Neonatal Stress or Morphine Treatment Alters Adult Mouse Conditioned Place Preference

Abstract

Background: Hospitalized preterm infants may experience pain and stress, and narcotics are often administered to lessen their suffering. However, prolonged narcotic therapy may be detrimental during neonatal brain development. Using a rat model combining neonatal stress and morphine, we found that neonatal morphine impaired adult learning. Here we describe a new mouse model examining lasting effects of neonatal stress and morphine. Objective: We tested whether repeated neonatal stress and/or morphine exposure affects early neurodevelopmental or adult behaviors. Methods: Five groups of C57/BL6 mice (1: untreated; 2: morphine (2 mg/kg s.c., b.i.d.); 3: saline, 4: stress + morphine; 5: stress + saline) were treated from postnatal day (P) 5 to P9. Stress consisted of daily maternal separation/isolation (08:00–15:00 h) with gavage feedings and twice daily exposure to brief hypoxia/hyperoxia. Developmental behaviors included righting (P5) and negative geotaxis (P9). Adult behaviors included elevated plus maze, morphine place-preference conditioning, and forced-swimming. Plasma con- centrations of morphine (P7) and corticosterone (P9 and adult) were measured. Results: Neonatal stress or neonatal morphine alone impaired adult place-preference conditioning, but the combination did not (interaction p < 0.01). Adult basal corticosterones were reduced by neonatal morphine treatment. There were no substantial differences in elevated plus maze or forced-swimming times. Conclusions: Neonatal stress and morphine treatment produced long-lasting behavioral and hormonal effects which suggest that neonatal morphine reduces adult arousal and neonatal stress exaggerates adult arousal, each to a degree sufficient to alter learning, while the combined impact of these neonatal treatments does not alter adult learning.

Effects of Repetitive Exposure to Pain and Morphine Treatment on the Neonatal Rat Brain

“…Morphine might protect the brain up to a certain limit. Previous animal studies also showed interactive effects between morphine and pain [14,15,16,17]. Morphine seems to downregulate specific stress-related changes in gene expression that protect the cell against apoptosis [13].…”

“…Apoptotic cell death of neuronal and glial cells was found only after high doses and prolonged use of morphine [13]. Both neonatal prolonged morphine treatment and repetitive inflammatory pain lead to behavioral changes and abnormal learning in adult rats, while these effects are reduced when pain and morphine treatment are combined [14,15]. Preemptive morphine attenuates increased hot plate thresholds, reduced place preference conditioning and reduced ethanol preferences in long-term behavioral rodent studies after neonatal pain exposure [14,16].…”

Postnatal Stress Produces Hyperglycemia in Adult Rats Exposed to Hypoxia-Ischemia

“…In particular, neonatal stress increased the susceptibility to white matter injury in the internal capsule and to thalamic injury. Perhaps the cognitive deficits seen after neonatal pain and stress in animal models (15,16,37,38) and recently in preterm infants (39) are related to increased vulnerability of specific brain regions.…”

“…The fact that prenatal exposure to dexamethasone increases fetal hepatic glucocorticoid receptor expression and produces adult hyperglycemia in rats strongly suggests that fetal stress may program adult function (14). Although our laboratory has found adult cognitive deficits in rodents exposed to postnatal stress (15,16), we have yet to examine the effects of postnatal stress on adult glucose metabolism.…”

Infant maternal separation impairs adult cognitive performance in BALB/cJ mice

“…Very few studies have examined the effects of IMS on adult learning and memory in mice. To our knowledge, only IMS-induced impairments in adult conditioned place preference (Boasen et al 2009) and Barnes maze performance (Fabricius et al 2008) have been reported.…”