Involvement of spinal NADPH oxidase 4 and endoplasmic reticulum stress in morphine-tolerant rats.

Morphine tolerance (MT) is currently a challenging issue related to intractable pain treatment. Studies have shown that reactive oxygen species (ROSs) derived from NADPH oxidase (NOX) and produced in response to endoplasmic reticulum (ER) stress participate in MT development. However, which NOX subtype initiates ER stress during MT development is unclear. NOX4 is mainly expressed on intracellular membranes, such as the ER and mitochondrial membranes, and its sole function is to produce ROS. Whether NOX4 is activated during MT development and the mechanisms underlying the association between NOX4 and ER stress during this process still need to be confirmed. In our study, we used the classic morphine-tolerant rat model and evaluated the analgesic effect of intrathecally injected morphine through a hot water tail-flick assay. Our research demonstrated for the first time that chronic morphine administration upregulates NOX4 expression in the spinal cord by activating three ER stress sensors, protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), subsequently leading to the activation of microtubule-associated protein 1 light chain 3 b (LC3B) and P62 (a well-known autophagy marker) in GABAergic neurons. Our results may suggest that regulating NOX4 and the key mechanism underlying ER stress or autophagy may be a promising strategy to treat and prevent MT development.

Alteration of static and dynamic intrinsic brain activity induced by short-term spinal cord stimulation in postherpetic neuralgia patients.

Introduction: Short-term spinal cord stimulation (stSCS) is an effective treatment for postherpetic neuralgia (PHN). However, how exactly stSCS affects time-dynamic intrinsic brain activity in PHN patients is not clear. The purpose of this study was to examine the static and dynamic variability of neural activity in PHN patients after stSCS. Methods: In this study, 10 patients with PHN underwent resting-state functional magnetic resonance imaging (rs-fMRI) at baseline and after SCS. The amplitude of low-frequency fluctuations (ALFF) and dynamic ALFF (dALFF) were used to investigate the static and dynamic variability of neural activity in PHN patients after stSCS. We additionally examined the associations between clinical parameters and functional changes in the brain. Results: There was a significant increase in dALFF in the left precuneus and right superior parietal gyrus, and a decrease in dALFF in the left inferior temporal gyrus, right gyrus rectus, left superior temporal gyrus, right orbitofrontal cortex, and left orbitofrontal cortex. There was significantly increased ALFF in the right inferior temporal gyrus, and decreased ALFF in the right lingual gyrus, left superior parietal gyrus, right superior parietal gyrus, and left precuneus. Furthermore, Pittsburgh sleep quality index scores were positively associated with dALFF changes in the left superior temporal gyrus and left orbitofrontal cortex. Hospital anxiety and depression scale scores and continuous pain scores exhibited significant negative correlation with dALFF changes in the right superior parietal gyrus. Conclusion: This study indicated that stSCS is able to cause dALFF changes in PHN patients, thus stSCS might alter brain functions to relieve pain, sleep, and mood symptoms. The findings provide new insights into the mechanisms of stSCS efficacy in the treatment of patients with PHN.

Cav3.2 T-Type calcium channels downregulation attenuates bone cancer pain induced by inhibiting IGF-1/HIF-1α signaling pathway in the rat spinal cord.

Background: Bone cancer pain (BCP) is one of the most ubiquitous and refractory symptoms of cancer patients that needs to be urgently addressed. Substantial studies have revealed the pivotal role of Cav3.2 T-type calcium channels in chronic pain, however, its involvement in BCP and the specific molecular mechanism have not been fully elucidated. Methods: The expression levels of Cav3.2, insulin-like growth factor 1(IGF-1), IGF-1 receptor (IGF-1R) and hypoxia-inducible factor-1α (HIF-1α) were detected by Western blot in tissues and cells. X-ray and Micro CT used to detect bone destruction in rats. Immunofluorescence was used to detect protein expression and spatial location in the spinal dorsal horn. Electrophoretic mobility shift assay used to verify the interaction between HIF-1α and Cav3.2. Results: The results showed that the expression of Cav3.2 channel was upregulated and blockade of this channel alleviated mechanical allodynia and thermal hyperalgesia in BCP rats. Additionally, inhibition of IGF-1/IGF-1R signaling not only reversed the BCP-induced upregulation of Cav3.2 and HIF-1α, but also decreased nociceptive hypersensitivity in BCP rats. Inhibition of IGF-1 increased Cav3.2 expression levels, which were abolished by pretreatment with HIF-1α siRNA in PC12 cells. Furthermore, nuclear HIF-1α bound to the promoter of Cav3.2 to regulate the Cav3.2 transcription level, and knockdown of HIF-1α suppresses the IGF-1-induced upregulation of Cav3.2 and pain behaviors in rats with BCP. Conclusion: These findings suggest that spinal Cav3.2 T-type calcium channels play a central role during the development of bone cancer pain in rats via regulation of the IGF-1/IGF-1R/HIF-1α pathway.

