Isoflurane prevents nicotine-evoked norepinephrine release from the mouse spinal cord at low clinical concentrations.
BACKGROUND
Volatile anesthetics inhibit nicotinic acetylcholine receptors at subanesthetic concentrations. In both animal and human studies, similar concentrations of volatile anesthetics have been associated with increased sensitivity to pain. Nicotinic analgesia is thought to involve the enhanced release of norepinephrine. These studies are intended as a "proof of concept" that alteration of the nicotinic facilitation of norepinephrine release is a potential mechanism for isoflurane-induced pronociception.


METHODS
We conducted our study using a murine lumbar spinal cord slice model. We evoked norepinephrine release with nicotine in the presence and absence of isoflurane. To identify the type of nicotinic receptor involved, we studied the effect of receptor and subtype-specific ligands and genetically engineered mice, which lacked the gene expression for the nicotinic beta2 subunit. The amount of [(3)H]-norepinephrine released was measured under the different conditions.


RESULTS
Nicotine-facilitated norepinephrine release was significantly and maximally inhibited by isoflurane at concentrations that enhance pain sensitivity in vivo (0.38%). Facilitation of norepinephrine release was mimicked by the alpha 7 selective agonist choline and inhibited in the presence of alpha-bungarotoxin, an alpha 7-nicotinic selective antagonist. Facilitation of norepinephrine release was not different in animals lacking beta2 subunits compared with matched controls.


CONCLUSIONS
Nicotinic facilitation of norepinephrine release in the spinal cord is inhibited by isoflurane at low clinically relevant concentrations. Because the net effect of noradrenergic tone in the spinal cord is inhibitory, the removal of this mechanism might be responsible for the enhanced pain sensitivity seen at these concentrations of isoflurane.
Rowley
Thomas J
TJ
Department of Anesthesiology, Columbia University, New York City, New York, USA.
Flood
Pamela
P
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D007530:Isoflurane / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009538:Nicotine / Q000494:pharmacology*; D009638:Norepinephrine / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology
D018685:Anesthetics, Inhalation; D002038:Bungarotoxins; D011978:Receptors, Nicotinic; D009538:Nicotine; D007530:Isoflurane; D009638:Norepinephrine