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Anesthesia & Analgesia, Vol 83, 1298-1306, Copyright © 1996 by International Anesthesia Research Society
Opioid neurotoxicity: fentanyl dose-response effects in rats
WA Kofke, RH Garman, RL Stiller, ME Rose and R Garman
Department of Anesthesiology, University of Pittsburgh, Pennsylvania, USA.
Opioids, when administered in large doses, produce brain damage, primarily
in the limbic system and association areas in rats. This investigation
examined the relationship between opioid dose and severity and frequency of
brain damage in rats. Forty male Sprague- Dawley rats were anesthetized
with halothane/N2O and underwent tracheal intubation, mechanical
ventilation, arterial/venous cannulation, and insertion of a rectal
temperature probe and biparietal electroencephalogram electrodes. After
surgery, halothane was discontinued and O2/N2O 30%/70% was administered for
1 h. Rats were then randomly assigned to one of eight groups. The control
group received a loading dose (LD) of 4 mL/kg of 0.9% normal saline
solution (NSS) and a maintenance dose (MD) of 4 mL.kg-1.h-1 NSS. The other
groups were given fentanyl lypophilized and reconstituted in NSS with the
LD ranging from 50 to 3200 micrograms/kg and the MD from 2 to 128
micrograms.kg-1.min-1. After 2 h of fentanyl or NSS infusion; all rats
received 100% O2 and, when alert, their tracheas were extubated; after 7
days the rats underwent cerebral perfusion fixation, followed by light
microscopic evaluation. Histopathologic lesions (primarily eosinophilic
neuron degeneration) were subjectively graded by a pathologist unaware of
the experimental treatment; the grades were based on the percentage of dead
neurons. There were no lesions observed in the brain areas in any of the
control or 200-8 (LD, microgram/kg; MD, microgram.kg-1.min-1) groups.
Eleven of 20 rats in the 400-16, 800- 32, 1600-64, and 3200-18 groups
showed evidence of brain damage primarily in limbic system structures and
association areas (P < 0.05). Our data confirm that fentanyl produces
limbic system brain damage in rats, and that the damage occurs over a broad
range of doses.
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