Paricalcitol improves cognitive dysfunction associated with chronic post-thoracotomy pain in rats

Although cognitive dysfunction associated with chronic pain has attracted growing attention, few studies have specifically focused on cognitive dysfunction induced by chronic post-thoracotomy pain (CPTP). Neuroinflammation is well recognized as a critical driver of chronic pain-related cognitive dysfunction, and vitamin D receptor (VDR) activation exerts potent anti-neuroinflammatory effects. However, whether the selective VDR agonist paricalcitol can ameliorate CPTP-induced cognitive dysfunction remains unclear. Here, we investigated the therapeutic effects of paricalcitol on CPTP-associated cognitive dysfunction and explored the underlying mechanisms. Rats were assigned to receive thoracotomy (to establish the CPTP model) or sham surgery as control. Paricalcitol or normal saline was intraperitoneally administered once daily for 5 days before surgery and once every other day for 28 days postoperatively. Mechanical pain threshold was evaluated using von Frey filaments. Locomotor activity, novel object recognition, and Barnes maze tests were performed to assess general locomotion and cognitive function. Hippocampal tissues were collected to detect key markers of neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2) and neuroinflammation (IL-1β, TNF-α, and Iba1). Cecal contents were analyzed for gut microbiota composition, and colonic VDR protein expression was further quantified. We found that CPTP successfully induced persistent mechanical hypersensitivity and severe cognitive dysfunction, accompanied by excessive neuroinflammation, impaired neurogenesis, reduced NR2B expression, significant gut microbiota dysbiosis, and decreased colonic VDR protein levels. Notably, paricalcitol treatment substantially alleviated mechanical pain hypersensitivity and rescued CPTP-associated cognitive dysfunction. These beneficial effects were accompanied by improved hippocampal neuroplasticity, suppressed neuroinflammation, restored gut microbial homeostasis, and reversal of surgery-induced colonic VDR downregulation. Collectively, our findings demonstrate that paricalcitol ameliorates CPTP-associated cognitive dysfunction. These protective effects are associated with restored colonic VDR expression, suggesting a potential involvement of VDR signaling. This study provides a novel experimental basis for the potential clinical application of paricalcitol in preventing and treating pain-related cognitive dysfunction.