Evidence that morphine tolerance may be regulated by endothelin in the neonatal rat

Biol Neonate. 2004;86(2):138-44. doi: 10.1159/000079272. Epub 2004 Jun 22.


Background: Opioids are widely used in the neonatal intensive care units for analgesia and sedation. Management of tolerance and withdrawal symptoms in neonates remains a major challenge.

Objectives: The present study investigates the involvement of a central endothelin (ET) mechanism in the development of tolerance to morphine in neonatal rats.

Methods: Pregnant female rats were rendered tolerant to morphine and rat pups were delivered at term by cesarean section. The affinity (Kd) and density (Bmax) of ET receptors was determined by [125I]ET-1 binding in the brains of neonatal rats. Changes in G-protein stimulation were determined in placebo and morphine-tolerant neonatal rats by [35S]-guanosine-5'-o-(3-thio)triphosphate ([35S]GTPgammaS)-binding assay.

Results: Morphine tolerance did not affect the characteristics (affinity and density) of the ET receptors in the neonatal rat brains. Morphine as well as ET-1 produced significantly lower (p < 0.05) maximal stimulation of [35S]GTPgammaS binding in morphine-tolerant neonatal rats compared to the placebo group. The ETA receptor antagonist, BMS182874, produced significantly higher stimulation of G proteins in the morphine-tolerant compared to the placebo group. The ETB receptor agonist, IRL1620, produced a similar effect in both placebo and morphine-tolerant rats.

Conclusions: This is the first report indicating the involvement of the G-protein-coupled ETA receptor in neonatal morphine tolerance.

MeSH terms

  • Animals
  • Animals, Newborn*
  • Brain / metabolism
  • Brain Chemistry
  • Dansyl Compounds / pharmacology
  • Drug Tolerance*
  • Endothelin A Receptor Antagonists
  • Endothelin-1 / metabolism
  • Endothelin-1 / pharmacology
  • Endothelins / pharmacology
  • Endothelins / physiology*
  • Female
  • GTP-Binding Proteins / physiology
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Morphine* / pharmacology
  • Peptide Fragments / pharmacology
  • Placebos
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A / physiology
  • Receptor, Endothelin B / agonists
  • Receptor, Endothelin B / physiology
  • Receptors, Endothelin / analysis
  • Receptors, Endothelin / metabolism


  • Dansyl Compounds
  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • Endothelins
  • Peptide Fragments
  • Placebos
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Receptors, Endothelin
  • sovateltide
  • 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Morphine
  • GTP-Binding Proteins