Up-Regulation of Pain Behavior and Glial Activity in the Spinal Cord after Compression and Application of Nucleus Pulposus onto the Sciatic Nerve in Rats

Masaki Norimoto,Yoshihiro Sakuma,Miyako Suzuki,Sumihisa Orita,Kazuyo Yamauchi,Gen Inoue,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Gou Kubota,Yasuhiro Oikawa,Kazuhide Inage,Takesh 대한척추외과학회 2014 Asian Spine Journal Vol.8 No.5

Study Design: Experimental animal study. Purpose: To evaluate pain-related behavior and changes in glial activity in the spinal dorsal horn after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. Overview of Literature: Mechanical compression and inflammation caused by prostaglandins and cytokines at disc herniation sites induce pain. Structural changes and pain-associated cytokines in the dorsal root ganglia and spinal dorsal horn contribute to prolonged pain. Glial cells in the spinal dorsal horn may also function in pain transmission. Methods: The sciatic nerve was compressed with NP for 2 seconds using forceps in the NP+nerve compression group; the shamoperated group received neither compression nor NP; and the control group received no operation. Mechanical hyperalgesia was measured for 3 weeks using von Frey filaments. Glial activity in the spinal dorsal horn was examined 7 days and 14 days postsurgery using anti-glial fibrillary acidic protein and anti-Ionized calcium binding adaptor molecule-1 antibodies to detect astrocytes and microglia, respectively. Results: Mechanical hyperalgesia was detected throughout the 14-day observation in the NP+nerve compression group, but not in control or sham-operated groups (p <0.05). Both astrocytes and microglia were significantly increased in the spinal dorsal horn of the NP+nerve compression group compared to control and sham groups on days 7 and 14 (p <0.05). Conclusions: Nerve compression with NP application produces pain-related behavior, and up-regulates astrocytes and microglia in the spinal dorsal horn, suggesting that these glia may be related to pain transmission.

Assessment of Clinical Symptoms in Lumbar Foraminal Stenosis Using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire

Yawara Eguchi,Munetaka Suzuki,Hajime Yamanaka,Hiroshi Tamai,Tatsuya Kobayashi,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Kazuhide Inage,Hirohito Kanamoto,Koki Abe,Yasuchika Aoki,Masao Koda,Takeo Fur 대한척추신경외과학회 2017 Neurospine Vol.14 No.1

Objective: It is important to develop an easy means of diagnosing lumbar foraminal stenosis (LFS) in a general practice setting. We investigated the use of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) to diagnose LFS in symptomatic patients. Methods: Subjects included 13 cases (mean age, 72 years) with LFS, and 30 cases (mean age, 73 years) with lumbar spinal canal stenosis (LSCS) involving one intervertebral disc. The visual analogue scale score for low back pain and leg pain, the JOABPEQ were evaluated. Results: Those with LFS had a significantly lower JOA score (p<0.001), while JOABPEQ scores (p<0.05) for lumbar dysfunction and social functioning impairment (p<0.01) were both significantly lower than the scores in LSCS. The following JOABPEQ questionnaire items (LFS vs. LSCS, p-value) for difficulties in: sleeping (53.8% vs. 16.6%, p<0.05), getting up from a chair (53.8% vs. 6.6%, p<0.001), turning over (76.9% vs. 40%, p<0.05), and putting on socks (76.9% vs. 26.6%, p<0.01) such as pain during rest, and signs of intermittent claudication more than 15 minutes (61.5% vs. 26.6%, p<0.05) were all significantly more common with LFS than LSCS. Conclusion: Results suggest that of the items in the JOABPEQ, if pain during rest or intermittent claudication is noted, LFS should be kept in mind as a cause during subsequent diagnosis and treatment. LFS may be easily diagnosed from LSCS using this established patient-based assessment method.

Transient Receptor Potential Vanilloid 1-Immunoreactive Innervation Increases in Fractured Rat Femur

Yuya Kawarai,Seiji Ohtori,Miyako Suzuki,Kensuke Yoshino,Gen Inoue,Sumihisa Orita,Kazuyo Yamauchi,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Go Kubota,Yoshihiro Sakuma,Yasuhiro Oik 연세대학교의과대학 2014 Yonsei medical journal Vol.55 No.1

Purpose: Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture. Materials and Methods: We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points. Results: Four weeks after fracture,complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture (p<0.05). Conclusion: Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain.

