山内 かづ代

Introduction. Spinal scoliosis and kyphosis in elderly people sometimes cause severe low back pain. Surgical methods such as osteotomy are useful for correcting the deformity. However, complications during and after surgery are associated with the osteotomy procedure. In particular, it is difficult to manage deformity correction surgery for patients with Parkinson's disease. Here, we present two cases of combined anterior and posterior surgery for deformity in patients with adult scoliosis and kyphosis due to Parkinson's disease. Case Presentation. Two 70-year-old women had spinal scoliosis and kyphosis due to Parkinson's disease. They had severe low back pain, and conservative treatment was not effective for the pain. Surgery was planned to correct the deformity in both patients. We performed combined posterior and anterior correction surgery. At first, posterior fusions were performed from T4 to the ilium using pedicle screws. Next, cages and autograft from the iliac crest were used in anterior lumbar surgery. The patients became symptom free after surgery. Bony fusion was observed 12 months after surgery. Conclusions. Combined posterior and anterior fusion surgery is effective for patients who show scoliosis and kyphosis deformity, and symptomatic low back pain due to Parkinson's disease.

We present a rare case of delayed onset of epidural hematoma after lumbar surgery whose only presenting symptom was vesicorectal disturbance. A 68-year-old man with degenerative spinal stenosis underwent lumbar decompression and instrumented posterolateral spine fusion. The day after his discharge following an unremarkable postoperative course, he presented to the emergency room complaining of difficulty in urination. An MRI revealed an epidural fluid collection causing compression of the thecal sac. The fluid was evacuated, revealing a postoperative hematoma. After removal of the hematoma, his symptoms disappeared immediately, and his urinary function completely recovered. Most reports have characterized postoperative epidural hematoma as occurring early after operation and accompanied with neurological deficits. But it can happen even two weeks after spinal surgery with no pain. Surgeons thus may need to follow up patients for at least a few weeks because some complications, such as epidural hematomas, could take that long to manifest themselves.

Developing sensory neurons require neurotrophic support for survival, neurite outgrowth and myelination. The low-density lipoprotein receptor-related protein-1 (LRP1) transactivates Trk receptors and thereby functions as a putative neurotrophin. Herein, we show that LRP1 is abundantly expressed in developing dorsal root ganglia (DRG) and that LRP1-dependent cell signaling supports survival, neurite extension and receptivity to Schwann cells even in the absence of neurotrophins. Cultured embryonic DRG neurons (E15) were treated with previously characterized LRP1 ligands, LRP1-receptor binding domain of α2-macroglobulin (RBD), hemopexin domain of MMP-9 (PEX) or controls (GST) for two weeks. These structurally diverse LRP1 ligands significantly activated and sustained extracellular signal-regulated kinases (ERK1/2) 5-fold (p<0.05), increased expression of growth-associated protein-43(GAP43) 15-fold (P<0.01), and increased neurite outgrowth 20-fold (P<0.01). Primary sensory neurons treated with LRP1 ligands survived > 2 weeks in vitro, to an extent equaling NGF, a finding associated with canonical signaling mechanisms and blockade of caspase-3 cleavage. LRP1 ligand-induced survival and sprouting were blocked by co-incubation with the LRP1 antagonist, receptor associated protein (RAP), whereas RAP had no effect on NGF-induced activity. Site directed mutagenesis of the LRP1 ligand, RBD, in which Lys(1370) and Lys(1374) are converted to alanine to preclude LRP1 binding, were ineffective in promoting cell signaling, survival or inducing neurite extension in primary sensory neurons, confirming LRP1 specificity. Furthermore, LRP1-induced neurite sprouting was mediated by Src-family kinase (SFK) activation, suggesting transactivation of Trk receptors. Co-cultures of primary embryonic neurons and Schwann cells showed that LRP1 agonists promoted axonal receptivity to myelination to Schwann cells. Collectively, these findings identify LRP1 as a novel and perhaps essential trophic molecule for sensory neuronal survival and development.

