Luciferase as a model for the site of inhaled anesthetic action.
The in vivo potencies of anesthetics correlate with their capacity to suppress the reaction of luciferin with luciferase. In addition, luciferin has structural resemblances to etomidate. These observations raise the issues of whether luciferin, itself, might affect anesthetic requirement, and whether luciferase resembles the site of anesthetic action. Because the polar luciferin is unlikely to cross the blood-brain barrier (we found that the olive oil/water partition coefficient was 100 +/- 36 x 10(-7)), we studied these issues in rats by measuring the effect of infusion of luciferin in artificial cerebrospinal fluid into the lumbar subarachnoidal space and into the cerebral intraventricular space on the MAC (the minimum alveolar anesthetic concentration required to eliminate movement in response to a noxious stimulus in 50% of tested subjects) of isoflurane. MAC in rats given lumbar intrathecal doses of luciferin estimated to greatly exceed anesthetizing doses of etomidate, did not differ significantly from MAC in rats receiving only artificial cerebrospinal fluid into the lumbar intrathecal space. MAC slightly decreased when doses of luciferin estimated to greatly exceed anesthetizing doses of etomidate were infused intraventricularly (P < 0.05). In contrast to the absent or minimal effects of luciferin, intrathecal or intraventricular infusion of etomidate at similar or smaller doses significantly decreased isoflurane MAC. Luciferin did not affect +-aminobutyric acid type A or acetylcholine receptors expressed in Xenopus oocytes. These results suggest that luciferin has minimal or no anesthetic effects. It also suggests that luciferin/luciferase may not provide a good surrogate for the site at which anesthetics act, if this site is on the surface of neuronal cells.


CONCLUSIONS
In proportion to their potencies, anesthetics inhibit luciferin's action on luciferase, and luciferin structurally resembles the anesthetic etomidate. However, in contrast to etomidate, luciferin given intrathecally or into the third cerebral ventricle does not have anesthetic actions, and it does not affect +-aminobutyric acid or acetylcholine receptors in vitro. Luciferase may not provide a good surrogate for the site at which anesthetics act.
Zhang
Y
Y
Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0464, USA.
Stabernack
C R
CR
Dutton
R
R
Sonner
J
J
Trudell
J R
JR
Mihic
S J
SJ
Yamakura
T
T
Harris
R A
RA
Gong
D
D
Eger
E I
EI
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics; D018686:Anesthetics, Intravenous / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000737:chemistry* / Q000494:pharmacology*; D049454:Firefly Luciferin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007275:Injections, Intravenous; D007278:Injections, Spinal; D007530:Isoflurane / Q000493:pharmacokinetics; D008156:Luciferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D014981:Xenopus
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D049454:Firefly Luciferin; D007530:Isoflurane; D008156:Luciferases; D005045:Etomidate