Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study.

Background: Frailty has been associated with mental illness (MI) observational studies, but the causal relationship between these factors remains uncertain. We aimed to assess the bidirectional causality between frailty and MI by two-sample Mendelian randomization (MR) analyses. Methods: To investigate the causal relationship among them, summary statistics of frailty index (FI) and six types of MI: anxiety, depression, affective disorder, mania, schizophrenia, and obsessive-compulsive disorder (OCD) were included in this MR study. This MR analysis was performed using inverse variance weighting (IVW), MR-Egger regression, and weighted median. The stability of the results was evaluated using Cochran's Q test, MR-Egger intercept test, Funnel Plots, and leave-one-out analysis. Results: Genetic predisposition to FI was significantly associated with increased anxiety (odds ratio [OR] = 1.62, 95% confidence interval [CI] 1.13-2.33, P = 8.18E-03), depression (OR = 1.88, 95% CI 1.30-2.71, P = 8.21E-04), affective disorder (OR = 1.70, 95% CI 1.28-2.27, P = 2.57E-04). However, our study findings do not demonstrate a causal relationship between FI and mania (OR = 1.02, 95% CI 0.99-1.06, P = 2.20E-01), schizophrenia (OR = 1.02, 95% CI 0.07-0.86, P = 9.28E-01). In particular, although the IVW results suggest a potential causal relationship between FI and OCD (OR = 0.64, 95% CI 0.07-0.86, P = 2.85E-02), the directions obtained from the three methods we employed ultimately show inconsistency. Therefore, the result must be interpreted with caution. The results of the reverse MR analysis indicated a statistically significant and causal relationship between anxiety (OR = 1.06, 95% CI 1.01-1.11, P = 2.00E-02), depression (OR = 1.14, 95% CI 1.04-1.26, P = 7.99E-03), affective disorder (OR = 1.15, 95% CI 1.09-1.21, P = 3.39E-07), and schizophrenia (OR = 1.02, 95% CI 1.01-1.04, P = 1.70E-03) with FI. However, our findings do not provide support for a link between mania (OR = 1.46, 95% CI 0.79-2.72, P = 2.27E-01), OCD (OR = 1.01, 95% CI 1.00-1.02, P = 2.11E-01) and an increased risk of FI. Conclusion: The MR results suggest a potential bidirectional causal relationship between FI and anxiety, depression, and affective disorder. Schizophrenia was found to be associated with a higher risk of FI. The evidence was insufficient to support a causal relationship between Fl and other Ml. These findings offer new insights into the development of effective management strategies for frailty and MI.

Comparison of the Efficacy of Short-term Peripheral Nerve Stimulation and Pulsed Radiofrequency for Treating Herpes Zoster Ophthalmicus Neuralgia.

OBJECTIVE: This study aimed to investigate the effect of therapy with peripheral nerve stimulation (PNS) and pulsed radiofrequency (PRF) combined or PNS and PRF separately in patients with herpes zoster ophthalmicus (HZO). MATERIALS AND METHODS: This cohort study included 106 cases of HZO. Three groups were identified according to the type of treatment received: combination therapy (PNS+PRF) (n=38), PRF (n=37), and PNS (n=31). The observations at 0, 1, 2, and 4 weeks; 3 and 6 months; and 1 and 2 years after the operation were analyzed. Observations at each follow-up included baseline characteristics, Numerical Rating Scale (NRS) and the Pittsburgh Sleep Quality Index (PSQI), concomitant pain medication usage, relapse rate, and adverse events. RESULTS: The postoperative NRS of all 3 groups were significantly lower than preoperative scores. The PSQI of the 3 groups was significantly improved postoperatively, and the concomitant pain medication gradually decreased. Regarding long-term efficacy, the pain NRS and PSQI scores of the PNS+PRF and PNS groups were significantly lower than those of the PRF group ( P <0.05), and the relapse rate of the PRF group was higher than that of the PNS+PRF and PNS groups ( P <0.05). No significant difference was observed between the PNS+PRF and the PNS groups. CONCLUSION: Both PNS and PRF treatment of HZO can decrease the pain score, yielding no serious complications. The combination of PNS and PRF or PNS alone resulted in more significant pain relief than treatment with PRF alone. Thus, PNS therapy may be a better treatment option for HZO.

Alterations in local activity and functional connectivity in patients with postherpetic neuralgia after short-term spinal cord stimulation.

