Chronic pain often leads to cognitive impairment. Resveratrol (Res), a natural polyphenol existing in Polygonum cuspidatum, has been widely investigated for its antinociceptive, anti-inflammatory, and neuroprotective properties. Our aim was to explore the ameliorating effects of resveratrol on pain-related behaviors and learning and memory deficits induced by cobra venom-induced trigeminal neuralgia (TN). The TN model of rats was established by injecting cobra venom solution beneath the epineurium of the infraorbital nerve. Resveratrol was intragastrically administered at a dose of 40 mg/kg twice daily beginning on postoperative day 15. CREB inhibitor 666-15 was intraperitoneally administered at a dose of 10 mg/kg from POD 35-42 after morning resveratrol treatment. Mechanical allodynia was measured via von Frey filaments. Rat free movement was videotaped and analyzed. Spatial learning and memory were evaluated via the Morris water maze test. Ultrastructures of the hippocampal DG region and infraorbital nerve were observed by transmission electron microscopy. We found that resveratrol alleviated TN-induced allodynia, ameliorated learning and memory deficits, restored the ultrastructure of hippocampal neurons and synapses, repaired the damaged myelin sheath of the infraorbital nerve, and activated the CREB/BDNF pathway in the hippocampus of TN rats. CREB inhibitor administration suppressed the resveratrol-rescued abnormal hippocampal ultrastructural changes and aggravated spatial learning and memory impairment by inhibiting CREB/BDNF pathway activation in the hippocampus. Our findings indicated that resveratrol alleviated pain and improved cognitive deficits, probably by regulating neural ultrastructure remodelling and the CREB/BDNF pathway.Copyright © 2022 Li Zhang et al.