1. 2022;25;E271-E283Potential Molecular Mechanisms of Electroacupuncture With Spatial Learning and Memory Impairment Induced by Chronic Pain on a Rat Model
   Animal Study
   Jian-Feng Zhang, MD, John P. Williams, MD, Wan-Rui Shi, MD, Xiao-Yan Qian, CRNA, Qian-Nan Zhao, MD, Guo-Fang Lu, MS, and Jian-Xiong An, MD, PhD.

BACKGROUND: It is frequently reported that neuropathic pain is associated with abnormalities in brain function and structure as well as cognitive deficits. However, the contributing mechanisms have remained elusive.

OBJECTIVES: We aimed to investigate the systemic ultrastructural changes of the peripheral nervous system (PNS) and central nervous system (CNS) in rats with trigeminal neuralgia (TN) induced by cobra venom, as well as the effects and mechanisms of electroacupuncture (EA) and pregabalin (PGB) on TN.

STUDY DESIGN: This study used an experimental design in rats.

SETTING: The research took place in the laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine.

METHODS: Male Sprague-Dawley rats were randomly divided into 4 groups (n = 12/group): cobra venom (CV), PGB, EA, and sham-operated (SHAM). The development of pain-related behaviors and spatial learning and memory abilities were measured using video recordings and Morris water maze tests, respectively. The ultrastructural changes of the PNS and CNS were examined using transmission electron microscopy. We also screened the differentially expressed genes and proteins in the prefrontal cortex  and hippocampus using  ribonucleic acid sequencing and isobaric tag for relative and absolute quantitation techniques, respectively. Data for the behavioral tests and molecular biology were analyzed with a one-way analysis of variance.

RESULTS: The rats in the CV group exhibited long-lasting pain-like behaviors, cognitive deficits, and systemic ultrastructural changes. Both EA and PGB alleviated the chronic pain syndrome, but EA also inhibited the chronic pain-induced cognitive dysfunction and restored normal cellular structures, while PGB was associated with no improvements. Transcriptomic and proteomic analyses revealed marcks, pak2 and acat1 were altered in rats with TN but were adjusted back to baseline by EA but not by PGB.

LIMITATIONS: We examined systemic ultrastructural alterations at different levels of the nervous system; however, the detailed timeline of the damage process was not explicitly delineated.  Moreover, the current study provides only preliminary evidence for the neurobiological mechanisms of cognitive impairment resulting from chronic pain.  Further research is still necessary (using models such as gene knockout rats and cell cultures) before a detailed mechanism can be postulated.

CONCLUSIONS: EA treatment may offer significant advantages when compared to PGB for the treatment of cognitive impairment associated with chronic pain. Moreover, marcks, pak2 and acat1 may be the potential therapeutic targets of EA.

KEY WORDS: Trigeminal neuralgia, cognitive dysfunction, electroacupuncture, pregabalin, ultrastructural changes, prefrontal cortex, hippocampus