Introduction: The efficacy of short-term spinal cord stimulation (stSCS) as a treatment for neuropathic pain in patients with postherpetic neuralgia (PHN) has already been validated. However, the potential alterations in brain functionality that are induced by such treatment have yet to be completely elucidated. Methods: This study use resting-state functional magnetic resonance imaging (rs-fMRI) to detect the changes in regional homogeneity (ReHo) and degree centrality (DC) related to stimulator-induced pain relief in patients with PHN. A total of 10 patients with PHN underwent an MRI protocol at baseline and after stSCS. Alterations in ReHo and DC were then compared between baseline and after stSCS. We investigated the relationship between clinical parameters and functional changes in the brain. Results: Clinical parameters on pain, emotion, and sleep quality were correlated with ReHo and DC. ReHo and DC were significantly altered in the middle temporal gyrus, precuneus, superior frontal gyrus, supramarginal gyrus, inferior parietal lobule, rolandic operculum, middle occipital gyrus, superior parietal gyrus, and the precentral gyrus after stSCS. A significant correlation was detected between ReHo changes in the middle occipital gyrus, precuneus, inferior parietal gyrus, and changes in pain, emotion, and sleep quality. A significant negative correlation was detected between DC changes in the middle temporal gyrus, rolandic operculum, supramarginal gyrus, precuneus, inferior parietal gyrus, and changes in pain, emotion, and sleep quality. Conclusion: This study found that stSCS is able to induce ReHo and DC changes in patients with PHN, thus suggesting that stSCS can change brain function to alleviate pain, sleep, and emotional disorder.

The Analysis of Percutaneous Balloon Compression on Efficacy and Negative Emotion in the Treatment of Recurrent Trigeminal Neuralgia After Surgical Procedures.

BACKGROUND: Recurrent trigeminal neuralgia (TN) after surgical operations can be quite difficult to treat, and treatment measures have not been standardized. Patients often have long-term, repeated severe pain, which may easily cause anxiety and depression and can exert a negative effect on the quality of life. Despite the known efficacy of percutaneous balloon compression (PBC) for TN, it is unclear whether PBC can be used as the preferred surgical treatment for postoperative recurrent TN and effectively improve patients' negative emotions. OBJECTIVES: This study aimed to evaluate the clinical curative effect of PBC in patients with postoperative recurrent TN and analyze the improvement in conditions such as anxiety, depression, and sleep disorders. STUDY DESIGN: Retrospective study. SETTING: Center of Pain Medicine, Department of Anesthesiology, pain, and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University. METHODS: Clinical data from 121 postoperative recurrent TN patients who underwent PBC between August 2017 and June 2019 were retrospectively reviewed and analyzed. The Barrow Neurological Institute pain intensity (BNI-P) score was used to measure the severity of pain. The Hospital Anxiety and Depression Scale (HADS) and Pittsburgh Sleep Quality Index (PSQI) were used to evaluate anxiety, depression, and sleep status. RESULTS: On postoperative day 1, 104 patients (86.0%) reported no pain, 9 patients (7.4%) had occasional pain that did not require medication, and 8 patients (6.6%) experienced no significant pain relief. The total efficacy was 93.4%. Moreover, 3 patients (2.5%) reported significant pain relief 2 weeks postoperatively. Within a follow-up time of 12 months, 101 (83.5%) patients remained pain-free, while 5 patients (4.1%) experienced recurrence. Taking into account economic factors, the patients were tolerant to pain after taking medication and did not undergo repeated PBC. Forty-six patients (38.0%) suffered from anxiety, 70 patients (57.9%) had depression, and 62 patients (51.2%) had poor sleep quality preoperatively. There were significant improvements in anxiety, depression, and sleep status postoperatively compared with preoperatively. Postoperative side effects included facial numbness in 115 patients (95.0%), masticatory muscle weakness in 86 patients (71.1%), herpes simplex in 18 patients (14.9%), and diplopia secondary to abducens nerve palsy in 2 patients (1.7%). None of the patients had corneal anesthesia, anesthesia dolorosa, aseptic meningitis, cerebrospinal fluid leakage, subarachnoid hemorrhage, carotid cavernous fistula, or death in this study. LIMITATIONS: This study was a single-center retrospective study, the sample size was small, and the follow-up time was relatively short. Therefore, the long-term efficacy of PBC for postoperative recurrent TN needs further evaluation from multiple centers with a large sample size and long-term follow-up. CONCLUSIONS: PBC is a minimally invasive, safe, and effective procedure. Moreover, it significantly improves the symptoms of anxiety, depression, and sleep quality caused by TN, so it appears to be regarded as an optimized choice for patients with recurrent TN after surgical procedures.

Spinal Ninjurin2 contributes to the neuropathic pain via NF-κB-mediated neuroinflammation in the spared sciatic nerve injury rats.

