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Experimental Biology and Medicine 231:1157-1160 (2006)
© 2006 Society for Experimental Biology and Medicine

PAIN

Involvement of Central Endothelin Receptors in Neonatal Morphine Withdrawal

Bhagya L. Puppala*, Shaifali Bhalla{dagger}, George Matwyshyn{dagger} and Anil Gulati{dagger},1

* Department of Pediatrics and Neonatology, Advocate Lutheran General Children’s Hospital, Park Ridge, Illinois 60068; and {dagger} Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60612

To whom requests for reprints should be addressed at 1 Department of Biopharmaceutical Sciences (M/C 865), The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612. E-mail: gulati{at}uic.edu

Abstract

The involvement of central endothelin (ET) receptors in neonatal morphine tolerance has been demonstrated. The present study investigates the role of central ET receptors in morphine withdrawal in neonatal rats. The aim was to determine whether activation of G-proteins coupled to opioid and ET receptors by morphine and various ET receptor modulators is affected during morphine withdrawal in neonatal rats. Pregnant female rats were rendered tolerant to morphine by chronic exposure to morphine pellets during 7 days. On Day 8, pellets were removed and rats were allowed to undergo withdrawal for 24 hrs. Rat pups were delivered by cesarean section. G-protein stimulation induced by morphine; ET-1; the ETA receptor antagonist, BMS182874; and the ETB receptor agonist, IRL1620, were determined in the brain of neonatal rats undergoing morphine withdrawal by [35S]GTP{gamma}S binding assay. Morphine produced higher (P < 0.05) maximal stimulation of G-protein in the morphine-withdrawal group (83.60%) compared with the placebo group (66.81%). ET-1–induced G-protein stimulation was also altered, and the median effective concentration (EC50) during morphine withdrawal (170.60 nM) was significantly higher than placebo (62.5 nM; P< 0.05). The maximal stimulation induced by the ETA receptor antagonist, BMS182874, in the morphine-withdrawal group (86.07%; EC50 = 31.25 nM) was significantly higher than in the placebo group (EC50 > 1000 nM). The ETB agonist, IRL1620, induced G-protein stimulation was similar in placebo (73.43%, EC50 = 13.26 nM) and morphine-withdrawal groups (75.08%, EC50 = 11.70 nM), respectively. To our knowledge, this is the first report indicating involvement of central ETA receptors in neonatal morphine withdrawal.

Key Words: morphine • BMS182874 (5-[dimethylamino]-N-[3,4-dimethyl-5-isoxazolyd]-1-naphthalenesulfonamide) • IRL1620 (N-Suc-[Glu9, Ala11,15]ET-1[8–21]) • [35S]GTP{gamma}S-binding withdrawal • endothelin • neonatal rats • central nervous system






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