Kinshi Kato

MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage

Matrix metalloproteinases (MMPs) emerge as modulators of neuropathic pain. Because myelin protects Abeta afferents from ectopic hyperexcitability and nociception from innocuous mechanical stimuli (or mechanical allodynia), we analyzed the role of MMPs in the development of mechanical allodynia through myelin protein degradation after rat and MMP-9-/- mouse L5 spinal nerve crush (L5 SNC). MMPs were shown to promote selective degradation of myelin basic protein (MBP), with MMP-9 regulating initial Schwann cell-mediated MBP processing after L5 SNC. Acute and long-term therapy with GM6001 (broad-spectrum MMP inhibitor) protected from injury-induced MBP degradation, caspase-mediated apoptosis, macrophage infiltration in the spinal nerve and inhibited astrocyte activation in the spinal cord. The effect of GM6001 therapy on attenuation of mechanical allodynia was robust, immediate and sustained through the course of L5 SNC. In conclusion, MMPs mediate the initiation and maintenance of mechanical nociception through Schwann cell-mediated MBP processing and support of neuroinflammation.

Immediate Anti-tumor Necrosis Factor-α (Etanercept) Therapy Enhances Axonal Regeneration After Sciatic Nerve Crush

Peripheral nerve regeneration begins immediately after injury. Understanding the mechanisms by which early modulators of axonal degeneration regulate neurite outgrowth may affect the development of new strategies to promote nerve repair. Tumor necrosis factor‐α (TNF‐α) plays a crucial role in the initiation of degenerative cascades after peripheral nerve injury. Here we demonstrate using real‐time Taqman quantitative RT‐PCR that, during the time course (days 1–60) of sciatic nerve crush, TNF‐α mRNA expression is induced at 1 day and returned to baseline at 5 days after injury in nerve and the corresponding dorsal root ganglia (DRG). Immediate therapy with the TNF‐α antagonist etanercept (fusion protein of TNFRII and human IgG), administered systemically (i.p.) and locally (epineurially) after nerve crush injury, enhanced the rate of axonal regeneration, as determined by nerve pinch test and increased number of characteristic clusters of regenerating nerve fibers distal to nerve crush segments. These fibers were immunoreactive for growth associated protein‐43 (GAP‐43) and etanercept, detected by anti‐human IgG immunofluorescence. Increased GAP‐43 expression was found in the injured nerve and in the corresponding DRG and ventral spinal cord after systemic etanercept compared with vehicle treatments. This study established that immediate therapy with TNF‐α antagonist supports axonal regeneration after peripheral nerve injury.

Participation of 5-hydroxytryptamine in pain-related behavior induced by nucleus pulposus applied on the nerve root in rats.

Study Design. The role of 5-hydroxytryptamine (5-HT) in sciatica in lumbar disc herniation (LDH) in rats was investigated. Objective. We evaluated the effects of exogenous 5-HT applied on the nerve root on pain-related behavior, the release of endogenous 5-HT in plasma, and the expression of 5-HT2A receptors in dorsal root ganglion (DRG) in a rat LDH model. Summary of Background Data. In previous studies, 5-HT2A receptor antagonists improved sciatica in patients with LDH and attenuated pain-related behavior induced by nucleus pulposus applied to the nerve root in rats. Methods. Adult female Sprague-Dawley rats were divided into four experimental groups [control group; low-dose (10 &mgr;g) 5-HT-group; high-dose (30 &mgr;g) 5-HT-group; and autologous nucleus pulposus (NP) and saline group] and each drug was applied to the L5 nerve root. Von Frey tests were used for pain-behavior testing. To assess levels of endogenous 5-HT released in capillaries surrounding inflamed nerve roots, we measured 5-hydroxyindole acetic acid (5-HIAA), a metabolite of 5-HT. Expression of 5-HT2A receptors in the left L5 DRG was examined by immunohistochemical and immunoblotting analyses in the control and NP groups. Results. Mechanical withdrawal thresholds of the high-dose 5-HT and the NP groups were significantly decreased after surgery compared with the control group and recovered after 14 days in the high-dose 5-HT group. 5-HIAA in plasma was increased by nucleus pulposus applied on the nerve root for 7 days after surgery. The expression of 5-HT2A receptors was enhanced in a time-dependent manner by nucleus pulposus. Conclusion. Exogenous 5-HT to the nerve root induced pain-related behavior with short-lasting effects compared with the nucleus pulposus application. 5-HIAA content in plasma and expression of 5-HT2A receptors in DRG neurons increased early time points after the nucleus pulposus application. These results suggest that 5-HT plays a role in the early phase of the chemical pathogenesis of sciatica in LDH in rats.

Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve

Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine that is implicated in the initiation of neuropathic pain. Locally administered TNF antagonist etanercept offers a promising new treatment approach to target neuropathic pain. Here we evaluate the distribution and binding specificity for TNF isoforms of locally administered etanercept into injured and uninjured rat sciatic nerve. Distribution and co-localization of etanercept and TNF in the injured and uninjured nerve was evaluated at 1, 24, 48 and 96 h after etanercept local application using immunohistochemistry. In addition, binding specificity of etanercept for TNF isoforms was analyzed using immunoblot assay system in nerve lysates. A new observation was that locally administered etanercept reached the endoneurium of the injured but not the uninjured nerve 1 h after its application and mainly co-localized with TNF-positive structures, morphologically similar to Schwann cells and macrophages. We further noticed that immunoblot analyses for etanercept demonstrated its preferential binding to transmembrane and trimer TNF isoforms. Finally, locally administered etanercept inhibited pain-related behaviors in a rat sciatic nerve crush model. We conclude that locally administered etanercept reaches the endoneurial space in the injured nerve and preferentially binds to transmembrane and bioactive trimer TNF isoforms to modulate neuropathic pain. Locally administered etanercept has potential as a targeted immunomodulating agent to treat local pathogenesis in neuropathic pain after peripheral nerve injury.

Interaction of 5-hydroxytryptamine and tumor necrosis factor-α to pain-related behavior by nucleus pulposus applied on the nerve root in rats.

Study Design. The effects of exogenous 5-hydroxytryptamine (5-HT), tumor necrosis factor(TNF)-&agr;, 5-HT + TNF in combination, and autologous nucleus pulposus (NP) at dorsal root ganglion (DRG) were examined using rat models. Objective. To examine the interaction of 5-HT with TNF for pain-related behavior in a rat lumbar disc herniation (LDH) model. Summary of Background Data. 5-HT and TNF have been shown to play roles in sciatica in lumbar disc herniation as chemical factors. Methods. Adult female Sprague-Dawley rats were divided into six groups: 5-HT group, TNF group, 5-HT + TNF (combination) group, NP group, control group, and naive group. Von Frey tests were used for pain-related behavior testing. Expressions of activating transcription factor 3 and calcitonin gene-related peptide (CGRP) were evaluated immunohistochemically. Expressions of TNF, TNF receptor 1 (TNFR1), and 5-HT2A receptors in the left L5 DRG were examined using western blotting. Plasma levels of 5-hydroxyindole acetic acid, a metabolite of 5-HT, were measured. Results. Mechanical withdrawal thresholds were significantly decreased in the 5-HT, TNF, combination, and NP groups compared with controls. Thresholds recovered after 14 days in the 5-HT and TNF groups, and after 28 days in the combination group. Exogenous 5-HT and TNF to the nerve root induced pain-related behavior and lasted for a shorter period compared with combination and NP groups. Activating transcription factor 3– and calcitonin gene-related peptide–immunoreactive DRG neurons were significantly increased only in the early phase in 5-HT, TNF, combination, and NP groups. TNF induced 5-HT2A receptor expressions in the DRG, while 5-HT induced TNF and TNF receptor 1 expressions. Conclusion. The present findings suggest that both 5-HT and TNF induce pain-related behavior and interact with each other to prolong pain-related behavior in a rat LDH model.

The effect of a 5-HT2A receptor antagonist on pain-related behavior, endogenous 5-hydroxytryptamine production, and the expression 5-HT2A receptors in dorsal root ganglia in a rat lumbar disc herniation model.

