Transcutaneous Auricular Vagus Nerve Stimulation Restores Cognitive Impairment in Morphine‐Withdrawn Rats: Role of BDNF and Glial Cells in the Hippocampus

Opioid use disorder (OUD) is a significant mental health problem, with prolonged usage potentially resulting in tolerance, addiction and cognitive decline, including learning and memory deficiency. At present, pharmacotherapy serves as the primary treatment approach for OUD. However, despite its status as a cornerstone of treatment, pharmacotherapy has certain limitations, thereby mandating the exploration of alternative modalities. This study evaluated the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) in multiple cognitive domains in morphine-withdrawn rats. To induce morphine dependence, the rats were administered 10 mg/kg morphine for 10 consecutive days. taVNS was administered to the left ear of each rat and continued for 2 weeks. After electrical stimulation, various cognitive and emotional functions were assessed through related behavioural tasks, including open field, Y-maze, novel object recognition and elevated plus maze tests. GFAP, Iba1 and BDNF expression levels in the hippocampus were determined via quantitative polymerase chain reaction (qPCR). Our investigation revealed that taVNS ameliorated the impairment of working and recognition memory induced by morphine in behavioural tests. Additionally, it exerts an anxiolytic effect. Moreover, taVNS counteracted the decreased concentration of brain-derived neurotrophic factor (BDNF) and elevated levels of glial fibrillary acidic protein (GFAP) caused by morphine. Nonetheless, taVNS applied only at a frequency of 100 Hz has the potential to lower Iba1 levels independently of prior exposure to morphine. taVNS has been shown to exert a neuroprotective effect on morphine-withdrawn rats. This outcome indicates that taVNS can be employed as a supplementary therapy with other pharmacological interventions for OUD.