The role of nicotinic inhibition in ketamine-induced behavior.
Several anesthetic drugs are nicotinic antagonists at or below levels used for anesthesia, including ketamine and volatile anesthetics. In contrast, propofol does not inhibit nicotinic receptors. To determine the potential behavioral ramifications of nicotinic inhibition by ketamine, we determined the doses of ketamine required to induce immobility, impair the righting reflex, and cause analgesia in the absence and presence of several nicotinic ligands. Propofol was used as a control in similar experiments. When used as a sole anesthetic drug, 383 +/- 22 mg/kg ketamine intraperitoneally (IP) was required for immobility and 180 +/- 17 mg/kg IP impaired righting reflex. Propofol, 371 +/- 34 mg/kg IP, induced immobility whereas 199 mg/kg IP inhibited the righting reflex. Nicotinic antagonists had no effect on the dose of propofol or ketamine required for either end-point. When nociceptive responses were tested at subhypnotic doses, no pronociceptive or antinociceptive phase was identified for propofol, whereas analgesia was induced at ketamine doses larger than 60 mg/kg IP. The broad-spectrum nicotinic antagonist mecamylamine enhanced the analgesic action of ketamine. These findings are different than those seen with volatile anesthetics, where nicotinic inhibition is thought to be responsible for a pronociceptive action. Such a phase is possibly obscured by analgesia induced as a result of N-methyl-d-aspartic acid antagonism by ketamine.


CONCLUSIONS
Ketamine and volatile anesthetics, but not propofol, inhibit neuronal nicotinic acetylcholine receptors in clinically relevant concentration ranges. Nicotinic inhibition by ketamine is not related to its immobilizing or sedating effects but may play a role in ketamine's analgesic action.
Udesky
Julia O
JO
Department of Anesthesiology, Columbia University, New York, New York.
Spence
Nicole Z
NZ
Achiel
Ron
R
Lee
Chrisitane
C
Flood
Pamela
P
D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D018686:Anesthetics, Intravenous; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D012018:Reflex / Q000187:drug effects
D000778:Anesthetics, Dissociative; D018686:Anesthetics, Intravenous; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D007649:Ketamine; D008464:Mecamylamine; D015742:Propofol