Influence of Skeletal Muscle Mass and Spinal Alignment on Surgical Outcomes for Lumbar Spinal Stenosis

Yawara Eguchi,Munetaka Suzuki,Hajime Yamanaka,Hiroshi Tamai,Tatsuya Kobayashi,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Kazuhide Inage,Kazuki Fujimoto,Hirohito Kanamoto,Koki Abe,Masaki Norimoto,Tom 대한척추외과학회 2018 Asian Spine Journal Vol.12 No.3

Study Design: Retrospective observational study. Purpose: We considered the relationship between spinal alignment and skeletal muscle mass on clinical outcomes following a surgery for lumbar spinal stenosis (LSS). Overview of Literature: There are no reports of preoperative factors predicting residual low back pain following surgery for LSS. Methods: Our target population included 34 women (mean age, 74.4 years) who underwent surgery for LSS. Prior to and 6 months after the surgery, systemic bone mineral density and lean soft tissue mass were measured using dual-energy X-ray absorptiometry. Skeletal muscle mass index (SMI) was calculated as the sum of the arm and leg lean mass in kilograms divided by height in meters squared. The spinal alignment was also measured. Clinical outcomes were evaluated using the Japanese Orthopedic Association scoring system, leg and low back pain Visual Analog Scale, and Roland–Morris Disability Questionnaire (RDQ). Additionally, we examined the bone mineral density, skeletal muscle mass, and spinal alignment before and after the surgery. We used the Spearman correlation coefficient to examine the associations among clinical outcomes, preoperative muscle mass, and spinal alignment. Results: Sarcopenia (SMI <5.46) was observed in nine subjects (26.5%). Compared with normal subjects (SMI >6.12), RDQ was significantly higher in subjects with sarcopenia (p =0.04). RDQ was significantly negatively correlated with SMI (r =−0.42, p <0.05). There was a significant positive correlation between postoperative RDQ and pelvic tilt (PT; r =0.41, p <0.05). SMI and PT were significantly negatively correlated (r =−0.39, r <0.05). Conclusions: Good postoperative outcomes were negatively correlated with low preoperative appendicular muscle mass, suggesting that postoperative outcomes were inferior in cases of decreased appendicular muscle mass (sarcopenia). Posterior PT due to decreased limb muscle mass may contribute to postoperative back pain, showing that preoperatively reduced limb muscle mass and posterior PT are predictive factors in the persistence of postoperative low back pain.

Increase of TRPV1-Immunoreactivity in Dorsal Root Ganglia Neurons Innervating the Femur in a Rat Model of Osteoporosis

Kensuke Yoshino,Seiji Ohtori,Miyako Suzuki,Yuya Kawarai,Yoshihiro Sakuma,Gen Inoue,Sumihisa Orita,Kazuyo Yamauchi,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Gou Kubota,Yasuhiro Oi 연세대학교의과대학 2014 Yonsei medical journal Vol.55 No.6

Purpose: Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselectivecation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervatingthe femur has not been reported. Materials and Methods: TRPV1-immunoreactive(ir) in dorsal root ganglia (DRG) neurons labeled with neurotracer [Fluoro-Gold (FG)] innervating the femurs of Sprague Dawley rats were examined in control, sham, and ovariectomized (OVX) rats. We evaluated osteoporosis in the femursand compared the proportion of TRPV1-ir DRG neurons innervating femur between the 3 groups of rats. Results: OVX rats showed osteoporotic cancellous bone in the femur. FG labeled neurons were distributed from L1 to L6 DRG, but there was no significant difference in the proportion of labeled neurons between the 3 groups (p>0.05). The proportions of FG labeled TRPV1-ir DRG neurons were 1.7%, 1.7%, and 2.8% of DRG neurons innervating the femur, in control, sham-operated,and OVX rats, respectively. The proportion of TRPV1-ir neurons in DRG innervating the femur in OVX rats was significantly higher than that in control and sham-operated rats (p<0.05). Conclusion: Under physiological conditions, DRG neurons innervating femurs in rats contain TRPV1. Osteoporosis increases the numbers of TRPV1-ir neurons in DRG innervating osteoporotic femurs in rats. These findings suggest that TRPV1 may have a role in sensory perception of osteoporoticfemurs.

