Shaoling Wu

Cross-cultural adaptation, reliability, and validity of the Chinese version of the STarT Back Screening Tool in patients with low back pain.

Study Design. Translation and psychometric testing. Objective. The study aims to investigate the reliability and validity of the Chinese version of the STarT Back Screening Tool (STarT) in Chinese-speaking patients with low back pain (LBP) after translation and cultural adaptation. Summary of Background Data. To date, no previous studies exist on the translation process and validation of the Chinese version of the STarT. Methods. The procedure of translation, which included 6 stages, was performed according to the current recommended guidelines. Psychometric testing included face validity, test-retest reliability, and discriminant validity. A total of 307 patients completed a questionnaire booklet containing the Chinese version of the STarT, Roland-Morris Disability Questionnaire, Coping Strategies Questionnaire, Tampa Scale for Kinesiophobia-17, and Hospital Anxiety and Depression Scale. Seventy-four randomly selected patients were asked to finish the STarT a second time within 24 to 48 hours. The demographic characteristics and outcomes of psychometric testing were compared with the original English cohort. Results. No items of the final version had reported ambiguity after the face validation and no floor or ceiling effects were noted. The intraclass correlation coefficient was 0.933 (95% confidence interval, 0.896–0.957), demonstrating very good reliability. Discriminant validity was established, with area under curve results in the range from 0.751 to 0.893 (95% confidence interval, 0.697–0.930) in the Chinese cohort compared with 0.840 to 0.925 (95% confidence interval, 0.772–0.948) in the original English cohort. Conclusion. The results confirm the successful translation and adaptation of the STarT into Chinese, with appropriate reliability and validity. Therefore, this version can be recommended for clinical and research use for Chinese patients with LBP. Level of Evidence: 4

Running Exercise Alleviates Pain and Promotes Cell Proliferation in a Rat Model of Intervertebral Disc Degeneration

Chronic low back pain accompanied by intervertebral disk degeneration is a common musculoskeletal disorder. Physical exercise, which is clinically recommended by international guidelines, has proven to be effective for degenerative disc disease (DDD) patients. However, the mechanism underlying the analgesic effects of physical exercise on DDD remains largely unclear. The results of the present study showed that mechanical withdrawal thresholds of bilateral hindpaw were significantly decreased beginning on day three after intradiscal complete Freund’s adjuvant (CFA) injection and daily running exercise remarkably reduced allodynia in the CFA exercise group beginning at day 28 compared to the spontaneous recovery group (controls). The hindpaw withdrawal thresholds of the exercise group returned nearly to baseline at the end of experiment, but severe pain persisted in the control group. Histological examinations performed on day 70 revealed that running exercise restored the degenerative discs and increased the cell densities of the annulus fibrosus (AF) and nucleus pulposus (NP). Furthermore, immunofluorescence labeling revealed significantly higher numbers of 5-bromo-2-deoxyuridine (BrdU)-positive cells in the exercise group on days 28, 42, 56 and 70, which indicated more rapid proliferation compared to the control at the corresponding time points. Taken together, these results suggest that running exercise might alleviate the mechanical allodynia induced by intradiscal CFA injection via disc repair and cell proliferation, which provides new evidence for future clinical use.

Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib

&NA; Bortezomib is a first‐line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib‐induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5 days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p‐STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p‐STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I‐201 attenuated bortezomib‐induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment.

Antinociceptive Effect of Intrathecal Microencapsulated Human Pheochromocytoma Cell in a Rat Model of Bone Cancer Pain

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.

Transport of Glial Cell Line-Derived Neurotrophic Factor into Liposomes across the Blood-Brain Barrier: In Vitro and in Vivo Studies

Glial cell line-derived neurotrophic factor (GDNF) was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB). In this study, GDNF conventional liposomes (GDNF-L) and GDNF target sterically stabilized liposomes (GDNF-SSL-T) were prepared. The average size of liposomes was below 90 nm. A primary model of BBB was established and evaluated by transendothelial electrical resistance (TEER) and permeability. This BBB model was employed to study the permeability of GDNF liposomes in vitro. The results indicated that the liposomes could enhance transport of GDNF across the BBB and GDNF-SSL-T had achieved the best transport efficacy. The distribution of GDNF liposomes was studied in vivo. Free GDNF and GDNF-L were eliminated rapidly in the circulation. GDNF-SSL-T has a prolonged circulation time in the blood and favorable brain delivery. The values of the area under the curve (AUC(0–1 h)) in the brain of GDNF-SSL-T was 8.1 times and 6.8 times more than that of free GDNF and GDNF-L, respectively. These results showed that GDNF-SSL-T realized the aim of targeted delivery of therapeutic proteins to central nervous system.

Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib

ABSTRACT Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD‐like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription‐3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno‐associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats. Furthermore, the expressions of p‐STAT3 were colocalized with NLRP3‐positive cells in DRG neurons, and inhibition of STAT3 by intrathecal injection of AAV‐Cre‐GFP into STAT3flox/flox mice or inhibitor S3I‐201 suppressed the upregulation of NLRP3 and mechanical allodynia induced by bortezomib treatment. Chromatin immunoprecipitation further found that bortezomib increased the recruitment of STAT3, as well as the acetylation of histone H3 and H4, in the NLRP3 promoter region in DRG neurons. Importantly, inhibition of the STAT3 activity by using S3I‐201 or DRG local deficiency of STAT3 also significantly prevented the upregulated H3 and H4 acetylation in the NLRP3 promoter region following bortezomib treatment. Altogether, our results suggest that the upregulation of NLRP3 in DRG via STAT3‐dependent histone acetylation is critically involved in bortezomib‐induced mechanical allodynia. HIGHLIGHTSUpregulation of the core inflammasome component NLRP3 in dorsal root ganglion played an important role in bortezomib‐induced mechanical allodynia.STAT3 activation in dorsal root ganglion contributed to bortezomib‐induced mechanical allodynia.STAT3 activation via histone hyperacetylation mediated NLRP3 upregulation following bortezomib treatment.

Palmitoylation of δ-catenin promotes kinesin-mediated membrane trafficking of Nav1.6 in sensory neurons to promote neuropathic pain

Blocking the palmitoylation of the cell adhesion protein δ-catenin or its subsequent interactions may be therapeutic in patients with chronic pain. Palmitoylation and pain Chronic pain is associated with inflammation and increased synaptic activity in sensory neurons. Zhang et al. found that induction of the inflammatory cytokine TNF-α after chemotherapy or nerve injury in rats promoted the formation of a complex between the cell adhesion protein δ-catenin, the voltage-gated sodium channel Nav1.6, and the kinesin motor protein KIF3A, which increased the trafficking of the sodium channel to the cell membrane. Formation of this complex was dependent on the palmitoylation of δ-catenin, and inhibiting the activity of palmitoyl acyltransferases prevented the increase in both Nav1.6 surface abundance in sensory neurons and pain sensitivity in rats. These findings reveal potential therapeutic targets for treating chronic, neuropathic pain in patients. Palmitoylation of δ-catenin is critical to synapse plasticity and memory formation. We found that δ-catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated δ-catenin and the palmitoyl acyltransferase DHHC3 were increased in dorsal root ganglion (DRG) sensory neurons in rat models of neuropathic pain. Inhibiting palmitoyl acyltransferases or decreasing δ-catenin abundance in the DRG by intrathecal injection of 2-bromopalmitate or shRNA, respectively, alleviated oxaliplatin or nerve injury–induced neuropathic pain in the rats. The palmitoylation of δ-catenin, which was induced by the inflammatory cytokine TNF-α, facilitated its interaction with the voltage-gated sodium channel Nav1.6 and the kinesin motor protein KIF3A, which promoted the trafficking of Nav1.6 to the plasma membrane in DRG neurons and contributed to mechanical hypersensitivity and allodynia in rats. These findings suggest that a palmitoylation-mediated KIF3A/δ-catenin/Nav1.6 complex enhances the transmission of mechanical and nociceptive signals; thus, blocking this mechanism may be therapeutic in patients with neuropathic pain.

CT-guided nucleoplasty with radiofrequency energy for the treatment of lumbar disk herniation.

