title: Role of endothelin in neonatal morphine tolerance.
abstract: Management of neonatal opioid tolerance and withdrawal symptoms remains a major challenge in neonatal intensive care units. We provide evidence that central endothelin (ET) mechanisms are involved in the development of morphine tolerance in neonatal rats. Pregnant rats were rendered tolerant to morphine and rat pups were delivered by cesarean section. The effect of morphine tolerance on characteristics of ET receptors in neonatal rats was determined. The affinity (Kd) and density (Bmax) of [I]ET-1 binding in the brain was found to be similar in placebo and morphine-tolerant neonatal rats. Morphine and ET-1-induced G-protein stimulation was determined in placebo and morphine-tolerant neonatal rats by [S]GTPgammaS binding assay. Morphine produced significantly lower (P < 0.05) maximal stimulation in morphine-tolerant neonatal rats (33.10%) when compared with placebo-treated neonatal rats (90.90%). Maximal stimulation produced by ET-1 in morphine-tolerant neonatal rats (41.26%) was also significantly lower (P < 0.05) as compared with placebo-treated neonatal rats (92.23%). This is the first report indicating the involvement of ET in neonatal morphine tolerance as evidenced by attenuation of ET-1-induced stimulation of GTP binding in neonatal rats tolerant to morphine.
authors.affiliation: Department of Pediatrics and Neonatology, Advocate Lutheran General Children's Hospital, Park Ridge, Illinois, USA.
authors.forename: Bhagya L
authors.initials: BL
authors.lastname: Puppala
authors.forename: George
authors.initials: G
authors.lastname: Matwyshyn
authors.forename: Shaifali
authors.initials: S
authors.lastname: Bhalla
authors.forename: Anil
authors.initials: A
authors.lastname: Gulati
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004361:Drug Tolerance; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009020:Morphine / Q000008:administration & dosage*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000378:metabolism; D013462:Sulfur Radioisotopes
chemical_list: D000701:Analgesics, Opioid; D004343:Drug Implants; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D019204:GTP-Binding Proteins