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


OBJECTIVE
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.
Puppala
Bhagya L
BL
Department of Pediatrics and Neonatology, Advocate Lutheran General Children's Hospital, Park Ridge, IL, USA.
Matwyshyn
George
G
Bhalla
Shaifali
S
Gulati
Anil
A
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D003619:Dansyl Compounds / Q000494:pharmacology; D004361:Drug Tolerance; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010919:Placebos; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000819:agonists / Q000502:physiology; D017466:Receptors, Endothelin / Q000032:analysis / Q000378:metabolism
D003619:Dansyl Compounds; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D010919:Placebos; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C074308:sovateltide; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D019204:GTP-Binding Proteins