The role of adrenergic and cholinergic transmission in volatile anesthetic-induced pain enhancement.
Volatile anesthetic drugs have a biphasic effect on pain transmission. At very small concentrations they enhance pain sensitivity whereas at larger subanesthetic concentrations they have an analgesic effect. Previous work has suggested that nicotinic inhibition could mediate the pronociceptive action of isoflurane. Furthermore, activation of nicotinic receptors facilitates the release of norepinephrine in the spinal cord. We hypothesize that nicotinic modulation of norepinephrine release in the spinal cord mediates isoflurane's pronociceptive action. We used hindpaw withdrawal latency as a measure of pain sensitivity after inhibition of adrenergic activity or treatment with nicotine in mice. Isoflurane's effect on pain is separable by concentration. The 50% effective concentration for pain enhancement is 0.16% isoflurane whereas the 50% effective concentration for the antinociceptive action of isoflurane is 0.8%. Depletion of systemic norepinephrine with the neurotoxin DSP-4 caused a reduction in baseline withdrawal latencies and prevented isoflurane pronociception. Baseline latency was also reduced by intrathecal yohimbine. After treatment with yohimbine, isoflurane had no additional pronociceptive effect. Nicotine administered through intracerebroventricular injection increased baseline latency but did not prevent isoflurane pronociception. Conversely, intrathecal applications of nicotine caused a slight reduction in baseline latency and prevented isoflurane's pronociceptive effect. We conclude that spinal noradrenergic transmission seems to be necessary for isoflurane pronociception to occur. Isoflurane may act by inhibiting tonically active nicotinic receptors that modulate the release of norepinephrine in the spinal cord.
Rowley
Thomas J
TJ
Department of Anesthesiology, Columbia University, New York, New York.
Daniel
Danette
D
Flood
Pamela
P
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000465:Algorithms; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007530:Isoflurane / Q000494:pharmacology; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement / Q000187:drug effects; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D018685:Anesthetics, Inhalation; D001596:Benzylamines; D011978:Receptors, Nicotinic; D015016:Yohimbine; D012701:Serotonin; D007530:Isoflurane; C012102:DSP 4; D004298:Dopamine; D009638:Norepinephrine