Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep

      This paper is only available as a PDF. To read, Please Download here.
      Objective: Our purpose was to assess the effects of an intravenous dose of a highly selective μ-(DALDA) and δ-(DPDPE) opioid peptide to determine which class of peptide has the best clinical potential.
      Study design: Chronically instrumented pregnant ewes recieved a 0.3 mg/kg intravenous bolus of each peptide with and without opioid receptor blockade by means of a randomized prospective design.
      Results: Intravenous DALDA produced only mild hypertension and a loss of heart rate variability, whereas DPDPE produced respiratory depression, maternal hypertension, and a fall in heart rate in both mother and fetus. Uterine blood flow, oxygen uptake, and glucose uptake were unchanged with both drugs. The effects of DALDA but not DPDPE were reversed by opioid receptor blockade.
      Conclusion: The δ-selective agonist had multiple nonopioid adverse effects, whereas the μ-selective agonist was well tolerated by the pregnant ewe, suggesting that μ-selective agonists have better potential for clinical use as an analgesic in pregnancy.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Martin WR
        Pharmacology of opioids.
        Pharmacol Rev. 1984; 35: 285-323
        • Brownstein MJ
        A brief history of opiates, opioid peptides and opioid receptors.
        in: Proc Natl Acad Sci. 90. 1993: 5391-5393
        • Clapp JF
        • Soong Y
        • Wu D
        • Olariu N
        • Yee J
        • Szeto HH
        Maternal cardiovascular and metabolic responses to intravenous Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol (DAMGO) in chronically instrumented pregnant sheep.
        Analgesia. 1996; 2: 137-143
        • Haddad GG
        • Schaeffer JI
        • Chang KJ
        Opposite effects of δ and μ-opioid receptor agonists on ventilation in conscious adult dogs.
        Brain Res. 1984; 323: 73-78
        • Kiritsy-Roy JA
        • Marson L
        • Van Loon GR
        Sympathoadrenal, cardiovascular and blood gas responses to highly selective mu and delta opioid peptides.
        J Pharmacol Exp Ther. 1989; 251: 1096-1103
        • Imai N
        • Kashiki M
        • Woolf PD
        • Liang C-S
        Comparison of cardiovascular effects of μ- and δ-opioid receptor agonists in dogs with congestive heart failure.
        Am J Physiol. 1994; 267: H912-H917
        • Gutkowska J
        • Schiller PW
        Renal effects of TAPP, a highly selective μ-opioid agonist.
        Br J Pharmacol. 1996; 119: 239-244
        • Uberti EC
        • Ambrosio MR
        • Vergnani L
        • Portaluppi F
        • Bondandelli M
        • Trasforini G
        • et al.
        Stress-induced activation of sympathetic nervous system is attenuated by the δ-opioid receptor agonist deltorphin in healthy man.
        J Clin Endocrinol Metab. 1993; 77: 1490-1494
      1. Hytten F Chamberlain G Clinical physiology in obstetrics. Blackwell Scientific, London1991
        • Clapp JF
        • Seaward BL
        • Sleamaker RH
        • Hiser J
        Maternal physiological adaptations to early human pregnancy.
        Am J Obstet Gynecol. 1988; 159: 1456-1460
        • Samii A
        • Bickel U
        • Stroth U
        • Pardridge WM
        Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue.
        Am J Physiol. 1994; 267: E124-E131
        • Greer JJ
        • Carter JE
        • Al-Zubaidy Z
        Opioid depression of respiration in neonatal rats.
        J Physiol. 1995; 485: 3
        • Greer JJ
        • Carter JE aiAl-Zubaidy^Z
        Opioid depression of respiration in neonatal rats.
        J Physiol. 1995; 485: 845-855
        • Schiller PW
        • Weltrowska G
        • Nguyen TM
        • Wilkes BC
        • Chung NN
        • Lemieux C
        TIPP[ψ]: a highly potent and stable pseudopeptide δ opioid receptor antagonist with extraordinary δ selectivity.
        J Med Chem. 1993; 36: 3182-3187
        • Winer BJ
        Statistical principles in experimental design.
        McGraw-Hill, Baltimore1971
        • Pfeiffer A
        • Feuerstein G
        • Kopin IJ
        • Faden AI
        Cardiovascular and respiratory effects of mu-, delta- and kappa-opiate agonists in-jected into the anterior hypothalamic brain area of awake rats.
        J Pharmacol Exp Ther. 1983; 225: 735-741
        • May CN
        • Dashwood MR
        • Whitehead CJ
        • Mathias CJ
        Differential cardiovascular and respiratory responses to central administration of selective opioid agonists in conscious rabbits: correlation with receptor distribution.
        J Pharmacol. 1989; 98: 903-913
        • Siren AL
        • Feuerstein G
        Hypothalamic opioid μ-receptors regulate discrete hemodynamic functions in the conscious rat.
        Neuropharmacol. 1991; 30: 143-152
        • Weitzell R
        • Illes P
        • Starke K
        Inhibition via opioid μ- and δ-receptors of vagal transmission in the rabbit.
        Arch Pharmacol. 1984; 328: 186-190