Meckel's Cave Size Measured by Magnetic Resonance Imaging in the Prognosis of Percutaneous Balloon Compression for Trigeminal Neuralgia.

BACKGROUND: Percutaneous balloon compression (PBC) is a safe and effective method to treat trigeminal neuralgia. Despite it is known that intraoperative balloon volume is crucial in the prognosis of PBC patients and correlates with Meckel's cave (MC) size, it is a lack of objective and valid criteria for intraoperative balloon volume of PBC. OBJECTIVES: The aim of this study was to evaluate the relationship between the size of MC and the volume of a pear-shaped balloon in improving the prognosis of patients receiving PBC. STUDY DESIGN: Retrospective study. METHODS: Patients were divided into 3 groups according to their prognosis, and simple linear regression equations were established separately. Group A was defined as having recurrence. Group B was defined as having no recurrence and a Barrow Neurological Institute facial numbness (BNI-N) score of 2 with no recurrence. Correlation analysis was carried out to determine the association of the intraoperative balloon volume with MC size. We attempted to construct simple linear regression models after verifying that both parameters were in compliance with the requirements of this model. RESULTS: Until the end of the 6-months follow-up, 60 patients (93.8%) reported no pain, and 4 patients (6.3%) experienced no significant pain relief. Sixteen (25.0%) patients had severe facial numbness, 48 (75.0%) patients had no facial numbness or had only mild numbness. All 3 groups had a significant correlation between balloon volume and MC size. Group A: Balloon volume (cm3) = -0.371 + 1.883*MC size (R2 = 0.882); Group B: Balloon volume (cm3) = 0.110 + 1.274*MC size (R2 = 0.861); and Group C: Balloon volume (cm3) = 0.011 + 1.835*MC size (R2 = 0.857). LIMITATIONS: The main limitation of our study is its observational retrospective nature, and we were unable to further analyze the intraoperative balloon pressure and volume, as well as validate the accuracy of the model. In additional this was a single-center study with a small sample size and a short follow-up period. These may have contributed to the bias in the final results. A multicenter, prospective study with a large sample size should be performed to further investigate the long-term effects of individualized balloon volumes and the correlation between pressures. CONCLUSIONS: The equation [balloon volume (cm3) = 0.110 cm3 + 1.274*MC size] yields an appropriate value at which the patient has a low recurrence rate and a low degree of facial numbness. Preoperative measurement of MC size can be used to guide the intraoperative balloon volume and to predict the patient's prognosis.

The role of botulinum toxin type A related axon transport in neuropathic pain induced by chronic constriction injury.

Background: The mechanism of peripheral axon transport in neuropathic pain is still unclear. Chemokine ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) as well as GABA transporter 1 (GAT-1) play an important role in the development of pain. The aim of this study was to explore the axonal transport of CXCL13/CXCR5 and GAT-1 with the aid of the analgesic effect of botulinum toxin type A (BTX-A) in rats. Methods: Chronic constriction injury (CCI) rat models were established. BTX-A was administered to rats through subcutaneous injection in the hind paw. The pain behaviors in CCI rats were measured by paw withdrawal threshold and paw withdrawal latencies. The levels of CXCL13/CXCR5 and GAT-1 were measured by western blots. Results: The subcutaneous injection of BTX-A relieved the mechanical allodynia and heat hyperalgesia induced by CCI surgery and reversed the overexpression of CXCL13/CXCR5 and GAT-1 in the spinal cord, dorsal root ganglia (DRG), sciatic nerve, and plantar skin in CCI rats. After 10 mmol/L colchicine blocked the axon transport of sciatic nerve, the inhibitory effect of BTX-A disappeared, and the levels of CXCL13/CXCR5 and GAT-1 in the spinal cord and DRG were reduced in CCI rats. Conclusions: BTX-A regulated the levels of CXCL13/CXCR5 and GAT-1 in the spine and DRG through axonal transport. Chemokines (such as CXCL13) may be transported from the injury site to the spine or DRG through axonal transport. Axon molecular transport may be a target to enhance pain management in neuropathic pain.

