title: The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia.
abstract: Neurons of the ventrolateral preoptic nucleus (VLPO) promote sleep and VLPO loss produces insomnia. Previous studies show that general anesthetics including isoflurane activate VLPO neurons, and may contribute to their sedative effects. However, it is not clear to what extent the activation of VLPO neurons contributes to general anesthesia. We tested whether destruction of the VLPO neurons would affect the onset, depth, or recovery from isoflurane's general anesthetic effects. The VLPO was ablated in 25 rats by bilateral local injection of orexin-saporin, and polysomnography was performed to measure baseline sleep loss and responses to isoflurane anesthesia at 1% and 2%. Eight rats received sham (saline) injections. We measured isoflurane effects on time to loss of righting reflex, onset of continuous slow wave activity, and burst suppression; burst-suppression ratio; and time to recovery of righting reflex and desynchronized EEG. VLPO neuron cell loss was quantified by post hoc histology. Loss of VLPO neurons as well as lesion size were associated with cumulative sleep loss (r=0.77 and r=0.62, respectively), and cumulative sleep loss was the strongest predictor of high sensitivity to anesthesia, expressed as decreased time to loss of righting reflex (-0.59), increased burst-suppression ratio (r=0.52) , and increased emergence time (r=0.54); an interaction-effect of isoflurane dose was observed (burst-suppression ratio: p<0.001). We conclude that the sleep loss caused by ablation of VLPO neurons sensitizes animals to the general anesthetic effects of isoflurane, but that the sedation produced by VLPO neurons themselves is not required for isoflurane anesthesia.
authors: Department of Anesthesia, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
authors: Matthias
authors: M
authors: Eikermann
authors: Ramalingam
authors: R
authors: Vetrivelan
authors: Martina
authors: M
authors: Grosse-Sundrup
authors: Mark E
authors: ME
authors: Henry
authors: Ulrike
authors: U
authors: Hoffmann
authors: Shigefumi
authors: S
authors: Yokota
authors: Clifford B
authors: CB
authors: Saper
authors: Nancy L
authors: NL
authors: Chamberlin
mesh_terms: D000768:Anesthesia, General; D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000502:physiology*
chemical_list: D018681:Anesthetics, General; D007530:Isoflurane