Abstract
Purpose: Management of neonatal opioid tolerance and withdrawal symptoms remains a major clinical challenge in NICUs. Numerous neuromodulators are involved in tolerance and withdrawal mechanisms. We have previously shown that central endothelin (ET) receptors are involved in morphine tolerance. The purpose of this study is to investigate the involvement of central ET receptors in morphine withdrawal in neonatal rats.
Methods: Pregnant rats were divided into two groups and rendered tolerant to placebo and morphine pellets, respectively, over a 7-day period. On day 8, both placebo and morphine pellets were removed and rats were allowed to undergo withdrawal for 24 hours. Rat pups were delivered by c-section. Neonatal rat brains were dissected and used for analysis. Changes in G-protein stimulation were determined by using [(35)S]-guanosine-5′-o-(3-thio)triphosphate ([35S]GTPγS) binding assay in the brain of neonatal rats undergoing placebo and morphine withdrawal.
Results: Morphine produced significantly higher (P<0.05) maximal stimulation in neonatal rats undergoing morphine withdrawal (83.60%) when compared to placebo (66.81%). EC50 values in morphine withdrawal group (6.825nM) were significantly lower (P<0.05) as compared to placebo (72.917nM). A significant increase in maximal G-protein stimulation was observed with ET-1 in the morphine withdrawal group (87.16%, P<0.05) as compared to placebo (74.88%). EC50 values for ET-1 in neonatal rats undergoing morphine withdrawal (93.75nM) were significantly higher (P<0.05) than placebo (62.5nM). ETA receptor antagonist, BMS182874, did not stimulate GTP binding in placebo brains (EC501000nM), but significantly increased (P<0.05) maximal stimulation of G-proteins in morphine withdrawal group (86.07%, EC50=31.25nM). ETB agonist, IRL1620-induced stimulation of G-proteins was similar in placebo (73.43%, EC50=13.26nM) and morphine withdrawal (75.08%, EC50=11.70nM), respectively.
Conclusion: Morphine-induced G-protein activation is increased while ET-1 induced G-protein activation is decreased in neonates undergoing morphine withdrawal. ETA antagonist increases activation of G-proteins during withdrawal in neonates. In conclusion we provide evidence for the first time that central ETA and not ETB receptors are involved in morphine withdrawal.
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Puppala, B., Bhalla, S., Matwyshyn, G. et al. Involvement Of Endothelin Receptors in Neonatal Morphine Withdrawal.. Pediatr Res 56, 670 (2004). https://doi.org/10.1203/00006450-200410000-00045
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DOI: https://doi.org/10.1203/00006450-200410000-00045