OBJECT: Ninjurin2 (nerve injury induced protein 2, NINJ2) is a molecule which mediates cell-to-cell and cell-to-extracellular matrix interactions in the nervous system. Clinical study shows NINJ2 is associated with the development of postherpetic neuralgia. However, it is lack of direct evidence that NINJ2 participated in neuropathic pain. In this study, we aim to investigate the role of NINJ2 in the development of neuropathic pain in spared sciatic nerve injury rats and the underlying mechanism. METHOD: Spared sciatic nerve injury (SNI) models were established. The level of NINJ2 and p-p65 (a NF-κB family member) were measured in SNI rats by western blots and immunofluorescent staining. Lentivirus encoding small interfering RNA targeting NINJ2 (RNAi) was intrathecally injected into rats. Then the change of pain behavior of rats induced by NINJ2 RNAi was tested by Von-Frey hairs. The change of p-p65 in the spinal cord in rats after NINJ2 RNAi treatment was also measured by western blots. inhibitor of p-p65-induced change of TNF-α, IL-1ß, and IL-6 levels were measured by ELISA. RESULTS: NINJ2 and p-p65 were increased in the spinal cord of SNI rats on the 3, 7, 14th days after modeling. NINJ2 were mainly expressed in neurons, and co-located with p-p65 in the spinal dorsal horn. When down regulating the level of NINJ2 by RNAi, the development of pain in SNI rats was partially blocked. Phosphorylation of p65 was also inhibited by NINJ2 RNAi. Blocking the phosphorylation of NF-κB pathway could inhibit the increase of TNF-α, IL-1ß, and IL-6 in the spinal cord of SNI rats. CONCLUSION: NINJ2 protein was increased in the spinal cord of SNI rats. It participated in the development of nerve injury-induced neuropathic pain by activating neuroinflammation in the spinal cord via NF-κB pathway. This study provides a new target to investigate the mechanism of neuropathic pain.

Downregulation of lncRNA FIRRE relieved the neuropathic pain of female mice by suppressing HMGB1 expression.

Long non-coding RNAs are novel regulators in neuropathic pain. In this study, we aimed to explore the role and the mechanism of lncRNA FIRRE in regulating the secretion of microglial cells-derived proinflammatory cytokines in neuropathic pain. The female mouse model of neuropathic pain was established by bilateral chronic constriction injury (CCI) surgery. The mouse primary microglial cells were induced by lipopolysaccharide (LPS). The interaction between FIRRE and high mobility group box 1 (HMGB1) was assessed by RNA immunoprecipitation, RNA pull-down, and ubiquitination assays. FIRRE expression was upregulated in the spinal cord tissue of female CCI mice and LPS-induced microglial cells. The concentrations of IL-1ß, TNF-α, and IL-6 from LPS-induced microglial cells were reduced by FIRRE knockdown. FIRRE bound to HMGB1 and negatively regulated its protein level. The ubiquitination degradation of HMGB1 was promoted by FIRRE silence. The HMGB1 over-expression reversed the inhibitory effect of FIRRE silence on the secretion of IL-1ß, TNF-α, and IL-6 from LPS-induced microglial cells. The in vivo experiment showed that FIRRE knockdown alleviated neuropathic pain of CCI female mice. Our findings indicated that lncRNA FIRRE downregulation inhibits the secretion of microglial cells-derived proinflammatory cytokines by decreasing HMGB1 expression, thereby relieving neuropathic pain of female mice.

LncRNA KCNA2-AS regulates spinal astrocyte activation through STAT3 to affect postherpetic neuralgia.

OBJECTIVES: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster, but the mechanism of PHN is still unclear. Activation of spinal astrocytes is involved in PHN. Our study aims to explore whether lncRNA KCNA2 antisense RNA (KCNA2-AS) regulates spinal astrocytes in PHN through signal transducers and activators of transcription 3 (STAT3). METHODS: Varicella zoster virus (VZV)-infected CV-1 cells were injected into rats to construct a PHN model. Primary spinal cord astrocytes were activated using S-Nitrosoglutathione (GSNO). Glial fibrillary acidic protein (GFAP; marker of astrocyte activation), phosphorylated STAT3 (pSTAT3), and KCNA2-AS were analyzed by immunofluorescence and RNA fluorescence in situ hybridization. RNA pull-down and RNA immunoprecipitation were used to detect binding of KCNA2-AS to pSTAT3. RESULTS: KCNA2-AS was highly expressed in the spinal cord tissue of PHN model rats, and was positively correlated with GFAP expression. GFAP was significantly increased in GSNO-induced cells, but the knockdown of KCNA2-AS reversed this result. Meanwhile, pSTAT3 was significantly increased in GSNO-induced cells, but knockdown of KCNA2-AS reduced pSTAT3 within the nucleus while the total pSTAT3 did not change significantly. pSTAT3 bound to KCNA2-AS and this binding increased with GSNO treatment. Furthermore, knockdown of KCNA2-AS in PHN model rats relieved mechanical allodynia. CONCLUSION: Down-regulation of KCNA2-AS alleviates PHN partly by reducing the translocation of pSTAT3 cytoplasm to the nucleus and then inhibiting the activation of spinal astrocytes.

Spinal Cord Stimulation in the Treatment of Pediatric Erythromelalgia.