Evaluation of Behavior and Expression of Receptor Activator of Nuclear Factor-Kappa B Ligand in Dorsal Root Ganglia after Sciatic Nerve Compression and Application of Nucleus Pulposus in Rats

Yoshiyuki Matsuyama,Yoshihiro Sakuma,Miyako Suzuki,Sumihisa Orita,Kazuyo Yamauchi,Gen Inoue,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Gou Kubota,Yasuhiro Oikawa,Kazuhide Inage,Ta 대한척추외과학회 2014 Asian Spine Journal Vol.8 No.5

Study Design: Experimental animal study. Purpose: To evaluate pain-related behavior and changes in nuclear factor-kappa B (NF-kB), receptor activator of NF-kB (RANK), and ligand (RANKL) in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. Overview of Literature: The pathological mechanisms underlying pain from lumbar-disc herniation have not been fully elucidated. RANKL are transcriptional regulators of inflammatory cytokines. Our aim was to evaluate pain-related behavior and RANKL expression in DRG after sciatic-nerve compression and application of NP in rats. Methods: Mechanical hyperalgesia and RANKL expression were assessed in three groups of rats: NP+sciatic nerve compression (2 seconds), sham-operated, and controls (n=20 each). Mechanical hyperalgesia was measured every other day for 3 weeks using von Frey filaments. RANKL expression in L5 DRGs was examined at five and ten days after surgery using immunohistochemistry. Results: Mechanical hyperalgesia was observed over the 12-day observation period in the NP+nerve compression group, but not in the control and sham-operated animal groups (p <0.05). RANKL immunoreactivity was seen in the nuclei of L5 DRG neurons, and its expression was significantly upregulated in NP+nerve compression rats compared with control and sham-operated rats (p <0.01). Conclusions: The exposure of sciatic nerves to mechanical compression and NP produces pain-related behavior and up-regulation of RANKL in DRG neurons. RANKL may play an important role in mediating pain after sciatic nerve injury with exposure to NP.

Dose Optimization for Single Intradiscal Administration of the Tumor Necrosis Factor-α Inhibitor, Etanercept, in Rat Disc Injury Models

Kazuhide Inage,Sumihisa Orita,Kazuyo Yamauchi,Takane Suzuki,Miyako Suzuki,Yoshihiro Sakuma,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga,Koki Abe,Hirohito Kanamoto,M 대한척추외과학회 2016 Asian Spine Journal Vol.10 No.4

Study Design: Experimental animal study. Purpose: We aimed to determine the optimal dose of a single direct injection of the tumor necrosis factor (TNF)-α inhibitor, etanercept, by using the rat model of degenerative intervertebral disc from injury. Overview of Literature: The pain-related peptide expression was suppressed in the etanercept (100 μg and 1,000 μg)-administered groups in a dose-dependent manner. Methods: The neurotracer FluoroGold (FG) was applied to the surfaces of L4/5 discs to label their innervating dorsal root ganglion (DRG) neurons (n=50). Ten rats were included in the nonpunctured disc sham surgery control group, whereas the other 40 were included in the experimental group in which intervertebral discs were punctured with a 23-gauge needle. Saline or etanercept (10 μg, 100 μg, or 1,000 μg) was injected into the punctured discs (n=10 for each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of FG-labeled CGRPimmunoreactive DRG neurons was evaluated in all the groups. Results: There were no significant differences between the puncture+saline group and the puncture+10-μg etanercept group (p >0.05). However, a significant decrease in the percentage of FG and CGRP double-positive cells in FG-positive cells was observed in the etanercept (100 μg and 1,000 μg)-administered groups in a dose-dependent manner (p <0.05). Conclusions: When a low dose of the TNF-α inhibitor (10 μg of etanercept) was directly administered to the rat intervertebral disc in the rat model of degenerative intervertebral disc from injury, no suppressive effect on the pain-related peptide expression was observed. However, when a higher dose of etanercept (100 μg and 1,000 μg) was administered, the pain-related peptide expression was suppressed in a dose-dependent manner.