Study Design. Controlled, interventional, animal study. Objective. To evaluate the effect of a 5-HT2A receptor antagonist on pain-related behavior, endogenous 5-hydroxytryptamine (5-HT) plasma levels, and expression of 5-HT2A receptors in dorsal root ganglia (DRGs) in a rat lumbar disc herniation model. Summary of Background Data. Application of nucleus pulposus on the nerve root induces immediate peripheral 5-HT production and the expression of 5-HT2A receptors in the adjacent DRG. However, the efficacy of a 5-HT2A receptor antagonist for pain relief in this situation and the mechanism remain unknown. Methods. Autologous nucleus pulposus was applied to the left L5 nerve root of 91 adult female Sprague-Dawley rats. The selective 5-HT2A receptor antagonist sarpogrelate hydrochloride (SPG; 1 mg/kg or 10 mg/kg) or vehicle was administered orally once a day from 1 to 21 days postoperatively. Von Frey tests were used to test pain behavior before and after surgery. To assess the effect of SPG on endogenous 5-HT release surrounding the inflamed nerve root, we measured levels of 5-hydroxyindole acetic acid, a 5-HT metabolite, in plasma. Expression of 5-HT2A receptors in the left L5 DRG was examined with immunoblotting. Results. The higher dose (10 mg/kg) of SPG significantly improved the mechanical withdrawal thresholds from 5 to 21 days after surgery compared with vehicle treatment. 5-hydroxyindole acetic acid in plasma was not significantly different among any groups at any time points. Both doses of SPG inhibited the expression of 5-HT2A receptors after surgery compared with vehicle treatment. Conclusion. A selective 5-HT2A receptor antagonist attenuated pain-related behavior and suppressed 5-HT2A receptor expression in the DRG, but did not affect peripheral 5-HT production. Selective 5-HT2A receptor antagonists may attenuate sciatica by blocking and downregulating 5-HT2A receptors in DRGs in lumbar disc herniation. Level of Evidence: NA

Age-Specific Prevalence and Clinical Characteristics of Humeral Medial Epicondyle Apophysitis and Osteochondritis Dissecans: Ultrasonographic Assessment of 4249 Players:

Background: Traction apophysitis of medial epicondyle (MEC) lesions and osteochondritis dissecans (OCD) of the capitellum are common elbow injuries in adolescent baseball players. However, the age-specific prevalence of these pathologies and their influence on elbow pain remain unknown. Purpose: To investigate the age-specific prevalence of each MEC lesion and capitellar OCD and to identify the incidence of elbow pain in each condition. Study Design: Descriptive epidemiology study. Methods: Study participants consisted of 4249 baseball players aged 6 to 17 years. A questionnaire was used to assess history of elbow pain, and morphological changes of the elbow joint were assessed using ultrasonography. Results: Regarding MEC lesions, fragmented (FG) and irregular (IR) lesions both reached their greatest respective prevalence at 11 to 12 years of age. After 14 years of age, IR decreased sharply, whereas FG was maintained at approximately 10%. Hypertrophic (HT) lesions increased sharply, reaching over 50% at 16 years of age, while there was a decrease in IR and FG lesions in the same age group. The prevalence of capitellar OCD remained the same (approximately 2%) throughout all ages except for in players aged 7 to 8 years (>7%). Players with MEC lesions had significantly greater prevalence of a history of elbow pain compared with those without (68.0% vs 39.1%) and were at a significantly greater risk for FG lesions (odds ratio [OR], 4.04; 95% CI, 3.16-5.22) compared with IR (OR, 3.22; 95% CI, 2.44-4.27) and HT lesions (OR, 2.03; 95% CI, 1.75-2.36). Players with capitellar OCD also had a significantly greater risk of a history of elbow pain (OR, 2.34; 95% CI, 1.40-4.11). Conclusion: Controlling the amount of practice and its intensity according to the condition of each player in the preadolescent and adolescent periods may be important in accelerating bony healing and decreasing preventable elbow pain in adulthood.

