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The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. We showed that ER stress was mutually promotive with oxidative stress during the process. We also tested the hypothesis that spinal sensitization arose from reduced activities of GABA-ergic interneurons and that spinal sensitization was mediated by SDH ER stress. Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain.

There is emerging evidence on the mechanisms of pancreatic cancer pain. Following the establishment of an orthotropic transplantation model of pancreatic cancer, microarray analysis was performed to identify changes in the expression levels of pain-associated genes in the spinal cord. A mouse model of pancreatic cancer-induced pain was established by implanting SW 1990 cells into the pancreases of female BALB/c-nu mice. The survival rate and body weight were measured following orthotropic transplantation. Gross anatomical techniques and hematoxylin and eosin staining were used to analyze the pancreatic tumor tissue. Multiple behavioral tests were also performed to assess pain-associated responses. Additionally, using samples from mice with or without observable pain, microarray analysis was performed to determine the gene expression profiles in the spinal cord dorsal horn. The survival rate of mice with pancreatic cancer was high during the initial 3 weeks post-surgery, although the body weight decreased progressively. Gross anatomical techniques demonstrated that the tumor size increased significantly following the surgery, and this result was confirmed by solid tumor masses in the pancreatic tissues of the mouse model. Observable pain behavioral responses were also examined in the pancreatic cancer model by measuring the mechanical threshold of the abdominal skin, hunching behavior and visceromotor responses. The profiles of 10 pain specific-associated genes in the spinal cord dorsal horn that accurately reflect the molecular pathological progression of disease were also identified. In conclusion, the present study has developed a novel animal model of pancreatic cancer pain in BALB/c-nu mice that resembles human pancreatic cancer pain, and the expression of pain-associated genes in the spinal cord dorsal horn has been profiled. The results of the present study may further the understanding of the molecular mechanisms that mediate pancreatic cancer pain.

Germinal centers (GC) are vital to adaptive immunity. BCL6 and miR-155 are implicated in control of GC reaction and lymphomagenesis. FBXO11 causes BCL6 degradation through ubiquitination in B-cell lymphomas. Chronic psychological stress is known to drive immunosuppression. Corticosterone (CORT) is an adrenal hormone expressed in response to stress and can similarly impair immune functions. However, whether GC formation is disrupted by chronic psychological stress and its molecular mechanism remain to be elucidated. To address this issue, we established a GC formation model in vivo, and a GC B cell differentiation model in vitro. Comparing Naive B cells to GC B cells in vivo and in vitro, the differences of BCL6 and FBXO11 mRNA do not match the changes at the protein level and miR-155 levels that were observed. Next we demonstrated that CORT increase, induced by chronic psychological stress, reduced GC response, IgG1 antibody production and miR-155 level in vivo. The effect of chronic psychological stress can be blocked by a glucocorticoid receptor (GR) antagonist. Similarly, impaired GC B cell generation and isotope class switching were observed. Furthermore, we found that miR-155 and BCL6 expression were downregulated, but FBXO11 expression was upregulated in GC B cells treated with CORT in vitro. In addition, we demonstrated that miR-155 directly down-regulated FBXO11 expression by binding to its 3́-untranslated region. The subsequent overexpression of miR-155 significantly blocked the stress-induced impairment of GC response, due to changes in FBXO11 and BCL6 expression, as well as increased apoptosis in B cells both in vivo and in vitro. Our findings suggest perturbation of GC reaction may play a role in chronic psychological stress-induced immunosuppression through a glucocorticoid pathway, and miR-155-mediated post-transcriptional regulation of FBXO11 and BCL6 expression may contribute to the impaired GC response.