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AbstractBackground:Critically ill neonates experience multiple stressors during hospitalization. Opioids are commonly prescribed to ameliorate their pain and stress. However, the enduring effects of stress and opioids are not understood. The kappa opioid system is important in the mediation of stress in adults, but little is known about its function in neonates. Objectives:To characterize kappa opioid receptor (KOR) distribution in the neonatal mouse brain and test whether neonatal exposure to morphine, stress, or both, change KOR signaling. Methods:Five groups of wild-type C57BL/6 or prodynorphin (Pdyn) knockout mice were tested: (1) untreated control (dam-reared, no handling), (2) saline-injected control, (3) morphine-injected control, (4) stressed with saline injections and (5) stressed with morphine injections. Mice were treated from postnatal day 5 to postnatal day 9, after which their brains were immunolabeled with a phospho-specific KOR antibody (KOR-P), glial fibrillary acidic protein or glutamic acid decarboxylase. Results:There were no effects of saline or morphine injection on KOR-P immunoreactivity. Neonatal stress increased KOR-P labeling in wild-type brains (p < 0.05), but not in Pdyn–/–animals. Mice exposed to stress and morphine showed region-specific increases in KOR-P immunoreactivity from 38 to 500 (p < 0.05 to p < 0.001), with marked gliosis. In stressed morphine-treated Pdyn–/–animals, KOR-P immunoreactivity was absent, but gliosis increased compared to wild-type animals. Conclusions:Neonatal stress increases KOR activation via the dynorphin system. Neonatal stress plus morphine treatment further increased this response and also resulted in hippocampal gliosis. Enhanced gliosis noted in Pdyn–/–animals suggests that the endogenous dynorphin may play a role in downregulating this inflammatory response.Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground:Erythropoietin (Epo) receptors (EpoR) are present in embryonic and postnatal mammalian bowel, and activation of EpoR signaling with recombinant Epo (rEpo) has trophic effects. Transgenic mice with absent Epo function are embryonic lethal, so it is not known whether Epo function is required for bowel development. Objective:To characterize bowel structure in the absence of EpoR signaling. Methods:Heterozygous EpoR knockout mice were mated. Bowel segments from their embryos were dissected and transplanted beneath the renal capsule of adult wild-type mice and residual embryo tissue was excised for genotyping. Transplants were harvested at 7, 14 or 21 days. The transplanted bowel segments were immunostained to identifyproliferation (BrdU+), as well as neuronal (PGP9.5+), endothelial (vWF+), and neuroendocrine (synaptophysin+) cells. Gross and microscopic characteristics of intestinal differentiation were evaluated. Results:50 transplants were performed: bowel from 49 embryos survived to harvest and 43 showed evidence of bowel development with appropriate small or large intestinal features. No differences in morphology, immunolabeling, or BrdU incorporation were observed between homozygous-null, heterozygote or wild-type bowel. Smooth muscle and mucosal cells were present, along with neuronal, endothelial, and neuroendocrine cells in all genotypes. Conclusions:Enteric EpoR signaling is not essential for intestinal morphogenesis.Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground: During critical care in neonatal intensive care units (NICU), infants experience stressors and treatments that may produce lasting effects on adult health. An animal model simulating the NICU experience is needed to understand the impact of specific neonatal stressors. Objective: We combined approaches to develop a neonatal rat model simulating NICU stressors in order to examine the hypothesis that early stress and morphine sulfate (MS) exposure would affect development and alter adult behavior. Methods: Rat pups were exposed to stressors and given twice daily MS injections (2 mg/kg s.c.) for 5 days (postnatal days 3–7). Stress included daily maternal separation (from 08.00 to 16.00 h), hand feedings, a daily hypoxia/hyperoxia episode (100% N2 for 8 min, then 100% O2 for 4 min), and cold exposure (4°C for 20 min/day). Five treatment groups were formed: (1) ‘control control’ (dam reared and untreated); (2) control vehicle; (3) stress vehicle; (4) control morphine, and (5) stress morphine. Early growth and developmental indices were measured. Adult neurobehavioral tests were paw flick, passive avoidance, and forced swimming. Neonatal MS pharmacokinetics, neonatal and adult corticosterone levels, and adult hematocrit and blood pressure values were measured. Results: Neonatal stress significantly increased the mortality. Neonatal stress and MS treatment slowed early growth. Neonatal MS impaired passive avoidance learning and increased frequency, duration, and distance of forced swimming. There were no differences in corticosterone, hematocrit, or blood pressure values. Conclusions: This model simulates NICU stressors and enables measurement of acute physiological and long-term neurobehavioral indices. Neonatal MS treatment impaired the adult cognitive functioning.Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]