Isoflurane hyperalgesia is modulated by nicotinic inhibition.
BACKGROUND
The inhaled anesthetic isoflurane inhibits neuronal nicotinic acetylcholine receptors (nAChRs) at concentrations lower than those used for anesthesia. Isoflurane produces biphasic nociceptive responses, with both hyperalgesia and analgesia within this concentration range. Because nicotinic agonists act as analgesics, the authors hypothesized that inhibition of nicotinic transmission by isoflurane causes hyperalgesia.


METHODS
The authors studied female mice at 6-8 weeks of age. They measured hind paw withdrawal latency at isoflurane concentrations from 0 to 0.98 vol% after the animals had received a nicotinic agonist (nicotine), a nicotinic antagonist (mecamylamine or chlorisondamine), or saline intraperitoneally. In addition, the authors tested the interactions between mecamylamine and isoflurane and nicotine and isoflurane in heterologously expressed alpha(4)beta(2) nAChRs.


RESULTS
Female mice had significant hyperalgesia from isoflurane. Nicotine administration prevented isoflurane-induced hyperalgesia without altering the antinociception produced by higher isoflurane concentrations. Mecamylamine treatment caused a biphasic nociceptive response similar to that caused by isoflurane. Mecamylamine and isoflurane had an additive effect, both at heterologously expressed alpha(4)beta(2) nAChRs and on the production of hyperalgesia in vivo. Mecamylamine thus potentiated hyperalgesia but did not affect analgesia.


CONCLUSIONS
Since hyperalgesia occurs in vivo at isoflurane doses that antagonize nAChRs in vitro, is prevented by a nicotinic agonist, and is mimicked and potentiated by nicotinic antagonists, the authors conclude that isoflurane inhibition of nAChRs activation is involved in the pathway that causes hyperalgesia. At subanesthetic doses, isoflurane can either enhance pain responses (produce hyperalgesia) or be analgesic (antinociceptive). In rats, low volatile anesthetic concentrations (0.1-0.2 minimum alveolar concentration [MAC]) elicit hyperalgesia, while 0.4-0.6 MAC elicits antinociception.
Flood
Pamela
P
Department of Anesthesiology, Columbia University, New York, New York 10032, USA. pdf3@columbia.edu
Sonner
James M
JM
Gong
Diane
D
Coates
Kristen M
KM
D000818:Animals; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced*; D007530:Isoflurane / Q000494:pharmacology*; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins / Q000187:drug effects; D014981:Xenopus
D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; C403531:nicotinic receptor alpha4beta2; D008464:Mecamylamine; D009538:Nicotine; D007530:Isoflurane