Abstract
The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01–10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1–10 mg/kg) but not by the mu selective antagonist naloxone (0.1–30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED50 values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1–1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adams JU, Paronis CA, Holtzman SG (1990) Assessment of relative intrinsic activity of mu-opioid analgesics in vivo using β-funaltrexamine. J Pharmacol Exp Ther 255:1027–1032
Butelman ER, Negus SS, Gatch MB, Chang K-J, Woods JH (1995) BW373U86, a δ-opioid receptor agonist, reverses bradykinin-induced thermal allodynia in rhesus monkeys. Eur J Pharmacol 277:285–287
Calcagnetti DJ, Holtzman SG (1991) Delta opioid antagonist, naltrindole, selectively blocks analgesia induced by DPDPE but not DAGO or morphine. Pharmacol Biochem Behav 38:185–190
Chang K-J, Rigdon GC, Howard JL, McNutt RW (1993) A novel, potent and selective nonpeptidic delta opioid receptor agonist BW373U86. J Pharmacol Exp Ther 267:852–857
Colpaert FC (1978) Discriminative stimulus properties of narcotic analgesic drugs. Pharmacol Biochem Behav 9:863–887
Comer SD, McNutt RW, Chang K-J, DeCosta BR, Mosberg HI, Woods JH (1993) Discriminative stimulus effects of BW373U86: a nonpeptide ligand with selectivity for delta opioid receptors. J Pharmacol Exp Ther 267:866–874
Cotton R, Giles MG, Miller L, Shaw JS, Timms D (1984) ICI 174,864: a highly selective antagonist for the opioid δ-receptor. Eur J Pharmacol 97:331–332
Drower EJ, Stapelfeld A, Rafferty MF, DeCosta BR, Rice KC, Hammond DL (1991) Selective antagonism by naltrindole of the antinociceptive effects of the delta opioid agonist cyclic [d-penicillamine2-d-penicillamine5]enkephalin in the rat. J Pharmacol Exp Ther 259:725–731
Dykstra LA, Gmerek DE, Winger G, Woods JH (1987) Kappa opioids in rhesus monkeys. II. Analysis of the actions of quadazocine and β-funaltrexamine. J Pharmacol Exp Ther 242:421–427
Dykstra LA, Schoenbaum GM, Yarbrough J, McNutt R, Chang K-J (1993) A novel delta opioid agonist, BW373U86, in squirrel monkeys responding under a schedule of shock titration. J Pharmacol Exp Ther 267:875–882
Hayes AG, Sheehan MJ, Tyers MB (1987) Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig to μ- and k-opioid receptor agonists. Br J Pharmacol 91:823–832
Herling S, Woods JH (1981) Discriminative stimulus effects of etorphine in rhesus monkeys. Psychopharmacology 72:265–267
Heyman JS, Mulvaney SA, Mosberg HI, Porreca F (1987) Opioid δ-receptor involvement in supraspinal and spinal antinociception in mice. Brain Res420:100–108
Heyman JS, Vaught JL, Mosberg HI, Haaseth R, Porreca F (1989) Modulation of μ-mediated antinociception by δ agonists in the mouse: selective potentiation of morphine and normorphine by [d-Pen,d-Pen]enkephalin. Eur J Pharmacol 165:1–10
Jiang Q, Mosberg HI, Porreca F (1990) Modulation of the potency and efficacy of mu-mediated antinociception by delta agonists in the mouse. J Pharmacol Exp Ther 254:683–689
Kovacs GL, Nyolczas N, Krivan M, Gulya K (1988) Analgesic and tolerance-inducing effects of the highly selective δ opioid agonists [d-Pen2,d-Pen5]enkephalin in mice. Eur J Pharmacol 150:347–353
Locke KW, Holtzman SG (1986) Behavioral effects of opioid peptides selective for mu or delta receptors. I. Morphine-like discriminative stimulus effects. J Pharmacol Exp Ther 238:990–996
Locke KW, Gorney B, Cornfeldt M, Fielding S (1989) Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat. Psychopharmacology 99:492–496
Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499
Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1987) Autoradiographic differentiation of mu, delta and kappa opioid receptors in rat forebrain and midbrain. J Neurosci 7:2445–2464
Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert P (1976) The effects of morphine-and nalorphine-like drugs in the non-dependent and morphine-dependent dog. J Pharmacol Exp Ther 197:517–532
Miller L, Shaw JS, Whiting EM (1986) The contribution of intrinsic activity to the action of opioids in vivo. Br J Pharmacol 87:595–601
Mosberg HI, Hurst R, Hruby VJ, Gee K, Akiyama K, Yamamura HI, Galligan JJ, Burks TF (1983) Bis-penicillamine enkephalins possess highly improved specificity toward δ receptors. Proc Natl Acad Sci USA 80:5871–5874
Negus SS, Picker MJ (1996) BW373U86: A non-peptidic, systemically-active δ-opioid agonist. CNS Drug Rev 2:52–74
Negus SS, Butelman ER, Chang K-J, DeCosta BR, Winger G, Woods JH (1994) Behavioral effects of the systemically active delta opioid agonist BW373U86 in rhesus monkeys. J Pharmacol Exp Ther 270:1025–1034
Picker MJ, Dykstra LA (1989) Discriminative stimulus effects of mu and kappa opioids in the pigeon: analysis of the effects of full and partial mu and kappa agonists. J Pharmacol Exp Ther 249:557–566
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
Picker MJ, Yarbrough J, Hughes CE, Smith MA, Morgan D, Dykstra LA (1993) Agonist and antagonist effects of mixed action opioids in the pigeon drug discrimination procedure: influence of training dose, intrinsic efficacy and interanimal differences. J Pharmacol Exp Ther 266:756–767
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
Smith MA, Benyas S, Thompson K, Horwitz JA, Picker MJ (1996) Discriminative stimulus effects of butorphanol: involvement of mu, kappa and delta opioid receptor activity
Tallarida RJ, Murray RB (1987) Manual of pharmacologic calculations with computer programs. Springer, New York
Ukai M, Holtzman SG (1988) Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory roled-Ala2-d-Leu5-enkaphalin (DADL) and dynorphin A(1-13). Psychopharmacology 94:32–37
Vaught JL, Takemori AE (1979) Differential effects of leucine enkephalin and methionine enkephalin on morphine-induced analgesia, acute tolerance and dependence. J Pharmacol Exp Ther 208:86–90
Vaught JL, Rothman RB, Westfall TC (1982) Mu and delta receptors: their role in analgesia and in the differential effects of opioid peptides on analgesia. Life Sci 30:1443–1455
Walker EA, Makhay MM, House JD, Young AM (1994) In vivo apparent pA2 analysis for naltrexone antagonism of discriminative stimulus and analgesic effects of opiate agonists in rats. J Pharmacol Exp Ther 271:959–968
Wild KD, McCormick J, Bilsky EJ, Vanderah T, McNutt RW, Chang K-J, Porreca F (1993) Antinociceptive actions of BW373U86 in mouse. J Pharmacol Exp Ther 267:858–865
Wood PL, Charleson SE, Lane D, Hudgin RL (1981) Multiple opioid receptors: differential binding of μ, k and δ agonists. Neuropharmacology 20:1215–1220
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Negus, S.S., Morgan, D., Cook, C.D. et al. Effects of the delta opioid agonist BW373U86 in pigeons trained to discriminate fentanyl, bremazocine and water in a three-choice drug discrimination procedure. Psychopharmacology 126, 199–205 (1996). https://doi.org/10.1007/BF02246449
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02246449