STUDY DESIGN: Case series. OBJECTIVE: To present the difficulty of diagnosing the origin of lower leg pain in patients with lumbar spinal stenosis and hip joint arthritis. SUMMARY OF BACKGROUND DATA: Pain arising from a degenerated hip joint is sometimes localized to the lower leg. Patients with lumbar spinal disease may also show radicular pain corresponding to the lower leg area. If patients present with both conditions and only pain at the lower leg, it is difficult to determine the origin of the pain. METHODS: We reviewed 420 patients who had leg pain with lumbar spinal stenosis diagnosed by myelography, computed tomography after myelography, or magnetic resonance imaging. Pain only at the ipsilateral lateral aspect of the lower leg but slight low back pain or pain around the hip joint was shown in 4 patients who had lumbar spinal stenosis and hip osteoarthritis. The symptoms resolved after L5 spinal nerve block, but remained after lidocaine infiltration into the hip joint. We performed decompression and posterolateral fusion surgery for these 4 patients. RESULTS: Leg pain did not resolve after lumbar surgery in all patients. Conservative treatment was not effective from 6 to 12 months, so ultimately we performed ipsilateral total hip replacement for all patients and they became symptom-free. CONCLUSION: It is difficult to determine the origin of lower leg pain by spinal nerve block and hip joint block in patients with lumbar spinal stenosis and hip osteoarthritis. We take this into consideration before surgery.

STUDY DESIGN: A case report. OBJECTIVE: An elderly patient presented with an acute lumbar spinal pseudogout attack after lumbar instrumented surgery. SUMMARY OF BACKGROUND DATA: Although gout and pseudogout are common diseases causing inflammatory arthropathy in peripheral joints, involvement of the spine is uncommon. Here, we report a patient experiencing an acute lumbar spinal pseudogout attack after lumbar instrumented surgery. METHODS: The patient was treated for lumbar spondylolisthesis at L4 and L5 level and afterward complained of lower back and bilateral leg pain. Conservative treatment was not effective for the patient; therefore, we preformed posterior transforaminal lumbar interbody fusion surgery. RESULTS: The postoperative course was uneventful; however, he experienced lower back pain 4 weeks after surgery. Magnetic resonance image showed changes in signal intensities of vertebra and fluid accumulation in posterior back muscles. A biopsy was performed, but the culture was negative for infection. Calcium pyrophosphate dehydrate was detected in the fluid. Thus, conservative therapy without antibiotics was performed, and the patient's symptoms disappeared within 2 weeks. CONCLUSION: Here, we reported the first case of acute lumbar spinal pseudogout attack after lumbar instrumented surgery. We recommend considering pseudogout before and after surgery.

UNLABELLED: In the present case of postoperative lumbar spinal stenosis after non-instrumented intertransverse fusion with granules of hydroxyapatite (HA), bone union was not completed and the patient felt the recurrence of his symptoms within two years. We performed re-decompression with fusion, and in hematoxylin and eosin staining of HA granulation harvested during revision surgery, fibrous tissue with hyaline degeneration surrounded the cavity where the HA had existed. Multinuclear giant cells and lymphocytes infiltrated some parts of the marginal layer of the cavity, and no obvious bony bridge had regenerated from autologous bone. No tartrate-resistant acid phosphate (TRAP) -positive osteoclasts could be seen in the new bone, suggesting that the activity of osteoclasts in the new bone decreased during the seven years after the primary surgery. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3483360258050263.

