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Logo of behbrainBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleBehavioral and Brain Functions : BBFJournal Front Page
 
Behav Brain Funct. 2008; 4: 35.
Published online Aug 7, 2008. doi:  10.1186/1744-9081-4-35
PMCID: PMC2527299
Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects
Cynthia R Rovnaghi,#1 Sarita Garg,#2 Richard W Hall,#3 Adnan T Bhutta,4 and K JS Anandcorresponding author5
1Pain Neurobiology Laboratory, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202, USA
2Department of Surgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
3Department of Pediatrics and Center for Translational Neuroscience, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
4Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
5Departments of Pediatrics, Anesthesiology, Pharmacology, Neurobiology & Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
corresponding authorCorresponding author.
#Contributed equally.
Cynthia R Rovnaghi: rovnaghicynthia/at/uams.edu; Sarita Garg: gargsarita/at/uams.edu; Richard W Hall: hallrichardw/at/uams.edu; Adnan T Bhutta: bhuttaadnant/at/uams.edu; K JS Anand: anandsunny/at/uams.edu
Received January 16, 2008; Accepted August 7, 2008.
Abstract
Background
Neonatal 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.
Methods
Using 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.
Results
Greater 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.
Conclusion
Neuroprotective 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.
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