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Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure

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Abstract

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphine's discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.

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References

  • Barry H (1974) Classification of drugs according to their discriminable effects in rats. Fed Proc 33:1814–1824

    PubMed  Google Scholar 

  • Bryant RM, Olley JE, Tyers MB (1983) Antinociceptive actions of morphine and buprenorphine given intrathecally in the conscious rat. Br J Pharmacol 78:659–663

    PubMed  Google Scholar 

  • Chang KJ, Cuatrecasas P (1981) Heterogeneity and properties of opiate receptors. Fed Proc 40:2729–2734

    PubMed  Google Scholar 

  • Colpaert FC, Janssen PAJ (1984) Agonist and antagonist effects of prototype opiate drugs in rats discriminating fentanyl from saline: characteristics of partial generalization. J Pharmacol Exp Ther 230:193–199

    PubMed  Google Scholar 

  • Cooper SJ, Moores WR, Jackson A, Barber DJ (1985) Effects of tifluadom on food consumption compared with chlordiazepoxide and kappa agonists in the rat. Neuropharmacology 24:877–883

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Cowan A, Lewis JW, MacFarlane IR (1977) Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol 60:537–545

    PubMed  Google Scholar 

  • Cowan A, Zhu XZ, Porecca F (1985) Studies in vivo with ICI174,864 and [D-Pen2, D-Pen5] enkephalin. Neuropeptides 5:311–314

    Article  PubMed  Google Scholar 

  • Demoliou-Mason CD, Barnard EA (1986) Distinct subtypes of the opioid receptor with allosteric interactions in brain membranes. J Neurochem 46:1118–1128

    PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278

    PubMed  Google Scholar 

  • Doty P, Picker MJ, Dykstra LA (1989) Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation. Eur J Pharmacol 174:171–180

    Article  PubMed  Google Scholar 

  • Dum J, Blasig J, Herz A (1981) Buprenorphine: demonstration of physical dependence liability. Eur J Pharmacol 70:293–300

    Article  PubMed  Google Scholar 

  • Dykstra LA (1985) Effects of buprenorphine on shock titration in squirrel monkeys. J Pharmacol Exp Ther 235:20–25

    PubMed  Google Scholar 

  • Dykstra LA, Massie CA (1988) Antagonism of the analgesic effects of mu and kappa opioid agonists in the squirrel monkey. J Pharmacol Exp Ther 246:813–821

    PubMed  Google Scholar 

  • France CP, Jacobson AE, Woods JH (1984) Discriminative stimulus effects of reversible and irreversible opiate agonists: morphine, oxymorphazone and buprenorphine. J Pharmacol Exp Ther 230:652–657

    PubMed  Google Scholar 

  • Gauvin DV, Young AM (1989a) Perceptual masking of drug stimuli. Drug Dev Res 16:151–162

    Article  Google Scholar 

  • Gauvin DV, Young AM (1989b) Evidence for perceptual masking of the discriminative morphine stimulus. Psychopharmacology 98:212–221

    PubMed  Google Scholar 

  • Genovese RF, Dykstra LA (1986) Tifluadom's effects under electric shock titration and tail-immersion procedures in squirrel monkeys. Life Sci 39:1713–1719

    Article  PubMed  Google Scholar 

  • Hayes A, Kelly A (1985) Profile of activity of k receptor agonists in the rabbit vas deferens. Eur J Pharmacol 110:317–322

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Holaday JW, Long JB, Torella FC (1985) Evidence for κ, μ and δ opioid binding site interactions in vivo. Fed Proc 44:2860–2862

    Google Scholar 

  • Holtzman SG (1985) Discriminative stimulus properties of opioids that interact with mu, kappa and PCP/Sigma receptors. In: Seiden LS, Balster RL (eds) Behavioral pharmacology: the current status. Liss, New York, pp 131–147

    Google Scholar 

  • Howard AD, Sarne Y, Gioannini TJ, Hiller JM, Simon EJ (1986) Identification of distinct binding site subunits of mu and delta opioid receptors. Biochemistry 25:357–360

    PubMed  Google Scholar 

  • Huidobro-Toro JP, Parada S (1985) K-opiates and urination: pharmacological evidence for an endogenous role of the K-opiate receptor in fluid and electrolyte balance. Eur J Pharmacol 107:1–10

    Google Scholar 

  • Jackson HC, Sewell RDE (1984) The role of opioid receptor sub-types in tifluadom-induced feeding. J Pharm Pharmacol 36:683–686

    PubMed  Google Scholar 

  • Kenakin TP (1987) Pharmacologic analysis of drug-receptor interaction. Raven Press, New York, pp 183–204

    Google Scholar 

  • Kramer TH, Shook JE, Kazmierski W, Ayres EA, Wire WS, Hruby VJ, Burks TF (1989) Novel peptidic mu opioid antagonists: pharmacologic characterization in vitro and in vivo. J Pharmacol Exp Ther 249:544–551

    PubMed  Google Scholar 

  • Leander DJ (1983a) A kappa opioid effect: increased urination in the rat. J Pharmacol Exp Ther 224:89–94

    PubMed  Google Scholar 

  • Leander DJ (1983b) Further study of kappa opioids on increased urination. J Pharmacol Exp Ther 227:35–41

    PubMed  Google Scholar 

  • Leander DJ (1984) K-opioid diuretic effects of tifluadom, a benzodiazepine opioid agonist. J Pharm Pharmacol 36:555–556