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.

Chemokine CXCL10 regulates pain behaviors via PI3K-AKT signaling pathway in mice.

The analgesic efficacy of morphine can be affected by a variety of factors. Our previous studies demonstrated that chemokine (CXC motif) ligand 10 (CXCL10) could induce algesia directly and attenuate the analgesic effect produced by a single dose of morphine. However, the underlying mechanism remains unclear. In the present study, we aimed to further investigate the mechanism of CXCL10-mediated inhibition on morphine analgesic effect. According to our findings, recombinant CXCL10 protein (rmCXCL10) could increase the phosphorylation of serine-threonine kinase AKT reduced by morphine in spinal cord. Blocking AKT activation by phosphoinositide 3-kinase (PI3K) inhibitor could effectively attenuate CXCL10-induced algesia, and reverse the decrease of paw withdrawal thresholds caused by the co-administration of morphine and rmCXCL10. Furthermore, rmCXCL10 could enhance the spinal expression of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1ß, which could be blocked by PI3K inhibitor. In summary, these findings suggest that PI3K-AKT signaling pathway mediates the effect of CXCL10 on the regulation of morphine analgesia and the release of cytokines in spinal cord. Our study provides a new insight into the mechanism of chemokine-relative pain regulation.

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.

NADPH-Oxidase 2 Promotes Autophagy in Spinal Neurons During the Development of Morphine Tolerance.

Repeated morphine administration results in analgesic tolerance. However, the underlying mechanism of morphine analgesic tolerance remains unclear. NADPH-oxidase 2 (NOX2) is the first discovered NADPH oxidase, which mainly functions to produce reactive oxygen species. Its specific role in morphine tolerance has not been fully investigated. In this work, we found that chronic morphine administration significantly increased the expression of NOX2 in spinal cord. Pretreatment of NOX2 inhibitor blocked the upregulation of NOX2 and autophagy markers, including LC3B and P62, and consequently the development of morphine tolerance. NOX2 and LC3B were both colocalized with NeuN in spinal dorsal horn in morphine-tolerant rats. Our results suggest that the increased autophagy activity in spinal neurons promoted by NOX2 activation contributes to the development of morphine tolerance. NOX2 may be considered as a new therapeutic target for morphine tolerance.

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.

Retracted Article: Upregulation of miR-26b alleviates morphine tolerance by inhibiting BDNF via Wnt/ß-catenin pathway in rats.

Background: Morphine is a commonly used analgesic drug. However, long-term use of morphine will cause tolerance which limits its clinical application in pain treatment. MicroRNAs (miRNAs) have been reported to be involved in the morphine tolerance, but the underlying mechanism is still poorly understood. Methods: Tail flick test was used to measure the maximum possible effect (MPE). Quantitative real-time PCR was employed to detect miR-26b, BDNF, and Wnt5a expression in rat dorsal root ganglia (DRG). Luciferase report assay was introduced to verify the binding relationship between miR-26b and Wnt5a. BDNF, Wnt5a and ß-catenin protein level were tested by western blotting. Results: MiR-26b was down-regulated during the development of morphine tolerance while BDNF was upregulated. Overexpression of miR-26b or BDNF inhibition alleviated morphine tolerance. Wnt5a was directly targeted and inhibited by miR-26b via binding to the 3'-UTR of Wnt5a. The Wnt/ß-catenin pathway was active in morphine tolerant rats. Moreover, overexpression of Wnt5a could partially enhance miR-26 mimic-mediated morphine tolerance, while a Wnt5a inhibitor could attenuate the tolerance. Conclusion: The present study demonstrated that miR-26b overexpression alleviated morphine tolerance by inhibiting BDNF via the Wnt/ß-catenin pathway in rats, highlighting a promising target for the treatment of morphine tolerance.

Effects of a family-support programme for pregnant women with foetal abnormalities requiring pregnancy termination: A randomized controlled trial in China.