BACKGROUND: In children, erythromelalgia is a rare but difficult to manage condition that results in bilateral episodic pain and redness in distal extremities. It is heat intolerant and relieved by cooling. Management of erythromelalgia is difficult and requires a complex multidisciplinary approach. CASE DESCRIPTION: We present a case of successful treatment of erythromelalgia with short-term spinal cord stimulation in a 12-year-old girl. The patient had severe burning pain, having undergone trials of multiple medical therapies before presenting to our department. Dual-lead spinal cord stimulator electrodes were successfully implanted without complication, leading to excellent pain control, now 8 months postimplant. CONCLUSIONS: This case spurs interest for future research in neuromodulation as part of the multimodal regimen to treat pediatric erythromelalgia.

The Roles of Chemokine CXCL13 in the Development of Bone Cancer Pain and the Regulation of Morphine Analgesia in Rats.

Chemokines are important regulators of immune, inflammatory, and neuronal responses in peripheral and central pain pathway. The aim of this study was to investigate whether chemokine (C-X-C motif) ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) involve in the development of bone cancer pain (BCP) and the regulation of morphine analgesia in rats. The change of pain behaviors in BCP rats were measured by testing paw withdrawal threshold (PWT). The levels of CXCL13, CXCR5 and signal pathway proteins (p-p38, p-ERK and p-AKT etc.) in the spinal cord were measured via western blots. The expression of CXCL13 and CXCR5 in spinal cord was increased in BCP rats. The BCP rats showed decrease of PWTs, which was relieved by CXCR5i. Intrathecally injection of murine recombinant CXCL13 (mrCXCL13) decreased the PWTs of BCP rats and opposed morphine-induced analgesia in BCP rats. In BCP rats, the signal pathway proteins (p38, ERK and AKT) in the spinal cord were activated. CXCL13 and morphine had contrary effect on the phosphorylation of these proteins. MrCXCL13 directly increased the levels of p-p38, p-ERK and p-AKT in BCP rats. However, morphine decreased the levels of these proteins in BCP rats. While blocking the activation of p-p38, p-ERK and p-AKT, morphine analgesia was enhanced. These results suggest CXCL13 participated in bone cancer pain and opposed morphine analgesia via p38, ERK and AKT pathways. It may be a target to enhance pain management in cancer pain patients.

CXCL12/CXCR4 signaling mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats.

Background: It has been demonstrated that upregulation of CXCL12 and CXCR4 in spinal cord involves in the pathogenesis of neuropathic, inflammatory, and cancer pain. However, whether CXCL12/CXCR4 signaling contributes to postsurgical pain remains unknown. The aim of the present study is to investigate the role of CXCL12/CXCR4 signaling in the genesis of postsurgical pain and the underlying mechanism. Results: Plantar incision in rat hind paw resulted in increased expressions of CXCL12 and CXCR4 in spinal dorsal horn. Double immunofluorescence staining revealed that CXCL12 expressed in neurons and astrocytes, and CXCR4 exclusively co-localized with neuronal cells. Prior administration of AMD3100, a specific antagonist of CXCR4, or CXCL12 neutralizing antibody, intrathecally attenuated plantar incision-induced mechanical allodynia and thermal hyperalgesia. Plantar incision also augmented the phosphorylation of NF-κB p65 in spinal cord. Pre intrathecal (i.t.) injection of PDTC, a specific NF-κB activation inhibitor, alleviated plantar incision-induced postsurgical pain and reduced the expression of CXCL12 in spinal cord. Correlated with the upregulation of CXCL12 and CXCR4, plantar incision also resulted in an increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in spinal cord. Prior i.t. administration of AMD3100 prevented extracellular signal-regulated kinase, but not Akt, activation in spinal cord. Rats when given a repetitive i.t. PD98059, a specific extracellular signal-regulated kinase inhibitor, started 30 min before surgery also ameliorate plantar incision-induced mechanical and thermal pain hypersensitivity. Conclusion: Our results suggests that plantar incision-induced activation of NF-κB signaling may mediate upregulation of CXCL12 in spinal cord, and CXCL12/CXCR4 signaling via extracellular signal-regulated kinase activation contributes to the genesis of postsurgical pain.

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats.

Emerging evidence indicates that CXCL12/CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism. Here, we determined that spared nerve injury (SNI) increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia (DRG) neurons and satellite glial cells. SNI also induced long-lasting upregulation of CXCL12 and CXCR4 in the ipsilateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI-induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-α synthesis inhibitor thalidomide reduced the SNI-induced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection (i.t.) of the CXCR4 antagonist AMD3100, both 30 min before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. administration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the activation of ERK in the spinal cord. The mechanical hypersensitivity induced in naïve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL12/CXCR4 signaling via ERK activation contributes to the development and maintenance of neuropathic pain.