Effect of perioperative preemptive analgesia on hippocampal GABAA receptor α1/α5 balance in aged mild cognitive impairment rats.

Abstract

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a frequent complication in elderly patients that delays recovery and increases long-term health risks. Preemptive analgesia may alleviate surgery-induced inflammation and central sensitization, but its role in improving postoperative neurocognitive disorder (PND) through modulation of hippocampal Gamma-aminobutyric acid type A (GABAA) receptor α1/α5 subunits in aged rats with mild cognitive impairment (MCI) remains unclear. METHODS: Twenty-two-month-old male Sprague-Dawley (SD) rats were used to establish the MCI model via severe bilateral common carotid artery stenosis. After successful modeling, rats were randomly divided into five groups: Control (Con, only tibial exposure and suturing), Surgery (intravenous 0.9% normal saline), Nalbuphine (Nal, 10 mg/kg), Dezocine (Dez, 10 mg/kg), and Sufentanil (Suf, 10 μg/kg). Drugs were administered 1 h preoperatively. Anesthesia was induced with a subanesthetic regimen (0.7 MAC sevoflurane + 1.2 μg/ml propofol, validated previously), followed by tibial fracture open reduction and internal fixation (ORIF). Postoperative evaluations included pain indicators (paw withdrawal latency [PWL], paw withdrawal threshold [PWT]), cognitive function, and hippocampal GABAA α1/α5 and PSD95 expression levels. RESULTS: This study examined preemptive analgesia's effects on postoperative outcomes in aged MCI rats. Behavioral tests (PWL, PWT) showed it alleviated postoperative pain, while Y-maze and novel object recognition tests improved anesthesia/surgery-related cognitive decline on postoperative days 1, 3, 7. Western blot revealed ORIF model rats had reduced hippocampal GABAA α1/α5 ratio on postoperative days 1, partial recovery on postoperative days 3, 7, abnormal balance on postoperative days 7, and sustained PSD95 downregulation. Preemptive nalbuphine, dezocine, or sufentanil prevented GABAA α1/α5 imbalance and attenuated PSD95 reduction. HE staining indicated mitigated hippocampal neutrophil infiltration and structural damage induced by anesthesia/surgery. CONCLUSION: Perioperative preemptive analgesia effectively reduces postoperative pain and improves neurocognitive function in aged MCI rats, via a mechanism linked to maintaining hippocampal GABAA receptor α1/α5 subunit balance and ameliorating hippocampal neural dysfunction. This study provides foundational evidence for clinical postoperative pain management and cognitive protection in elderly MCI patients.