AIM: We examined the effects of a family-support programme for pregnant women with foetal abnormalities in terms of family support, depression, and post-traumatic stress symptoms. METHOD: A randomized controlled trial was conducted from November 2016 to June 2017. A total of 124 pregnant women with foetal abnormalities were recruited and randomly assigned to the intervention group that received a family-support programme or control group that received only routine care. Self-reported questionnaires including the Family Adaptation Partnership Growth Affection and Resolve Index, the Edinburgh Postnatal Depression Scale, and the Impact of Event Scale-Revised were administered before and after intervention. RESULTS: Relative to the control group, posttest Family Adaptation Partnership Growth Affection and Resolve Index scores and scores on the intimacy domain were significantly higher in the intervention group, the Edinburgh Postnatal Depression Scale and Impact of Event Scale-Revised scores and the scores on all subscales except the intrusion subscale were significantly lower in the intervention group. CONCLUSION: The findings of this study suggest that family-support programme represents an effective and feasible support approach of improving family support and reducing depression and post-traumatic stress symptoms for pregnant women with foetal abnormalities requiring pregnancy termination.

Potential role of CXCL10/CXCR3 signaling in the development of morphine tolerance in periaqueductal gray.

Tolerance to morphine antinociception hinders its long-term use in clinical practice. Interaction between neuron and microglia has been proved to play critical role in the mechanism of morphine tolerance, while CXCL10/CXCR3 signaling has been implicated in neuron-glia signaling and morphine analgesia. This study aims to investigate whether CXCL10/CXCR3 signaling in periaqueductal gray (PAG) contributes to the development of morphine tolerance by modulating neuron-microglia interaction. The results showed that the expressions of CXCR3 and CXCL10 were gradually increased in parallel with repeated morphine administration and activation of microglia. CXCR3 was co-localized with neuronal marker NeuN, while CXCL10 was derived from microglia. Microglia inhibitor minocycline significantly attenuated the expression of CXCL10, besides, both minocycline and CXCR3 inhibitor alleviated the development of morphine tolerance. Taken together, our study provided the evidence that CXCL10/CXCR3 signaling in PAG is involved in the development of morphine analgesic tolerance via neuron-microglia interaction.

Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer-induced bone pain.

Morphine is viewed as one of the classical treatments for intractable pain, but its role is limited by side effects, including analgesic tolerance. A few chemokines have been reported to be engaged in the mechanisms of morphine tolerance. However, the exact roles of CXC chemokine 11 (CXCL11) in chronic morphine tolerance remain unknown. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibia of rats to provoke cancer-induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We found that the level of CXCL11 in lumbar spinal cord was increased during the development of morphine tolerance in cancer-induced bone pain rats. Meanwhile, CXCL11 was co-localized with markers of astrocytes and neurons in the spinal cord. Inhibition of CXCL11 by neutralizing antibodies could remarkably attenuate the degree of morphine tolerance and decrease the activation of astrocytes. Moreover, blocking astrocyte activation by d, l-Fluorocitric acid could distinctly alleviate morphine tolerance and reduce the expression of CXCL11. Finally, morphine stimulation could induce the release of CXCL11 by cultured astrocytes and neurons in vitro. In summary, our results provide evidence that spinal CXCL11 plays a powerful modulatory role in the development of morphine tolerance through cross-talking between astrocytes and neurons. Read the Review series "Pain".

Activation of PI3Kγ/Akt pathway mediates bone cancer pain in rats.

Bone cancer pain (BCP) is one of the most common and severe complications in patients suffering from primary bone cancer or metastatic bone cancer such as breast, prostate, or lung, which profoundly compromises their quality of life. Emerging lines of evidence indicate that central sensitization is required for the development and maintenance of BCP. However, the underlying mechanisms are largely unknown. In this study, we investigated the role of PI3Kγ/Akt in the central sensitization in rats with tumor cell implantation in the tibia, a widely used model of BCP. Our results showed that PI3Kγ and its downstream target pAkt were up-regulated in a time-dependent manner and distributed predominately in the superficial layers of the spinal dorsal horn neurons, astrocytes and a minority of microglia, and were colocalized with non-peptidergic, calcitonin gene-related peptide-peptidergic, and A-type neurons in dorsal root ganglion ipsilateral to tumor cell inoculation in rats. Inhibition of spinal PI3Kγ suppressed BCP-associated behaviors and the up-regulation of pAkt in the spinal cord and dorsal root ganglion. This study suggests that PI3Kγ/Akt signal pathway mediates BCP in rats. Central sensitization is required for the development and maintenance of bone cancer pain (BCP). In this study, we reported that PI3Kγ/Akt mediated the function of ephrinBs/EphBs in the central sensitization under BCP condition, and inhibition of spinal PI3Kγ suppressed BCP-associated behaviors. Our results suggest that inhibition of PI3Kγ/Akt may be a new target for the treatment of BCP.