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.

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This study aims to explore the value of serum galectin-3 in patients with herpes zoster neuralgia (HZN) and postherpetic neuralgia (PHN) and other factors influencing HZN and PHN occurrence. Samples from forty patients with herpes zoster neuralgia (HZN) (Group H), 40 patients with nonherpes zoster neuralgia (Group N), and 20 cases of health check-up were collected. Patients were divided into PHN group (Group A) and non-PHN group (Group B) according to the occurrence of PHN in Group H. Galectin-3, T-lymphocyte subsets, and IL-6 were recorded in all patients. The changes of galectin-3 in patients with early HZN and PHN were analyzed by single-factor analysis and multifactor analysis. The age (P=0.012) and NRS scores (P<0.001) of PHN patients were significantly higher than those of non-PHN patients and other neuralgia patients. The ratio of CD3+ (F = 80.336, P<0.001), CD4+ (F = 12.459, P<0.001) lymphocyte subsets, and CD4+/CD8+ (F = 15.311, P<0.001) decreased significantly in PHN patients. The level of blood IL-6 (F = 139.446, P<0.001) in PHN patients was significantly increased. Serum galectin-3 was significantly higher in HZN patients than in PHN patients (P<0.05); IL-6 (OR = 10.002, 95% CI: 3.313–30.196, P<0.001) and galectin-3 (OR = 3.719, 95% CI: 1.261–10.966, P=0.017) were the risk factors for HZN; galectin-3 (OR = 17.646, 95% CI: 2.795–111.428, P=0.002) was also the risk factor for PHN. ROC curve analysis also showed that serum galectin-3 was a better predictor of poor prognosis (AUC = 0.934, P<0.001). Therefore, as an independent risk factor of HZN and PHN, serum galectin-3 may be used as a new biochemical marker in clinical practice.

BackgroundPrevious observational studies have shown that low back pain (LBP) often coexists with sleep disturbances, however, the causal relationship remains unclear. In the present study, the causal relationship between sleep disturbances and LBP was investigated and the importance of sleep improvement in the comprehensive management of LBP was emphasized.MethodsGenetic variants were extracted as instrumental variables (IVs) from the genome-wide association study (GWAS) of insomnia, sleep duration, short sleep duration, long sleep duration, and daytime sleepiness. Information regarding genetic variants in LBP was selected from a GWAS dataset and included 13,178 cases and 164,682 controls. MR-Egger, weighted median, inverse-variance weighted (IVW), penalized weighted median, and maximum likelihood (ML) were applied to assess the causal effects. Cochran’s Q test and MR-Egger intercept were performed to estimate the heterogeneity and horizontal pleiotropy, respectively. Outliers were identified and eliminated based on MR-PRESSO analysis to reduce the effect of horizontal pleiotropy on the results. Removing each genetic variant using the leave-one-out analysis can help evaluate the stability of results. Finally, the reverse causal inference involving five sleep traits was implemented.ResultsA causal relationship was observed between insomnia-LBP (OR = 1.954, 95% CI: 1.119–3.411), LBP-daytime sleepiness (OR = 1.011, 95% CI: 1.004–1.017), and LBP-insomnia (OR = 1.015, 95% CI: 1.004–1.026), however, the results of bidirectional MR analysis between other sleep traits and LBP were negative. The results of most heterogeneity tests were stable and specific evidence was not found to support the disturbance of horizontal multiplicity. Only one outlier was identified based on MR-PRESSO analysis.ConclusionThe main results of our research showed a potential bidirectional causal association of genetically predicted insomnia with LBP. Sleep improvement may be important in comprehensive management of LBP.

Background: Management of bone cancer pain is difficult because of its complex mechanisms, which has a major impact on the quality of patients' daily life. Recent studies have indicated that endoplasmic reticulum stress is involved in many neurological and inflammatory pathways associated with pain. However, the factors that contribute to endoplasmic reticulum stress and its causes in bone cancer pain are still unknown. In this study, we examined whether the endoplasmic reticulum stress response is involved in caspase signaling pathway-dependent apoptosis in neurons in the spinal dorsal horn of tumor-bearing rats and whether it thereby induces bone cancer pain. Methods: Bone cancer pain was measured behaviorally by the paw withdrawal threshold. The expression levels of endoplasmic reticulum stress markers, namely, immunoglobulin-binding protein/glucose-regulated protein 78 (BIP/GRP78), activating transcription factor-6 (ATF6), phosphorylated inositol-requiring enzyme-1 (p-IRE1), phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) and cleaved caspase-3, were quantitatively assessed by western blot. The distribution of p-eIF2a (an endoplasmic reticulum marker) and cleaved caspase-3 in the lumbar enlargement of the spinal cord was determined by immunohistochemistry in spinal dorsal horn slices. Results: Bone cancer pain suffered bone damage and persistent mechanical allodynia. Bone cancer pain increased the expression of GRP78, ATF6, p-PERK, p-IRE1, and cleaved caspase-3 in a rat model of bone cancer pain. In addition, p-eIF2a and cleaved caspase-3 were localized to neurons. The intrathecal injection of tauroursodeoxycholic acid as a specific inhibitor of endoplasmic reticulum stress attenuated bone cancer pain and reduced the expression of GRP78, ATF6, p-PERK, p-IRE1, and cleaved caspase-3 in the spinal cord. Moreover, Z-DEVD-FMK (FMK) was also shown to attenuate bone cancer pain. Conclusion: Endoplasmic reticulum stress causes the activation of caspase signaling pathway-dependent apoptosis in neuronal cells and induces bone cancer pain-related hyperalgesia.