title: Opioid neurotoxicity: neuropathologic effects in rats of different fentanyl congeners and the effects of hexamethonium-induced normotension.
abstract: We tested the hypotheses that convulsant doses of opioids would produce limbic system damage exacerbated by hexamethonium. Ventilated paralyzed rats received intravenous (IV) isovolumic infusion of fentanyl loading dose (LD) 1000 micrograms/kg, maintenance dose (MD) 40 micrograms.kg-1.min-1 (n = 10), sufentanil LD 400 micrograms/kg, MD 13.3 micrograms.kg-1.min-1 (n = 10), alfentanil LD 1500 micrograms/kg, MD 150 micrograms.kg-1.min-1 (n = 10), or 0.9% saline control LD 4 mliter/kg, MD 4 mliter.kg-1.h-1 (n = 10), with O2/N2 30%/70% during opioid infusion and O2/N2O in controls during saline infusion. Hexamethonium (LD 20 mg/kg, MD 40-120 mg.kg-1.h-1) was given IV during opioid infusion to half of the rats. Cerebral perfusion-fixation with formalin was performed 24 h later, followed by histopathologic assessment. None of the control rats showed any histologic abnormalities. Overall summed neuropathologic severity was worse in opioid treated groups (P = 0.01). Lesions occurred primarily in cortical regions and limbic system structures. When arterial blood pressure was controlled to a lower level with hexamethonium (147 vs 100 mm Hg), rats had less severe lesions (P = 0.02). These data indicate that fentanyl, sufentanil, and alfentanil all can produce histopathologic evidence of brain injury in rats mitigated by hexamethonium.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh School of Medicine, Pennsylvania, USA. wak@med.pitt.edu
authors.forename: W A
authors.initials: WA
authors.lastname: Kofke
authors.forename: R H
authors.initials: RH
authors.lastname: Garman
authors.forename: J
authors.initials: J
authors.lastname: Janosky
authors.forename: M E
authors.initials: ME
authors.lastname: Rose
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001831:Body Temperature / Q000187:drug effects; D005283:Fentanyl / Q000633:toxicity*; D005730:Ganglionic Blockers / Q000494:pharmacology*; D018738:Hexamethonium / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D001786:Blood Glucose; D005730:Ganglionic Blockers; D018738:Hexamethonium; D005283:Fentanyl