Electroacupuncture Attenuates Cancer-Induced Bone Pain via NF-κB/CXCL12 Signaling in Midbrain Periaqueductal Gray

Abstract

Electroacupuncture (EA) is effective in various chronic pains. NF-κB and CXCL12 modulate the formation of chronic pain. Herein, we hypothesized that EA alleviates cancer-induced bone pain (CIBP) through NF-κB/CXCL12 axis in midbrain periaqueductal gray (PAG), which participates in “top-down” pain modulatory circuits. In order to filter the optimum EA frequency for CIBP treatment, 2, 100, or 2/100 Hz EA was set up. In addition, ipsilateral, contralateral, and bilateral EA groups were established to affirm the optimal EA scheme. Bilateral 2/100 Hz EA was considered as the optimal therapeutic scheme and was applied in a subsequent experiment. Western blotting along with immunofluorescence illustrated that CIBP induces a rapid and substantial increase in CXCL12 protein level and NF-κB phosphorylation in vlPAG from day 6 to day 12. Anti-CXCL12 neutralizing antibody and pAAV-U6-shRNA­(CXCL12)-CMV-EGFP-WPRE in vlPAG remarkably improved the mechanical pain threshold of the hind paw in CIBP model relative to the control. EA inhibited the upregulation of pNF-κB and CXCL12 in vlPAG of CIBP. The recombinant CXCL12 and pAAV-CMV-CXCL12-EF1a-EGFP-3Xflag-WPRE reversed the abirritation of EA in the CIBP rat model. NF-κB phosphorylation mediated-CXCL12 expression contributed to CIBP allodynia, whereas EA suppressed NF-κB phosphorylation in CIBP. According to the above evidence, we conclude that bilateral 2/100 Hz EA is an optimal therapeutic scheme for CIBP. The abirritation mechanism of EA might reduce the expression of CXCL12 by inhibiting the activation of NF-κB, which might lead to the restraint of descending facilitation of CIBP.

Effects of Acupuncture on Cancer Pain in Animal Intervention Studies: A Systematic Review and Quality Assessment

“…Finally, 18 studies were included in this review. 17-34 The literature selection process is detailed in Figure 1.…”

Neurophysiological characteristics in the periventricular/periaqueductal gray correlate with pain perception, sensation, and affect in neuropathic pain patients

“…Nociceptive neurons located in laminae VII and VIII of the spinal cord and laminae V and VI of the SpV project to the PAG ( Mouton and Holstege, 2000 , Vanderhorst et al, 1996 ), posterior hypothalamic nucleus ( Çavdar et al, 2001 ), and intralaminar thalamic nuclei ( Carstens and Trevino, 1978 , Royce et al, 1991 , Shigenaga et al, 1983 ). The PAG-involved pain matrix has also been reported in all pain types, such as neuropathic pain ( Samineni, et al, 2017 ), inflammatory pain ( Li and Sheets, 2018 ), and cancer-induced bone pain ( Xu, et al, 2021 ). In a recent study, dopamine neurons in the ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DR) through projections to the bed nucleus of the stria terminalis (BNST) contributed to sex differences in regulating pain-related behaviors ( Yu, et al, 2021 ).…”

Bibliometric Analysis of Acupuncture Therapy for Cancer Pain Over the Past 10 Years

“…Journal of Pain Research 2023:16 998 chronic pain in these patients. 107 The underlying mechanism of cancer-induced bone pain includes reducing the expression of CXCL12 by inhibiting the activation of NF-κB, 108 suppressing the expression of 5-HT and 5-HT3AR, and increasing the expression of MOR and endomorphin-1 in the RVM-spinal cord pathway. 109 Recently, animal research revealed mTOR as a potential target in bone cancer pain and electroacupuncture analgesia.…”