Abstract
It is widely accepted that the induction dose of anesthetics is higher in infants than in adults, although the relevant molecular mechanism remains elusive. We previously showed neuronal hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to hypnotic actions of propofol and ketamine. Interestingly, the expression of HCN channels in neocortex significantly changes during postnatal periods. Thus, we postulated that changes in HCN channels expression might contribute to sensitivity to intravenous anesthetics. Here we showed the EC50 for propofol- and ketamine-induced loss-of-righting reflex (LORR) was significantly lower for P35 than for P14 mice. Cerebrospinal fluid concentrations of propofol and ketamine were significantly higher in P14 mice than in P35 mice, with similar propofol- and ketamine-induced anesthesia at the LORR EC50. Western blotting indicated that the expression of HCN channels in neocortex changed significantly from P14 to P35 mice. In addition, the amplitude of HCN currents in the neocortical layer 5 pyramidal neurons and the inhibition of propofol and ketamine on HCN currents dramatically increased with development. Logistic regression analysis indicated that the changes of HCN channels were correlated with the age-related differences of propofol- and ketamine-induced anesthesia. These data reveal that the change of HCN channels expression with postnatal development may contribute to sensitivity to the hypnotic actions of propofol and ketamine in mice.
Highlights
It is well established that the induction dose of anesthetics is influenced by age [1,2,3]
Similar results were observed for ketamine (Figure 2D, Cerebrospinal fluid (CSF) concentration of ketamine: 109 ± 6.74 μg/ml for P14 mice, 93 ± 6.07 μg/ml for P21 mice, 69 ± 7.37 μg/ml P28 mice, and 47 ± 6.72 μg/ml for P35 mice, n=5, F=81.39, P
The results showed that the HCN current in cortical pyramidal neurons steadily increased with increasing age (Figure 4A left), Figure 2: Cerebrospinal fluid (CSF) concentrations of propofol and ketamine needed to produce the same LORR decreased with increasing age of mice. (A) Representative high-performance liquid chromatography (HPLC) revealed the CSF
Summary
It is well established that the induction dose of anesthetics is influenced by age [1,2,3]. Since millions of infants and children undergo anesthesia around the world every year, an accurate understanding of these age-related differences is very important for clinical practice and basic research. Previous studies explained this age-related sensitivity to anesthetics based on the different pharmacokinetics parameters in patients of different ages [2, 3], as infants and children have higher cardiac output relative to body weight and are considered to exhibit lower www.impactjournals.com/oncotarget concentration of anesthetics in the blood perfusing the brain compared to adults [2, 4]. The age-related changes were significantly different between anesthesia with propofol or with thiopental, another intravenous anesthetic, even though thiopental and propofol have similar pharmacokinetics parameters [1, 2], indicating that differences in pharmacokinetics parameters could not fully explain the age-related differences in the induction dose of anesthetics [2,3,4]
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