Abstract
Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover (Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABAA receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.
Highlights
Patients suffering from chronic pain often have emotional comorbidities that affect mood, sleep, activity, and cognition
The total distance traveled in Open field (OF) tests and the total arm entries in elevated plus maze (EPM) tests were comparable among the investigated groups of mice, indicating that normal locomotor activity is maintained after complete Freund’s adjuvant (CFA) injection and FMNT treatment (F3,24 = 0.197, P = 0.897, Fig. 1e; F3,24 = 0.338, P = 0.798, Fig. 1i; F4,25 = 0.332, P = 0.854, Additional file 1: Figure S1c; F4,25 = 0.022, P = 0.999, Additional file 1: Figure S1f )
These results suggest that FMNT treatment has anxiolytic effects in mice injected with CFA
Summary
Patients suffering from chronic pain often have emotional comorbidities that affect mood, sleep, activity, and cognition. The prevalence of anxiety disorders among patients with chronic pain ranges from 20 to 40%, compared to 7–18% in the general population [1, 2]. Epidemiological studies have reported that the pervasiveness of pain in subjects with anxiety or depression, and that of anxiety or depression in subjects with pain, are higher than in the cohort with either condition alone [3,4,5]. Opioids are the most effective treatment for pain. The incidence of anxiety among opioid-treated chronic pain patients is 48.4% [6]. An effective treatment of chronic pain requires a combination of analgesics as well as anxiolytics [7]
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