title: Ketamine reduces the cell death following inflammatory pain in newborn rat brain.
abstract: Premature infants experience untreated repetitive pain that may alter their brain development. Effects of ketamine and repetitive pain on cellular death and subsequent behavior were studied in neonatal rats. Rat pups were randomized to undisturbed controls (C), 4% formalin injection (F), ketamine alone (K, 5 mg/kg) or formalin plus ketamine (KF) and were assessed for neuroactivation with Fos protein, cellular death with FluoroJade-B, cognition with the radial arm maze, and pain thresholds with the hot-plate. Greater Fos expression and cell death occurred in F vs. C groups in defined brain areas at 1 and 4 h in F compared with other groups. Cell death was accentuated 3.3-fold in cortical areas and 1.6-fold in subcortical areas in the F compared with the C group following repetitive pain and sacrifice 18-20 h later. These effects were ameliorated by ketamine. Compared with the F group, all other groups demonstrated greater exploratory and rearing behaviors and decreased time for bait consumption at 1-h and 3-h intervals. Significantly greater thermal pain latencies occurred in the KF and F groups. Repetitive neonatal pain accentuates neuronal excitation and cell death in developmentally regulated cortical and subcortical areas, which decreases the acquisition of visual-spatial clues, short-term and long-term memory, and increases pain latencies. Ketamine analgesia mitigates most of these effects.
authors.affiliation: Pain Neurobiology Lab, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202, USA. anandsunny@uams.edu
authors.forename: Kanwaljeet J S
authors.initials: KJ
authors.lastname: Anand
authors.forename: Sarita
authors.initials: S
authors.lastname: Garg
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Rovnaghi
authors.forename: Umesh
authors.initials: U
authors.lastname: Narsinghani
authors.forename: Adnan T
authors.initials: AT
authors.lastname: Bhutta
authors.forename: Richard W
authors.initials: RW
authors.lastname: Hall
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007249:Inflammation / Q000188:drug therapy*; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011247:Pregnancy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011897:Random Allocation; D051381:Rats
chemical_list: D000700:Analgesics; D016760:Proto-Oncogene Proteins c-fos; D007649:Ketamine