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Updated: Aug 23, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Evidence that morphine tolerance may be regulated by endothelin in the neonatal rat
Bhagya L Puppala1, George Matwyshyn, Shaifali Bhalla
1Department of Pediatrics and Neonatology, Advocate Lutheran General Children's Hospital, Park Ridge, IL, USA.
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.
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