Abstract
BackgroundNeonatal rats exposed to repetitive inflammatory pain have altered behaviors in young adulthood, partly ameliorated by Ketamine analgesia. We examined the relationships between protein expression, neuronal survival and plasticity in the neonatal rat brain, and correlated these changes with adult cognitive behavior.MethodsUsing Western immunoblot techniques, homogenates of cortical tissue were analyzed from neonatal rats 18–20 hours following repeated exposure to 4% formalin injections (F, N = 9), Ketamine (K, 2.5 mg/kg × 2, N = 9), Ketamine prior to formalin (KF, N = 9), or undisturbed controls (C, N = 9). Brain tissues from another cohort of rat pups (F = 11, K = 12, KF = 10, C = 15) were used for cellular staining with Fos immunohistochemistry or FluoroJade-B (FJB), followed by cell counting in eleven cortical and three hippocampal areas. Long-term cognitive testing using a delayed non-match to sample (DNMS) paradigm in the 8-arm radial maze was performed in adult rats receiving the same treatments (F = 20, K = 24, KF = 21, C = 27) in the neonatal period.ResultsGreater cell death occurred in F vs. C, K, KF in parietal and retrosplenial areas, vs. K, KF in piriform, temporal, and occipital areas, vs. C, K in frontal and hindlimb areas. In retrosplenial cortex, less Fos expression occurred in F vs. C, KF. Cell death correlated inversely with Fos expression in piriform, retrosplenial, and occipital areas, but only in F. Cortical expression of glial fibrillary acidic protein (GFAP) was elevated in F, K and KF vs. C. No significant differences occurred in Caspase-3, Bax, and Bcl-2 expression between groups, but cellular changes in cortical areas were significantly correlated with protein expression patterns. Cluster analysis of the frequencies and durations of behaviors grouped them as exploratory, learning, preparatory, consumptive, and foraging behaviors. Neonatal inflammatory pain exposure reduced exploratory behaviors in adult males, learning and preparatory behaviors in females, whereas Ketamine ameliorated these long-term effects.ConclusionNeuroprotective effects of Ketamine attenuate the impaired cognitive behaviors resulting from pain-induced cell death in the cortical and hippocampal fields of neonatal rats. This cell death was not dependent on the apoptosis associated proteins, but was correlated with glial activation.
Highlights
Neonatal rats exposed to repetitive inflammatory pain have altered behaviors in young adulthood, partly ameliorated by Ketamine analgesia
Differences in the limbic system, which included the dorsal endopiriform cortex showed no differences in cell death, but significantly lower Fos expression in F
Neonatal exposure to repetitive inflammatory pain contributes to greater cell death, reduced Fos expression, and glial activation
Summary
Neonatal rats exposed to repetitive inflammatory pain have altered behaviors in young adulthood, partly ameliorated by Ketamine analgesia. Synaptogenesis, expression of excitatory receptors [7] and developmentally regulated neuronal cell death [8] occur at this time, which may explain why repetitive neonatal pain persistently alters pain processing, in rats [9], mice [10], and humans [11,12,13]. Prolonged treatment of infant rats with high doses of analgesic or anesthetic agents triggers widespread neurodegeneration in their brain [14]. It is important, to study the mechanisms by which repetitive pain or prolonged anesthetic exposure alter development in the neonatal brain, through factors altering cell survival, neuronal activity, or plasticity. We are the first to report 26 rat behaviors assessing cognitive deficits in a delayed nonmatch to sample (DNMS) paradigm, correlated with the expression of various cellular proteins that regulate the mechanisms of cell death and plasticity
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