Psychopharmacology

, Volume 118, Issue 4, pp 444–450 | Cite as

Kappa opioid agonists produce anxiolytic-like behavior on the elevated plus-maze

  • T. H. Privette
  • D. M. Terrian
Original Investigation

Abstract

The selectivek agonist U-50,488H was evaluated on the elevated plus-maze test of anxiety. U-50,488H was administered intraperitoneally to male Sprague-Dawley rats 20 min before testing, first in an open field apparatus, then followed immediately on the elevated plus-maze. No significant change in spontaneous locomotor activity was measured in the open field apparatus, suggesting that U-50,488H was devoid of sedative effects in the dose range tested (0.1–1000 µg/kg, IP). Doses between 10 and 1000 µg/kg produced significant increases in elevated plus-maze behavior that were consistent with anxiolytic actions for U-50,488H. These anxiolytic-like effects were antagonized by naloxone (2.0 mg/kg, IP), suggesting an opioid receptor site of action. In addition, we tested thek1-selective U-50,488H-derivative, U-69,593 (100 µg/kg, IP), which was also shown to mimic the anxiolytic-like effects produced by U-50,488H. These results suggest that low doses of the selectivek1 agonists U-50,488H and U-69,593 are endowed with anxiolytic properties in rodents and that thek opioid system may be involved in the behavioral response to anxiety.

