FUS Contributes to Nerve Injury-Induced Nociceptive Hypersensitivity by Activating NF-κB Pathway in Primary Sensory Neurons.

Dysregulation of pain-associated genes in the dorsal root ganglion (DRG) is considered to be a molecular basis of neuropathic pain genesis. Fused in sarcoma (FUS), a DNA/RNA-binding protein, is a critical regulator of gene expression. However, whether it contributes to neuropathic pain is unknown. This study showed that peripheral nerve injury caused by the fourth lumbar (L4) spinal nerve ligation (SNL) or chronic constriction injury (CCI) of the sciatic nerve produced a marked increase in the expression of FUS protein in injured DRG neurons. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5-expressing Fus shRNA into the ipsilateral L4 DRG mitigated the SNL-induced nociceptive hypersensitivities in both male and female mice. This microinjection also alleviated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in the ipsilateral L4 dorsal horn. Furthermore, mimicking this increase through microinjection of AAV5 expressing full-length Fus mRNA into unilateral L3/4 DRGs produced the elevations in the levels of p-ERK1/2 and GFAP in the dorsal horn, enhanced responses to mechanical, heat and cold stimuli, and induced the spontaneous pain on the ipsilateral side of both male and female mice in the absence of SNL. Mechanistically, the increased FUS activated the NF-κB signaling pathway by promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Our results indicate that DRG FUS contributes to neuropathic pain likely through the activation of NF-κB in primary sensory neurons.SIGNIFICANCE STATEMENT In the present study, we reported that fused in sarcoma (FUS), a DNA/RNA-binding protein, is upregulated in injured dorsal root ganglion (DRG) following peripheral nerve injury. This upregulation is responsible for nerve injury-induced translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Because blocking this upregulation alleviates nerve injury-induced nociceptive hypersensitivity, DRG FUS participates in neuropathic pain likely through the activation of NF-κB in primary sensory neurons. FUS may be a potential target for neuropathic pain management.

Effect of intrathecal NIS-lncRNA antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes mellitus.

BACKGROUND: Blocking increased expression of nerve injury-specific long non-coding RNA (NIS-lncRNA) in injured dorsal root ganglia (DRG) through DRG microinjection of NIS-lncRNA small hairpin interfering RNA or generation of NIS-lncRNA knockdown mice mitigates neuropathic pain. However, these strategies are impractical in the clinic. This study employed a Food and Drug Administration (FDA)-approved antisense oligonucleotides strategy to examine the effect of NIS-lncRNA ASOs on neuropathic pain. METHODS: Effects of intrathecal injection of NIS-lncRNA antisense oligonucleotides on day 7 or 14 after chronic constriction injury (CCI) of the sciatic nerve, fourth lumbar (L4) spinal nerve ligation, or intraperitoneal injection of paclitaxel or streptozotocin on the expression of DRG NIS-lncRNA and C-C chemokine ligand 2 (CCL2, an NIS-lncRNA downstream target) and nociceptive hypersensitivity were examined. We also assessed whether NIS-lncRNA antisense oligonucleotides produced cellular toxicity. RESULTS: Intrathecal NIS-lncRNA antisense oligonucleotides attenuated CCI-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and ongoing nociceptive responses, without changing basal or acute nociceptive responses and locomotor function. Intrathecal NIS-lncRNA antisense oligonucleotides also blocked CCI-induced increases in NIS-lncRNA and CCL2 in the ipsilateral L3 and L4 DRG and hyperactivities of neurones and astrocytes in the ipsilateral L3 and L4 spinal cord dorsal horn. Similar results were found in antisense oligonucleotides-treated mice after spinal nerve ligation or intraperitoneal injection of paclitaxel or streptozotocin. Normal morphologic structure and no cell loss were observed in the DRG and spinal cord of antisense oligonucleotides-treated mice. CONCLUSION: These findings further validate the role of NIS-lncRNA in trauma-, chemotherapy-, or diabetes-induced neuropathic pain and demonstrate potential clinical application of NIS-lncRNA antisense oligonucleotides for neuropathic pain management.

Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study.

