title: Effects of general anesthetics on substance P release and c-Fos expression in the spinal dorsal horn.
abstract: BACKGROUND
  The authors examined in vivo the effects of general anesthetics on evoked substance P release (primary afferent excitability) and c-Fos expression (neuronal activation) in superficial dorsal horn.
  
  
  METHODS
  Rats received saline, propofol (100 mg/kg), pentobarbital (50 mg/kg), isoflurane (2 minimum alveolar concentration), nitrous oxide (66%), or fentanyl (30 μg/kg). During anesthesia, rats received intraplantar 5% formalin (50 μl) to left hind paw. Ten minutes later, rats underwent transcardial perfusion with 4% paraformaldehyde. Substance P release from small primary afferents was assessed by incidence of neurokinin 1 receptor internalization in the superficial dorsal horn. In separate studies, rats were sacrificed after 2 h and c-Fos expression measured.
  
  
  RESULTS
  Intraplantar formalin-induced robust neurokinin 1 receptor internalization in ipsilateral dorsal horn (ipsilateral: 54 ± 6% [mean ± SEM], contralateral: 12 ± 2%; P < 0.05; n = 4). Fentanyl, but not propofol, pentobarbital, isoflurane, nor nitrous oxide alone inhibited neurokinin 1 receptor internalization. However, 2 minimum alveolar concentration isoflurane + nitrous oxide reduced neurokinin 1 receptor internalization (27 ± 3%; P < 0.05; n = 5). All agents reduced c-Fos expression (control: 34 ± 4, fentanyl: 8 ± 2, isoflurane: 12 ± 3, nitrous oxide: 11 ± 2, isoflurane + nitrous oxide: 12 ± 1, pentobarbital: 11 ± 2, propofol: 13 ± 3; P < 0.05; n = 3).
  
  
  CONCLUSIONS
  General anesthetics at anesthetic concentrations block spinal neuron activation through a mechanism that is independent of an effect on small primary afferent peptide release. The effect of fentanyl alone and the synergistic effect of isoflurane and nitrous oxide on substance P release suggest a correlative rationale for the therapeutic use of these anesthetic protocols by blocking nociceptive afferent transmitter release and preventing the initiation of cascade, which is immediately postsynaptic to the primary afferent.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0818, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takasusuki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hamaguchi
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D018681:Anesthetics, General / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D005283:Fentanyl / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D009609:Nitrous Oxide / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D013373:Substance P / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018681:Anesthetics, General; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D016760:Proto-Oncogene Proteins c-fos; D013373:Substance P; D012965:Sodium Chloride; D007530:Isoflurane; D010424:Pentobarbital; D009609:Nitrous Oxide; D005283:Fentanyl; D015742:Propofol