Vertebral fracture at the caudal end of a surgical fusion for thoracic vertebral fracture in a patient with diffuse idiopathic skeletal hyperostosis (DISH)

The patient was an 86-year-old woman with back pain after a fall. She had no neurological findings at the initial visit. Plain radiographs and magnetic resonance imaging (MRI) showed diffuse idiopathic skeletal hyperostosis (DISH) and a Th10 fracture. Two weeks later, she started gait exercise with immobilization by a rigid orthosis. Twenty-five days later, she presented with paralysis and numbness of her legs. Computed tomography (CT) showed anterior expansion in the vertebral body of Th10. MRI showed an intramedullary high-intensity area on T2-weighted images at the same level. She was diagnosed as having delayed paraplegia after a Th10 fracture and transferred to our hospital for surgery. Laminectomy of Th10, posterior fusion from Th7 to L1 with pedicle screws and hooks to Th6 and L1 laminae, anterior fusion from Th9 to Th11 with a plate, and autologous bone grafting were performed simultaneously. The patients paralysis improved, and she started gait exercise with no limitation of bed rest and without an orthosis after surgery. At 8 days after surgery, she again presented with low back pain and paralysis in her legs. CT revealed an L1 fracture, which was the caudal end of the surgical fusion. The decreased kyphosis after surgery compared to that at pre-injury might have caused a subsequent horizontal shear force to L1 when the patient sat on the bed and when she walked. In conclusion, to avoid postoperative adjacent vertebral fracture after fusion, appropriate correction of spinal alignment to that at pre-injury is needed for vertebral fractures in patients with DISH.

Psychosocial Stress After a Disaster and Low Back Pain-related Interference With Daily Living Among College Students: A Cohort Study in Fukushima

Study Design. A cohort study. Objective. To investigate the association between psychosocial stress and low back pain (LBP)-related interference with daily living among college students. Summary of Background Data. Few longitudinal studies have examined the likelihood of developing LBP in the presence of a designated psychosocial stressor. All participants in the present study were suddenly affected by the Great East Japan disaster after enrolment in our cohort study. Methods. The present study was initiated among 95 students at Fukushima Medical University in January 2011. We assessed psychosocial stress in students using the Japanese version of the Perceived Stress Scale (JPSS). Follow-up surveys were conducted in July 2011 and May 2013, analyzing 94 students. Students were then divided into three groups (improved, −19 to −4; Maintained, −3 to +4; Aggravated, +5 to +22) based on the tertile points of JPSS change from baseline to 4 months after the disaster. LBP-related interference with daily living was assessed using the Brief Pain Inventory (BPI) questionnaire. Linear regression modeling was performed with BPI at 4 months after the disaster as the outcome, and JPSS change, sex, history of LBP, baseline physical activity, and baseline BPI as explanatory variables. Results. We found a significant increase in BPI score for the aggravated stress group (&bgr; coefficient, +0.79; 95% confidence interval, +0.06–+1.53), compared with the improved stress group. History of LBP and higher physical activity were also significantly associated with BPI. Conclusion. The present study suggests that perceived psychosocial stress induced by the disaster may be associated with LBP-related interference with daily living among college students in Fukushima. Level of Evidence: 3

The prevalence of scapular malalignment in elementally school aged baseball player and its association to shoulder disorder

BACKGROUND Various shoulder disorders have been reported to be associated with scapulothoracic joint dysfunction in adult overhead athletes. However, little is known about the prevalence of scapular malalignment and its relationship to shoulder injuries in skeletally immature baseball players. The purpose of the current study was to investigate the prevalence of scapular malalignment in elementary school-aged baseball players, as well as its association with shoulder disorder. METHODS One hundred sixty-nine baseball players in higher elementary school grades (aged 11-12 years) were enrolled in this study. Shoulder pain experience pain over the previous one year, as well as other individual and environmental factors were surveyed by a self-completed questionnaire. Scapula malalignment was assessed using still images of both arms both at the side and in an elevated position. The relative position of the dominant scapula to the non-dominant side was assessed by two independent examiners. RESULTS Scapular malalignment was observed in 126 subjects (74.6%), and the dominant scapula tended to deviate inferiorly and medially, as well as tilt anteriorly, compared with the non-dominant side. Forty-four of the 169 subjects (23.8%) experienced shoulder pain over the one year period. The prevalence of shoulder pain was significantly increased with the increasing scapular anterior tilt and the superior shift of the dominant scapula, whereas no significant correlation between shoulder pain and scapular horizontal shift or upward-downward rotation was observed. CONCLUSION About three-quarters of the elementary school-aged baseball players in the current study presented with scapular malalignment, and those with anterior tilt and superior shift of the dominant scapula were at higher risk of shoulder pain.