BACKGROUND: TN is one of the most common causes of facial pain. A higher prevalence of psychiatric co-morbidities, especially depressive disorder, has been proven in patients with TN; however, a clear temporal-causal relationship between TN and specific psychiatric disorders has not been well established. We performed a nationwide population-based retrospective cohort study to explore the relationship between TN and the subsequent development of psychiatric disorders, including schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. METHODS: We identified subjects who were newly diagnosed with TN between January 1, 2000 and December 31, 2010 in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed for patients without TN who were matched according to age and sex. All TN and control patients were observed until diagnosed with psychiatric disorders, death, withdrawal from the National Health Institute system, or until December 31, 2010. RESULTS: The TN cohort consisted of 3273 patients, and the comparison cohort consisted of 13,092 matched control patients without TN. The adjusted hazard ratio (aHR) of depressive disorder, anxiety disorder and sleep disorder in subjects with TN was higher than that of the controls during the follow-up [aHR: 2.85 (95% confidence interval: 2.11-3.85), aHR: 2.98 (95% confidence interval: 2.12-4.18) and aHR: 2.17 (95% confidence interval: 1.48-3.19), respectively]. CONCLUSIONS: TN might increase the risk of subsequent newly diagnosed depressive disorder, anxiety disorder, and sleep disorder, but not schizophrenia or bipolar disorder. Additional prospective studies are required to confirm these findings.

Risk of Chronic Low Back Pain Among Parturients Who Undergo Cesarean Delivery With Neuraxial Anesthesia: A Nationwide Population-Based Retrospective Cohort Study.

To investigate the risk of chronic low back pain (LBP) in parturients undergoing cesarean delivery (CD) with neuraxial anesthesia (NA). LBP is common during pregnancy and also after delivery, but its etiology is poorly understood. Previous studies that investigated the correlation between epidural labor analgesia and chronic low back pain were inconclusive. These studies lacked objective diagnostic criteria for LBP and did not exclude possible confounders. We performed this nationwide population-based retrospective cohort study to explore the relationship between CD with NA and subsequent LBP. From the Taiwan National Health Insurance Research Database (NHIRD), we identified all primiparas who had given birth between January 1, 2000 and December 31, 2013. Using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes, we identified the women who had vaginal delivery (VD) and those who had CD. The mode of anesthesia was ascertained by the NHI codes. Multivariable logistic regression was used to estimate the odds of postpartum LBP in women undergoing CD with NA compared with those having VD. The outcome was a diagnosis of LBP according to the first ICD-9-CM diagnosis code. The patients were observed for 3 years after delivery or until diagnosis of postpartum LBP, withdrawal from the NHI system, death, or December 31, 2013. Of the 61,027 primiparas who underwent delivery during the observation period, 40,057 were eligible for inclusion in the study. Of these women, 27,097 (67.6%) received VD, 8662 (21.6%) received CD with spinal anesthesia, and 4298 (10.7%) received CD with epidural anesthesia (EA). Women who received CD with EA were found to have higher risk of LBP than did women who received VD, with the adjusted OR being 1.26 (95% CI: 1.17-1.34). CD with EA might increase the risk of subsequent chronic LBP.

Risk of Psychiatric Disorders Following Symptomatic Menopausal Transition: A Nationwide Population-Based Retrospective Cohort Study.

Menopausal transition is highly symptomatic in at least 20% of women. A higher prevalence of psychiatric symptoms, including depression, anxiety, and sleep disturbance, has been shown in women with symptomatic menopausal transition. However, a clear correlation between symptomatic menopausal transition and psychiatric disorders has not been established.We explored the association between symptomatic menopausal transition and subsequent newly diagnosed psychiatric disorders, including schizophrenia as well as bipolar, depressive, anxiety, and sleep disorders.We investigated women who were diagnosed with symptomatic menopausal transition by an obstetrician-gynecologist according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort comprised age-matched women without symptomatic menopausal transition. The incidence rate and the hazard ratios of subsequent newly diagnosed psychiatric disorders were evaluated in both cohorts, based on the diagnoses of psychiatrists.The symptomatic menopausal transition and control cohorts each consisted of 19,028 women. The incidences of bipolar disorders (hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.01-2.80), depressive disorders (HR = 2.17, 95% CI = 1.93-2.45), anxiety disorders (HR = 2.11, 95% CI = 1.84-2.41), and sleep disorders (HR = 2.01, 95% CI = 1.73-2.34) were higher among the symptomatic menopausal transition women than in the comparison cohort. After stratifying for follow-up duration, the incidence of newly diagnosed bipolar disorders, depressive disorders, anxiety disorders, and sleep disorders following a diagnosis of symptomatic menopausal transition remained significantly increased in the longer follow-up groups (1-5 and ≥ 5 years).Symptomatic menopausal transition might increase the risk of subsequent newly onset bipolar disorders, depressive disorders, anxiety disorders, and sleep disorders. A prospective study is necessary to confirm these findings.