OPIOID NEUROTOXICITY - FENTANYL DOSE-RESPONSE EFFECTS IN RATS

Opioids, when administered in large doses, produce brain damage, prima rily in the limbic system and association areas in rats. This investig ation examined the relationship between opioid dose and severity and f requency of brain damage in rats. Forty male Sprague-Dawley rats were anesthetized with halothane/N2O and underwent tracheal intubation, mec hanical ventilation, arterial/venous cannulation, and insertion of a r ectal temperature probe and biparietal electroencephalogram electrodes . After surgery, halothane was discontinued and O-2/N2O 30%/70% was ad ministered for 1 h. Rats were then randomly assigned to one of eight g roups. 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 mu g/kg a nd the MD from 2 to 128 mu g . kg(-1) . min(-1). After 2 h of fentanyl or NSS infusion, all rats received 100% O-2 and, when alert, their tr acheas were extubated; after 7 days the rats underwent cerebral perfus ion fixation, followed by light microscopic evaluation. Histopathologi c lesions (primarily eosinophilic neuron degeneration) were subjective ly graded by a pathologist unaware of the experimental treatment; the grades were based on the percentage of dead neurons. There were no les ions observed in the brain areas in any of the control or 200-8 (LD, m u g/kg; MD, mu g . 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 d amage primarily in limbic system structures and association areas (P < 0.05). Our data confirm that fentanyl produces limbic system brain da mage in rats, and that the damage occurs over a broad range of doses.