title: Adult responses to an ischemic stroke in a rat model of neonatal stress and morphine treatment.
abstract: Critically ill newborn infants experience stressors that may alter brain development. Using a rodent model, we previously showed that neonatal stress, morphine, and stress plus morphine treatments each influence early gene expression and may impair neurodevelopment and learning behavior. We hypothesized that the combination of neonatal stress with morphine may alter neonatal angiogenesis and/or adult cerebral blood vessel density and thus increase injury after cerebral ischemia in adulthood. To test this, neonatal Lewis rats underwent 8 h/d maternal separation, plus morning/afternoon hypoxia exposure and either saline or morphine treatment (2 mg/kg s.c.) from postnatal day 3-7. A subset received bromodeoxyuridine to track angiogenesis. Adult brains were stained with collagen IV to quantify cerebral blood vessel density. To examine vulnerability to brain injury, postnatal day 80 adult rats underwent right middle cerebral artery occlusion (MCAO) to produce unilateral ischemic lesions. Brains were removed and processed for histology 48 h after injury. Brain injury was assessed by histological evaluation of hematoxylin and eosin, and silver staining. In contrast to our hypothesis, neither neonatal morphine, stress, nor the combination affected cerebral vessel density or MCAO-induced brain injury. Neonatal angiogenesis was not detected in adult rats possibly due to turnover of endothelial cells. Although unrelated to angiogenesis, hippocampal granule cell neurogenesis was detected and there was a trend (P = 0.073) toward increased bromodeoxyuridine incorporation in rats that underwent neonatal stress. These findings are discussed in contrast to other data concerning the effects of morphine on cerebrovascular function, and acute effects of morphine on hippocampal neurogenesis.
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, WA 98195-6320, USA. hayss@uw.edu
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hays
authors.forename: Olga A
authors.initials: OA
authors.lastname: Valieva
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: McPherson
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Juul
authors.forename: Christine A
authors.initials: CA
authors.lastname: Gleason
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000401:mortality; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009294:Narcotics / Q000627:therapeutic use*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000401:mortality / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality
chemical_list: D009294:Narcotics; D009020:Morphine; D001973:Bromodeoxyuridine