Long-Term Outcomes of In Situ Fusion for Treating Dysplastic Spondylolisthesis

Kazuhide Inage,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Yoshihiro Sakuma,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga,Koki Abe,Hirohito Kanamoto,Masahiro Inoue 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.2

Study Design: Retrospective, observational, single-center study. Purpose: To investigate the long-term outcomes of in situ fusion procedures for treating dysplastic spondylolisthesis. Overview of Literature: In situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications. Methods: In total, 12 of 28 patients who underwent in situ fusion for treating dysplastic spondylolisthesis at Chiba University Hospital from 1974 to 2004 were followed up in August 2013. Surgical complications were evaluated. Low back pain and leg pain were assessed using a visual analog scale (VAS). Vertebral alignment, including the lumbosacral angle and lumbar lordosis angle measurement on radiographic images (profile view in the neutral standing position), was evaluated during preoperative, postoperative, and final examinations. Results: The mean follow-up duration, patient age at the final examination, and patient age at operation were 20.0±7.2, 42.3±13.3, and 22.3±11.4 years, respectively. No complications were reported. Mean VAS scores for low back pain and leg pain were significantly lower at the final examination than at the preoperative examination (p <0.05). At the preoperative, postoperative, and final examinations, the mean lumbosacral angle was 32.3°±14.2°, 33.7°±11.8°, and 36.5°±16.4°, while the mean lumbar lordosis angle was 51.0°±14.8°, 48.6°±18.8°, and 49.6°±15.5°, respectively. No significant differences were noted among these values across the different time periods (p <0.05). Conclusions: In situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications such as nerve paralysis that may occur after repositioning operation and maintains appropriate long-term sagittal alignment, even 20 years after operation.

Diagnosis of Lumbar Foraminal Stenosis using Diffusion Tensor Imaging

Yawara Eguchi,Seiji Ohtori,Munetaka Suzuki,Yasuhiro Oikawa,Hajime Yamanaka,Hiroshi Tamai,Tatsuya Kobayashi,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Yasuchika Aoki,Atsuya Watanabe,Hirohito Kanamoto 대한척추외과학회 2016 Asian Spine Journal Vol.10 No.1

Diagnosis of lumbar foraminal stenosis remains difficult. Here, we report on a case in which bilateral lumbar foraminal stenosis was difficult to diagnose, and in which diffusion tensor imaging (DTI) was useful. The patient was a 52-year-old woman with low back pain and pain in both legs that was dominant on the right. Right lumbosacral nerve compression due to a massive uterine myoma was apparent, but the leg pain continued after a myomectomy was performed. No abnormalities were observed during nerve conduction studies. Computed tomography and magnetic resonance imaging indicated bilateral L5 lumbar foraminal stenosis. DTI imaging was done. The extraforaminal values were decreased and tractography was interrupted in the foraminal region. Bilateral L5 vertebral foraminal stenosis was treated by transforaminal lumbar interbody fusion and the pain in both legs disappeared. The case indicates the value of DTI for diagnosing vertebral foraminal stenosis.

Improvements in Intractable Lumbar and LowerExtremity Symptoms after Systemic Administration of Tocilizumab, an Anti-interleukin-6 Receptor Antibody

Sainoh Takeshi,Orita Sumihisa,Miyagi Masayuki,Suzuki-Narita Miyako,Sakuma Yoshihiro,Oikawa Yasuhiro,Kubota Go,Sato Jun,Shiga Yasuhiro,Fujimoto Kazuki,Eguchi Yawara,Koda Masao,Aoki Yasuchika,Akazawa Ts 대한척추외과학회 2022 Asian Spine Journal Vol.16 No.1

Study Design: Prospective cohort study (open-label, single-arm, and non-blinded).Purpose: This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms.Overview of Literature: IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain.Methods: This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months’ chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events.Results: Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events.Conclusions: Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1–4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.