Key words

Opioids Stress Anxiety Rat Benzeneacetamides H-50,488H U-69,593 Naloxone Open field Spontaneous locomotor activity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bals-Kubic B, Herz A, Shippenberg TS (1989) Evidence that the aversive effects of opioid antagonists andκ-agonists are centrally mediated. Psychopharmacology 98:203–206Google Scholar
  2. Barr GA, Wang S, Carden S (1994) Aversive properties of theκ opioid agonist U-50,488 in the week-old rat pup. Psychopharmacology 113:422–428Google Scholar
  3. Bechara A, Van der Kooy K (1987) Kappa receptors mediate the peripheral aversive effects of opiates. Pharmacol Biochem Behav 28:227–233Google Scholar
  4. Bock MG, DiPardo RM, Evans BE, Rittle KE, Whitter WL, Veber DF, Friedinger RM, Chang RSL, Chen TB, Lotti VJ (1990) Cholecystokinin-A receptor ligands based on theκ-opioid agonist tifluadom. J Med Chem 33:450–455Google Scholar
  5. Brioni JD, O'Neill AB, Kim DJB, Decker MW (1993) Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze. Eur J Pharmacol 238:1–8Google Scholar
  6. Bueno L, Gue M, Fargeas MJ, Alvinerie M, Junien JL, Fioramonti J (1989) Vagally mediated inhibition of acoustic stress-induced cortisol release by orally administeredκ-opioid substances in dogs. Endocrinology 124:1788–1793Google Scholar
  7. Chappell PB, Leckman JF, Scahill LD, Hardin MT, Anderson G, Cohen DJ (1993) Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in tourette's syndrome: a pilot study. Psychiatry Res 47:267–280Google Scholar
  8. Christmas AJ, Maxwell DR (1970) A comparison of the effects of some benzodiazepines and other drugs on aggressive and exploratory behaviour in mice and rats. Neuropharmacology 9:17–29Google Scholar
  9. Corbett AD, Peterson SJ, McKnight AJ, Magnan J, Kosterlitz HW (1982) Dynorphin 1–8 and dynorphin 1–9 are ligands for theκ subtype of opiate receptor. Nature 299:79–81Google Scholar
  10. Cunha JM, Masur J (1978) Evaluation of psychotropic drugs with a modified open field test. Pharmacology 16:259–267Google Scholar
  11. Dykstra LA, Powell KR, Lin Y-P (1993) Antinocioceptive effects of the kappa opioid, U-50,488: lack of modulation by 5-HT2 antagonists. Psychopharmacology 112:116–120Google Scholar
  12. Fallon JH, Leslie FM (1986) Distribution of dynorphin and enkephalin peptides in the rat brain. J Comp Neurol 249:293–336Google Scholar
  13. Feuerstein G, Faden AI (1984) Cardiovascular effects of dynorphin A-(1-13) and dynorphin A-(1-17) microinjected into the preoptic medialis nucleus of the rat. Neuropeptides 5:295–298Google Scholar
  14. File SE (1990) Interactions of anxiolytic and antidepressant drugs with hormones of the hypothalamic-pituitary-adrenal axis. Pharmacol Ther 46:357–375Google Scholar
  15. File SE, Hitchcott PK (1990) A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomenon. Psychopharmacology 101:525–532Google Scholar
  16. Grant EC, Mackintosh JH (1963) A comparison of the social postures of some common laboratory rodents. Behaviour 2:246–259Google Scholar
  17. Handley SL, McBlane JW (1993a) 5HT drugs in animals models of anxiety. Psychopharmacology 112:13–20Google Scholar
  18. Handley SL, McBlane JW (1993b) As assessment of the elevated X-maze for studying anxiety and anxiety-modulating drugs. J Pharmacol Methods 29:129–138Google Scholar
  19. Heinrichs SC, Pich EM, Miczek KA, Britton KT, Koob GF (1992) Corticotropin -releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action. Brain Res 581:190–197Google Scholar
  20. Ho BY, Takamori AE (1989) Serotonergic involvement in the antinociceptive active of and the development of tolerance to the kappa-opioid receptor agonist, U-50,488H. J Pharmacol Exp Ther 250:508–514Google Scholar
  21. Ho BY, Takamori AE (1990) Release by U-50,488H of [3H]serotonin from brain slices and spinal cord synaptosomes of U-50,488H-tolerant and nontolerant mice. J Pharmacol Exp Ther 254:8–12Google Scholar
  22. Hughes J, Boden P, Costall B, Domeney A, Kelly E, Horwell DC, Hunter JC, Pinnock RD, Woodruff GN (1990) Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci 87:6728–6732Google Scholar
  23. Iwamoto ET (1988) Dynorphin A (1–17) induces reward in rats in the place conditioning paradigm, Life Sci 43:503–508Google Scholar
  24. Lyengar S, Kim HS, Wood PL (1987) Mu, delta, kappa and sigma opioid receptor modulation of the hypothalamic, pituitary, adrenocortical (HPA) axis: subchronic tolerance studies of endogenous opioid peptides. Brain Res 435:220–228Google Scholar
  25. Jhamandas K, Sutak M, Lemaire S (1986) Comparative analgesic action of dynorphin-1-8, dynorphin-1-13, and aκ receptor agonist U-50,488. Can J Physiol Pharmacol 64:263–268Google Scholar
  26. Jones B, Costall B, Domeney A, Kelly M, Naylor R, Oakley N, Tyers M (1988) The potential anxiolytic effect of GR38032F, a 5-HT3 receptor antagonist. Br J Pharmacol 93:985–990Google Scholar
  27. Lahti RA, Mickelson, MM, McCall JM, Von Voightlander PF (1985) [3H]U-69593 a highly selective ligand for the opioidκ receptor. Eur Pharmacol 109:281–284Google Scholar
  28. Lee C, Rodgers RJ (1990) Antinociceptive effects of elevated plusmaze exposure: influence of opiate receptor manipulations. Psychopharmacology 102:507–513Google Scholar
  29. Lister RG (1990) Ethologically-based animal models of anxiety disorders. Pharmacol Ther 46:321–340Google Scholar
  30. Morris BJ, Herz A (1986) Autoradiographic localization in rat brain ofκ opiate binding sites labelled by [3H]bremazocine. Neuroscience 19:839–846Google Scholar
  31. Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology 86:274–280Google Scholar
  32. New JS (1990) The discovery and development of buspirone: a new approach to the treatment of anxiety. Med Res Rev 10:283–293Google Scholar
  33. Nock B, Rajpara A, O'Connor LH, Cicero T (1988) Autoradiography of [3H]U-69593 binding sites in the brain: evidence forκ opioid receptor subtypes. Eur J Pharmacol 154:27–34Google Scholar
  34. Nova Screen®/National Institute of Mental Health Psychotherapeutic Drug Discover and Development Program (1994). Receptor binding assays performed by NovaScreen®, Hanover, Maryland, report no. BCN 17611Google Scholar
  35. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167Google Scholar
  36. Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated byκ opiate receptors. Science 233:774–776Google Scholar
  37. Powell KR, Picker MJ, Dykstra LA (1993) The role of serotonin in the discriminative stimulus effects of mu- and kappa-opioids. Soc Neurosci Abstr 19:1459Google Scholar
  38. Privette TH, Terrain DM (1993) Reversal of colchicine-induced hyperlocomotion by the kappa opioid agonist U-50,488H. Trans Am Soc Neurochem vol. 24:101Google Scholar
  39. Privette TH, Wang JQ, Ingenito AJ, Terrian DM (1994) Dentate granule cells as a central cardioregulatory site in the rat. Brain Res 656:295–301Google Scholar
  40. Römer D, Büscher HH, Hill RC, Maurer R, Petcher TJ, Zeugner H, Benson W, Finner E, Milkowski W, Thies PW (1982) An opioid benzodiazepine. Nature 298:759–760Google Scholar
  41. Sapolsky R, Krey L, McEwen B (1984) Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. Proc Natl Acad Sci USA 81:6174–6177Google Scholar
  42. Stanley BG, Lanthier D, Leibowitz SF (1989) Multiple brain sites sensitive to feeding stimulation by opioid agonists: a cannulaemapping study. Pharmacol Biochem Behav 31:825–832Google Scholar
  43. Stevens KE, Shiotsu G, Stein L (1991) Hippocampal μ-receptors mediate opioid reinforcement in the CA3 region. Brain Res 545:8–16Google Scholar
  44. Szmuszkovicz J, Von Voightlander PF (1982) Benzeneacetamide amines: structurally novel non-mu opioids. J Med Chem 25:1125–1126Google Scholar
  45. Thai L, Lee PHK, Ho J, Suh H, Hong JS (1992) Regulation of prodynorphin gene expression in the hippocampus by glucocorticoids. Mol Brain Res 16:150–157Google Scholar
  46. Van der Poel (1979) A note on “stretched attention”, a behavioural element indicative of an approach-avoidance conflict in rats. Anim Behav 27:446–450Google Scholar
  47. Von Voigtlander PF, Lahti RA, Ludens JH (1983) U-50,488: a selective and structurally novel non-mu (kappa) opioid agonist. J Pharmacol Exp Ther 224:7–12Google Scholar
  48. Von Voightlander PF, Lewis RA, Neff GL (1984) Kappa opioid analgesia is dependent on serotonergic mechanisms. J Pharmacol Exp Ther 231[2]:270–274Google Scholar
  49. Wada T, Fukuda N (1991) Effects of DN-2327, a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze. Psychopharmacology 104:444–450Google Scholar
  50. Wollemann M, Benyhe S, Simon J (1993) The kappa opioid receptor: evidence for the different subtypes. Life Sci 52:599–611Google Scholar
  51. Xie Z, Commissaris RL (1992) Anxiolytic-like effects of the non-competitive NMDA antagonist MK 801 (1992) Pharmacol Biochem Behav 43:471–477Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • T. H. Privette
    • 1
  • D. M. Terrian
    • 1
  1. 1.Department of Anatomy and Cell BiologyEast Carolina University School of MedicineGreenvilleUSA

Personalised recommendations