Disruption of hippocampal mitochondrial function underlies opioid-induced postoperative cognitive dysfunction in aged rats.

Postoperative cognitive dysfunction (POCD) is a common and persistent complication in aging individuals following surgery, particularly when opioids are used for perioperative pain management. Although opioids are widely administered in the perioperative setting, the mechanisms by which they contribute to long-term cognitive impairment remain poorly understood. Here, using an aged rat model of surgery with perioperative morphine administration, we investigated how synaptic, axonal, and mitochondrial abnormalities contribute to persistent hippocampal memory deficits, and evaluated therapeutic strategies targeting neuroinflammation and mitochondrial dysfunction. We found that these memory impairments were not attributable to systemic illness or gross dendritic degeneration. Instead, surgery and morphine-treated animals exhibited selective reductions in dendritic spine subtypes associated with synaptic stability, impaired late-phase long-term potentiation, and blunted experience-dependent upregulation of the AMPA receptor subunit GluA1. These synaptic alterations were accompanied by elevated circulating neurofilament light chain (Nf-L), indicating sustained axonal perturbation. Surgery and morphine treatment also produced persistent hippocampal mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced respiratory reserve capacity, and increased DNA oxidation. These effects were not observed in liver tissue, arguing against a widespread mitochondrial deficit. Pharmacological inhibition of central TLR4 signaling at the time of surgery, which previously rescued the memory deficit, attenuated oxidative stress and partially restored mitochondrial function, implicating early neuroinflammatory signaling in the development of long-term mitochondrial impairment. Finally, targeted mitochondrial rejuvenation with SS-31 four weeks post-surgery robustly rescued hippocampal-dependent memory and normalized mitochondrial respiratory function despite persistently elevated DNA oxidation and Nf-L. Together these findings identify sustained hippocampal mitochondrial dysfunction as a key mechanistic substrate underlying long-term cognitive deficits following surgery and morphine exposure in aged rats, and highlight mitochondrial bioenergetics as a promising therapeutic target for POCD.