STUDY DESIGN: Prospective trial. OBJECTIVE: To examine the clinical efficacy of teriparatide for bone union after instrumented lumbar posterolateral fusion using local bone grafting in women with postmenopausal osteoporosis. SUMMARY OF BACKGROUND DATA: Intermittent parathyroid hormone (PTH) treatment increases bone mass and reduces the risk for osteoporotic vertebral fractures. Recombinant human PTH (1-34) has already been approved as a treatment for severe osteoporosis. Preclinical data support the efficacy of PTH for lumbar spinal fusion. However, clinical results of PTH for spinal fusion have not yet been reported. METHODS: Fifty-seven women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 2 treatment groups, a teriparatide group (n = 29; daily subcutaneous injection of 20 μg of teriparatide) and a bisphosphonate group (n = 28; weekly oral administration of 17.5 mg of risedronate). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Fusion rate, duration of bone union, and pain scores were evaluated 1 year after surgery. RESULTS: Pain scores improved after surgery; however, no significant difference was noted between the groups after surgery. The rate of bone union was 82% in the teriparatide group and 68% in the bisphosphonate group. Average duration of bone union was 8 months in the teriparatide group and 10 months in the bisphosphonate group. The rate of bone union and average of duration of bone union in the teriparatide group patients were significantly superior to those in the bisphosphonate group. CONCLUSION: Daily subcutaneous injection of teriparatide for bone union using local bone grafting after instrumented lumbar posterolateral fusion in women with postmenopausal osteoporosis was more effective than oral administration of bisphosphonate.

STUDY DESIGN: Prospective trial. OBJECTIVE: To examine the bone union and clinical results after unilateral or bilateral instrumented posterolateral fusion surgery using a local bone graft. SUMMARY OF BACKGROUND DATA: The iliac crest bone graft technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone has been used for bilateral multisegment fusion surgery; however, outcomes have been poor because of insufficient amounts of local bone used. This study evaluated unilateral and bilateral posterolateral fusion at 3 levels using a local bone graft. METHODS: Sixty-two patients diagnosed with degenerated spondylolisthesis at 3 levels were divided into 2 groups. All underwent decompression and bilateral instrumented posterolateral fusion. However, a unilateral local bone graft was used in 32 patients and bilateral local bone graft was used in 30 patients. The amount of bone grafting, proportion of patients with bone union, duration of bone union, visual analog scale score, Japanese Orthopedic Association score, and Oswestry Disability Index were evaluated before and 2 years after surgery. RESULTS: Visual analog scale score, Japanese Orthopedic Association score, and Oswestry Disability Index were not significantly different between the 2 groups before and after surgery (P > 0.05). The amount of local bone graft used for each segment was significantly less in the bilateral group (P < 0.05). The proportion of patients with rates of bone union and instability were 86% and 9%, respectively, in the unilateral group, but significantly poorer at 60% and 34% in the bilateral group. CONCLUSION: If multisegment fusion (3-level fusion) is performed, bilateral local bone grafting results in a poor rate of bone union because of an insufficiency of local bone. Unilateral bone grafting is recommended because better rates of bone union and stability are achieved.

In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2α was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-α (TNF-α), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-α. Furthermore, the effects of TNF-α on phosphorylated eIF2α, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.

INTRODUCTION: Diffusion-weighted imaging (DWI) can provide valuable structural information that may be useful for evaluating pathological changes of the lumbar nerve root. Diffusion-weighted magnetic resonance (MR) neurography has recently been introduced as an alternative way to visualize nerves, but to date, quantitative DWI and MR neurography have not been applied to evaluate the pathology of lumbar nerve roots. METHODS: Our purpose was to visualize lumbar nerve roots and to analyze their morphology by MR neurography, and to measure the apparent diffusion coefficient (ADC) of lumbar nerve roots compressed by herniated disks using 1.5-T MR imaging. Ten consecutive patients (median age, 48.0 and range, 20-72 years) with monoradicular symptoms caused by a lumbar herniated disk and 14 healthy volunteers were studied. Regions of interests were placed on the lumbar roots at dorsal root ganglia (DRG) and distal spinal nerves on DWI to quantify mean ADC values. The spinal nerve roots were also visualized by MR neurography. RESULTS: In the patients, mean ADC values were significantly greater in the compressed DRG and distal spinal nerves than in intact nerves. MR neurography also showed abnormalities such as nerve swelling at and below the compression in the symptomatic nerve root. Increased ADC values were considered to be because of edema and Wallerian degeneration of compressed nerve roots. CONCLUSION: DWI is a potential tool for analysis of the pathophysiology of lumbar nerve roots compressed by herniated disks.

