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

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

Author information

1
Department of Pediatrics and Neonatology, Advocate Lutheran General Children's Hospital, Park Ridge, IL, USA.

Abstract

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.

PMID:
15218283
DOI:
10.1159/000079272
[Indexed for MEDLINE]

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