Potential Molecular Mechanisms of Electroacupuncture With Spatial Learning and Memory Impairment Induced by Chronic Pain on a Rat Model.

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.

Neuropathic Pain Creates Systemic Ultrastructural Changes in the Nervous System Corrected by Electroacupuncture but Not by Pregabalin.

PURPOSE: It is unclear whether neuropathological structural changes in the peripheral nervous system and central nervous system can occur in the spared nerve injury model. In this study, we investigated the pathological changes in the nervous system in a model of neuropathic pain as well as the effects of electroacupuncture (EA) and pregabalin (PGB) administration as regards pain relief and tissue repair. PATIENTS AND METHODS: Forty adult male SD rats were equally and randomly divided into 4 groups: spared nerve injury group (SNI, n = 10), SNI with electroacupuncture group (EA, n = 10), SNI with pregabalin group (PGB, n =10) and sham-operated group (Sham, n=10). EA and PGB were given from postoperative day (POD) 14 to 36. EA (2 Hz and 100 Hz alternating frequencies, intensities ranging from 1-1.5-2 mA) was applied to the left "zusanli" (ST36) and "Yanglingquan" (GB34) acupoints for 30 minutes. The mechanical withdrawal thresholds (MWTs) were tested with von Frey filaments. Moreover, the organizational and structural alterations of the bilateral prefrontal cortex, hippocampus, sciatic nerves and the thoracic, lumbar spinal cords and dorsal root ganglions (DRGs) were examined via light and electron microscopy. RESULTS: MWTs of left hind paw demonstrated a remarkable decrease in the SNI model (P < 0.05). In the SNI model, ultrastructural changes including demyelination and damaged neurons were observed at all levels of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, EA improved MWTs and restored the normal structure of neurons. However, the effect was not found in the PGB treatment group. CONCLUSION: Chronic pain can induce extensive damage to the central and peripheral nervous systems. Meanwhile, EA and PGB can both alleviate chronic pain syndromes in rats, but EA also restores the normal cellular structures, while PGB is associated with no improvement.

Multimodal sleep, an innovation for treating chronic insomnia: case report and literature review.

The authors present the clinical case of a 67-year-old man with severe insomnia for 5 years with an exacerbation about 1 year before consultation. He did not have enough concentration and energy for his daily work and developed depression and anxiety because of his excessive daytime sleepiness. During his insomniac state, a drug treatment provided partial relief, but the effects were not long-lasting. Consequently, the drug dosage increased, and major side effects gradually manifested. We decided to use a completely new therapeutic strategy for this patient to improve his sleep quality and mental symptoms. In time, the patient could stop oral medications and that is multimodal sleep. After the end of multimodal sleep, the patient typically experiences improvement in sleep quality and architecture. Additionally, the dosage of hypnotics used before multimodal sleep is discontinued without severe withdrawal symptoms. CITATION: Zhang J-F, Williams JP, Zhao Q-N, et al. Multimodal sleep, an innovation for treating chronic insomnia: case report and literature review. J Clin Sleep Med. 2021;17(8):1737-1742.

A New Rat Model of Thalamic Pain Produced by Administration of Cobra Venom to the Unilateral Ventral Posterolateral Nucleus.

BACKGROUND: Thalamic pain is a neuropathic pain syndrome that occurs as a result of thalamic damage. It is difficult to develop therapeutic interventions for thalamic pain because its mechanism is unclear. To better understand the pathophysiological basis of thalamic pain, we developed and characterized a new rat model of thalamic pain using a technique of microinjecting cobra venom into the ventral posterolateral nucleus (VPL) of the thalamus. OBJECTIVES: This study will establish a new thalamic pain rat model produced by administration of cobra venom to the unilateral ventral posterolateral nucleus. 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 subjected to the administration of cobra venom or saline into the left VPL. The development of mechanical hyperalgesia and changes in pain-related behaviors and motor function were measured after intrathalamic cobra venom microinjection using the von Frey test, video recording, and cylinder test, respectively. On postoperative days 7 to 35, both electroacupuncture and pregabalin (PGB) were administered to verify that the model reproduced the findings in humans. Moreover, the organizational and structural alterations of the thalamus were examined via transmission electron microscopy (TEM). RESULTS: The threshold for mechanical stimuli in the left facial skin was significantly decreased on day 3 after thalamic pain modeling as compared with pre-venom treatment. Furthermore, the ultrastructural alterations of neurons such as indented neuronal nuclei, damaged mitochondria and endoplasmic reticulum, and dissolved surrounding tissues were observed under TEM. Moreover, electroacupuncture treatment ameliorated mechanical hyperalgesia, pain-like behaviors, and motor dysfunction, as well as restore normal structures of neurons in the thalamic pain rat model. However, no such beneficial effects were noted when PGB was administered. LIMITATIONS: The pathophysiological features were different from the present model and the patients in clinical practice (in most cases strokes, either ischemic or hemorrhagic). CONCLUSION: The cobra venom model may provide a reasonable model for investigating the mechanism of thalamic pain and for testing therapies targeting recovery and pain after thalamic lesions. KEY WORDS: Thalamic pain, cobra venom, electroacupuncture, pregabalin, indented neuronal nuclei, damaged mitochondria, dissolved endoplasmic reticulum, golgi body.