Opioid neurotoxicity: Neuropathologic effects in rats of different fentanyl congeners and the effects of hexamethonium-induced normotension

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 μg/kg, maintenance dose (MD) 40 μg · kg^-1 · min^-1 (n = 10), sufentanil LD 400 μg/kg, MD 13.3 μg · kg^-1 · min^-1 (n = 10), alfentanil LD 1500 μg/kg, MD 150 μg · kg^-1 · min^-1 (n = 10), or 0.9% saline control LD 4 mL/kg, MD 4 mL · kg^-1 · h^-1 (n = 101, with O₂/N₂ 30%/70% during opioid infusion and O₂/N₂O in controls during saline infusion. Hexamethonium (LD 20 mg/kg, MD 40-120mg · 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.