Differential effects of fentanyl compared to morphine on neuroinflammatory signaling in the brain in EcoHIV-infected mice

HIV-associated neurocognitive disorders (HAND) pose significant challenges, particularly in individuals with comorbid opioid use disorder (OUD). Fentanyl, a potent synthetic opioid, is a leading contributor to opioid-related fatalities, yet its effects in the context of HIV remain poorly understood. This study investigated the differential impacts of fentanyl and morphine on neuroinflammatory signaling, blood-brain barrier (BBB) integrity, and antiretroviral (ARV) brain accumulation in EcoHIV-infected mice. C57BL/6 mice were assigned to morphine, fentanyl, or saline treatment groups, with or without EcoHIV infection. Tight junction proteins claudin-5 and ZO-1 were measured in striatum and hippocampus via ELISA, while proinflammatory chemokines were analyzed by multiplex assay. In EcoHIV-infected mice, both opioids significantly increased CCL2, CCL4, CCL5, and CCL11 concentrations in the striatum, with fentanyl causing greater increases in CCL2 than morphine. Additionally, fentanyl, but not morphine, significantly decreased CCL3 concentrations in the striatum. Principal component analysis revealed distinct treatment-specific patterns within the striatum, underscoring opioid-specific differences. Tight junction protein expression data demonstrate opioid-specific, sex-specific, and region-specific effects on the key BBB proteins, ZO-1 and claudin-5. Both opioids also reduced ARV brain concentrations in infected mice, with region- and opioid-specific effects. Fentanyl decreased dolutegravir in the hippocampus, while morphine decreased abacavir in both regions. These findings demonstrate that fentanyl and morphine exposure in the context of HIV produce distinct impacts on neuroinflammatory response, BBB integrity, and ARV brain exposure. Understanding these opioid-specific effects is critical for improving clinical outcomes and treatment strategies for individuals with HIV and OUD.