Naeseth JS, Portoghese PS (1988a) Norbinaltorphimine, a highly selective kappa-opioid antagonist in analgesic and receptor binding assays. J Pharmacol Exp Ther 246:255–258

    PubMed  Google Scholar 

  • Takemori AE, Schwartz MM, Portoghese PS (1988b) Suppression by nor-binaltorphimine of kappa opioid-mediated diuresis in rats. J Pharmacol Exp Ther 247:971–974

    PubMed  Google Scholar 

  • Tallarida RJ, Murray RB (1981) Manual of pharmacologic calculations with computer programs. Springer, New York

    Google Scholar 

  • Von Voigtlander PF, Lewis RA (1982) U-50,488: a selective kappa opioid agonist: comparison to other reputed kappa agonists. Prog Neuropsychopharmacol Biol Psychiatry 6:467–470

    Google Scholar 

  • Ward SJ, Portoghese PS, Takemori AE (1982) Pharmacological characterization in vivo of the novel opiate,β-funaltrexamine, J Pharmacol Exp Ther 220:494–498

    PubMed  Google Scholar 

  • Wood PL, Charleson SE, Lane D, Hudgin RL (1981) Multiple opiate receptors: differential binding ofμ, κ andδ agonists. Neuropharmacology 20:1215–1220

    Article  PubMed  Google Scholar 

  • Zimmerman DM, Leander JD, Reel JK, Hynes MD (1987) Use ofβ-funaltrexamine to determine mu opioid receptor involvement in the analgesic activity of various opioid ligands. J Pharmacol Exp Ther 241:374–378

    PubMed  Google Scholar 

  • Zukin RS, Eghbali M, Olive D, Unterwald EM, Tempel A (1988) Characterization and visualization of rat and guinea pig brainκ opioid receptors: evidence forκ 1 andκ 2 opioid receptors. Proc Natl Acad Sci USA 85:4061–4065

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Michigan, 48109, Ann Arbor, MI, USA

    Jillian H. Broadbear, S. Stevens Negus, Eduardo R. Butelman & James H. Woods

  2. Department of Psychology, University of Michigan, 48109, Ann Arbor, MI, USA

    James H. Woods

  3. NIH-NIDDK, 20892, Bethesda, MD, USA

    Brian R. de Costa

Authors
  1. Jillian H. Broadbear
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Stevens Negus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eduardo R. Butelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian R. de Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James H. Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

A preliminary report of these findings was made at the International Narcotic/Research/Conference in Keystone, CO, June, 1992. This work was supported by USPHS grant DA 00254. Animals used in these studies were maintained in accordance with the University Committee on Use and Care of Animals, University of Michigan, and guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1983)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Broadbear, J.H., Stevens Negus, S., Butelman, E.R. et al. Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on κ-opioid agonists in the mouse writhing assay. Psychopharmacology 115, 311–319 (1994). https://doi.org/10.1007/BF02245071

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02245071

Key words

Search

Navigation