Study Design: A clinical randomized controlled trial. Objective: This study sought to compare the clinical effectiveness of CT-guided nucleoplasty, CT-guided nucleoplasty combined with nerve root injection, and CT-guided transforaminal lumbar epidural injections in treating patients with contained lumbar disk herniation and leg pain, which are caused by radicular encroachment. Summary of Background Data: Lumbar disk herniation is the most common cause of nerve root pain. The conservative treatment is proved to be effective for the majority of these patients, and the remaining patients are not ideal surgical candidates. Studies have found that minimally invasive percutaneous disk procedures may be preferable to open surgery in certain clinical situations. However, nucleoplasty in treating contained lumbar disk herniation and leg pain caused by radicular encroachment is still a controversy. Design: A total of 97 patients with leg pain and MRI evidence of small-sized or medium-sized herniated disks correlating with the symptoms participated in the study. The patients were randomly allocated into 3 groups: the CT-guided nucleoplasty group (N=33), the CT-guided nucleoplasty with nerve root injection group (N=35), and CT-guided transforaminal lumbar epidural injections group (N=29). Numeric Rating Scale (NRS) pain score and Oswestry Disability Index (ODI) values were applied at pretreatment and 1 week, 1 month, 3 months, and 12 months at posttreatment. Results: There were statistically significant decreases (P=0.000) in the NRS and ODI scores for all posttreatment time points when compared with the pretreatment values in all the 3 groups. The average NRS and ODI results for the transforaminal lumbar epidural injections group were significantly higher than those for the other 2 groups at 3 and 12 months posttreatment (P<0.05). The combination of nucleoplasty with nerve root injection produced a significantly greater reduction in the NRS and ODI scores when compared with nucleoplasty at 1 week (P=0.000 for NRS and P=0.004 for ODI) and 1 month (P=0.000 for NRS and P=0.007 for ODI) after the treatment. Conclusions: The results of this study suggest that CT-guided nucleoplasty with radiofrequency energy is a relative effective and safe technique for treating leg pain caused by radicular encroachment. Furthermore, nucleoplasty combined with nerve root injection had achieved a significant greater improvement in pain management and functional level in short term (within 1 mo) after treatment than nucleoplasty alone.

Epigenetic upregulation of CXCL12 expression contributes to the acquisition and maintenance of morphine-induced conditioned place preference

ABSTRACT Addiction and rewarding effect is a primary side effect of morphine, which is commonly used to relieve the acute or chronic pain. Several lines of evidence have suggested that inflammation response in the VTA contributes to morphine‐induced reward (conditioned place preference, CPP), while the mechanism are poorly understood. The present study showed that repeated morphine conditioning persistently increased the expression of CXCL12 mRNA and protein in VTA. Furthermore, inhibition of CXCL12 prevented the acquisition and maintenance, but not the expression, of morphine‐induced CPP in rodent. In addition, molecular analysis revealed that morphine conditioning increased the occupancy of p‐STAT3 in the specific binding site (‐1667/‐1685) of CXCL12 promoter regions, and enhanced the interaction between acetyltransferase p300 and STAT3, and, hence, induced the histone H4 hyperacetylation in the promoter region and facilitated the transcription and expression of CXCL12 in VTA. Collectively, these results, for the first time, provided the evidence that persisted increase of VTA CXCL12 via epigenetic mechanism mediated the acquisition and maintenance, but not the expression, of morphine CPP. HIGHLIGHTSPersistently increased CXCL12 expression in the VTA contributed to the acquisition and maintenance of morphine CPP.p‐STAT3 bound to special sites in the CXCL12 promoter region and regulated CXCL12 expression.Interaction between p‐STAT3 and P300 induced epigenetic upregulation of CXCL12 after morphine conditioning.

Ultrasonography-Guided Lumbar Periradicular Injections for Unilateral Radicular Pain

Objective. The aim of this study was to compare the accuracy and efficacy of sonographically guided lumbar periradicular injections through in-plane or out-of-plane approach techniques for patients with unilateral lower lumbar radicular pain. The feasibility and accuracy of these techniques were studied by means of computed tomography (CT). Methods. A total of 46 patients with chronic unilateral lumbar radicular pain were recruited and randomly assigned to either the in-plane or out-of-plane injection group. A mixture of 3 mL 1% lidocaine and 7 mg betamethasone was injected. The visual analog scale (VAS) was used to assess pain before and after treatment. Results. The pain intensity, as measured by VAS, significantly decreased in both in-plane and out-of-plane injection groups. Conclusions. The sonographically guided periradicular injections are feasible and effective in treating lumbar unilateral radicular pain.