    PubMed  Google Scholar 

  • Leander DJ (1985) Behavioral effects of agonist and antagonist actions at kappa opioid receptors. In: Seiden LS, Balster RL (ed) Behavioral pharmacology: the current status. Liss, New York, pp 93–110

    Google Scholar 

  • Leander DJ (1987) Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacology. 26:1445–1447

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Magnan J, Stewart JP, 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 non-dependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532

    PubMed  Google Scholar 

  • Mucha RF, Herz A (1985) Motivational properties of kappa- and mu- opioid receptor agonists studied with place and taste preference conditioning procedures. Psychopharmacology 86:274–280

    Article  PubMed  Google Scholar 

  • Negus SS, and Dykstra LA (1988) Kappa antagonist properties of buprenorphine in the shock titration procedure. Eur J Pharmacol 156:77–86

    Article  PubMed  Google Scholar 

  • Negus SS, Picker MJ, Dykstra LA (1989) Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats. Psychopharmacology 98:141–143

    Google Scholar 

  • Nencini P, Woolverton WL (1988) Effects of nimodipine on the discriminative stimulus properties ofd-amphetamine in rats. Psychopharmacology 96:40–44

    PubMed  Google Scholar 

  • Overton DA (1988) Similarities and differences between behavioral control by drug-produced stimuli and by sensory stimuli. In: Corpert FC, Balster RL (ed) Transduction mechanisms of drug stimuli. Springer, Berlin Heidelberg New York, pp 176–198

    Google Scholar 

  • Petrillo P, Gambino MC, Tavani 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 

  • Picker MJ, Doty P, Negus SS, Mattox SR, Dykstra LA (1990) Discriminative stimulus properties of U50,488 and morphine: effects of training dose on stimulus substitution patterns produced by mu and kappa opioid agonists. J Pharmacol Exp Ther 254:13–22

    PubMed  Google Scholar 

  • Ramarao P, Jablonski HI, Rehder KR, Bhargava NH (1988) Effect of k-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats. Eur J Pharmacol 156:239–246

    Article  PubMed  Google Scholar 

  • Richards ML, Sadee W (1985) Buprenorphine is an antagonist at the kappa opioid receptor. Pharmacol Res 2:178–181

    Article  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 agonist. Life Sci 27:971–978

    Article  PubMed  Google Scholar 

  • Rothman RB, Westfall TC (1982) Allosteric coupling between morphine and enkephalin receptors in vitro. Mol Pharmacol 21:548–557

    PubMed  Google Scholar 

  • Rothman RB, Bykov V, Long JB, Brady LS, Jacobson AE, Rice KC, Holaday JW (1989) Chronic administration of morphine and naltrexone up-regulate mu-opioid binding sites labeled by [3H]D-Ala2,MePhe4,Gly-ol5]enkephalin: further evidence for two mu-opioid binding sites. Eur J Pharmacol 160:71–82

    Article  PubMed  Google Scholar 

  • Shannon HE, Cone EJ, Gorodetzky CW (1984) Morphine-like discriminative stimulus effects of buprenorphine and demethoxybuprenorphine in rats: quantitative antagonism by naloxone. J Pharmacol Exp Ther 229:768–774

    PubMed  Google Scholar 

  • Sheldon RJ, Nunan L, Porreca F (1987) Mu antagonist properties of kappa agonists in a model of urinary bladder motility in vivo. J Pharmacol Exp Ther 243:234–240

    PubMed  Google Scholar 

  • Smith JR, Simon EJ (1980) Selective protection of stereospecific enkephalin and opiate binding against inactivation by N-ethylmaleimide: evidence for two classes of opiate receptors. Proc Natl Acad Sci USA 77:281–284

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Ureta H, Lopez LF, Perez A, Huidobro-Toro JP (1987) K-opiate-induced diuresis and changes in blood pressure: demonstration of receptor stereoselectivity using (+)- and (−)-tifluadom. Eur J Pharmacol 135:289–295

    Article  PubMed  Google Scholar 

  • Von Voigtlander PF, Lahti RA, Ludens JH (1983) U50,488: a selective and structurally novel non-mu (kappa) opioid agonist. J Pharmacol Exp Ther 224:7–12

    PubMed  Google Scholar 

  • Wood PL, Charleson SE, Lane D, Hudgin RL (1981) Multiple opiate receptors: differential binding of mu, kappa and delta agonists. Neuropharmacology 20:1215–1220

    Article  PubMed  Google Scholar 

  • Wood PL, Sanschagrin D, Richard JW, Thakur M (1983) Multiple opiate receptor affinities of kappa and agonist/antagonist analgesics: in vivo assessment. J Pharmacol Exp Ther 226:545–550

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Curriculum in Neurobiology, University of North Carolina, 27599, Chapel Hill, NC, USA

    S. Stevens Negus

  2. Department of Psychology, University of North Carolina, 27599, Chapel Hill, NC, USA

    Mitchell J. Picker & Linda A. Dykstra

  3. Department of Pharmacology, University of North Carolina, 27599, Chapel Hill, NC, USA

    Linda A. Dykstra

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  1. S. Stevens Negus
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  2. Mitchell J. Picker
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  3. Linda A. Dykstra
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Negus, S.S., Picker, M.J. & Dykstra, L.A. Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure. Psychopharmacology 102, 465–473 (1990). https://doi.org/10.1007/BF02247126

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  • DOI: https://doi.org/10.1007/BF02247126

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