STUDY DESIGN: Prospective trial. OBJECTIVE: To examine the difference in bone union and clinical results after one-, two-, and three-level instrumented posterolateral fusion surgery using a local bone graft. SUMMARY OF BACKGROUND DATA: The iliac crest bone graft technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone has been used for fusion surgery; however, its reliability as a graft for multiple segments has not been fully reported. METHODS: One hundred twenty-two patients diagnosed with degenerated spondylolisthesis were divided into three groups [spondylolisthesis at 1 level (n = 42), at 2 levels (n = 40), and at 3 levels (n = 40)]. All patients underwent decompression and instrumented posterolateral fusion with a local bone graft. The amount of bone graft, proportion of patients with (rate) and duration of bone union, Visual Analog Scale (VAS) score, Japanese Orthopedic Association Score (JOAS), and Oswestry Disability Index (ODI) were evaluated before and 2 years after therapy. RESULTS: VAS score, JOA score, and ODI were not significantly different among the three groups before and after surgery (P > 0.05). Average amount of local bone graft used for one segment significantly decreased in proportion to the number of fusion levels (P < 0.05). The rate of bone union was 88% in the one-level group, 85% in the two-level group, and 62.5% in the three-level group, which was significantly lower than that in the one- and two-level groups (P < 0.05). CONCLUSION: If one- and two-level posterolateral fusion were performed, the local bone graft technique provides a good and uniform bone union rate; however, for three-level fusion poor results were obtained because of an insufficient amount of local bone.

BACKGROUND: Surgery for lumbar spondylolisthesis is widely performed. However, there have been no reports comparing posterolateral and anterior interbody fusion prospectively. We compared instrumented posterolateral fusion with anterior interbody fusion for L4 spondylolisthesis in a prospective study. METHODS: Forty-six patients diagnosed with L4 degenerated spondylolisthesis were divided into two groups. Twenty-two consecutive patients underwent non-instrumented anterior interbody fusion using an iliac bone graft (ALIF; L4-L5 level), and 24 consecutive patients underwent instrumented posterolateral fusion with local bone (PLF; L4-L5 level). The rates of bone union, visual analog scale (VAS) score, Japanese Orthopedic Association (JOA) score, Oswestry Disability Index (ODI), surgical invasion, and complications were evaluated before and 2 years after surgery. RESULTS: Age, VAS score, JOA score, and ODI were not significantly different between the two groups before surgery (P > 0.05). Success of bone union between the two groups was not significantly different (P > 0.05). Blood loss during surgery was significantly less; however, periods of bed rest and hospital stay were significantly longer in the ALIF group (P < 0.05). Overall patient satisfaction, and low back and leg pain in both groups were significantly improved after surgery; however, low back pain showed greater improvement in the ALIF group compared with the PLF group (P < 0.05). Complications such as donor site pain (4 patients in the ALIF group) and dural tearing (3 patients in the PLF group) were observed. CONCLUSIONS: If single level fusion for L4 spondylolisthesis is performed, both anterior and posterior methods reduce patients' low back and leg pain. Improvement of low back pain was significantly greater after ALIF; however, periods of hospital stay and of bed rest were significantly longer.

In pathologic radicular pain of lumbar spinal stenosis, cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (ILs) play a crucial role in the pathogenesis of nerve degeneration and pain. We investigated TNF-α and IL-6 levels in the cerebrospinal fluid (CSF) of patients with radicular pain caused by lumbar spinal stenosis (LSS). A total of 30 LSS patients and 10 age-matched controls were examined. CSF samples were obtained adjacent to the level of stenosis in 30 LSS patients, and at the L4-L5 level in the 10 control patients. TNF-α and IL-6 levels in the samples were analyzed using enzyme-linked immunosorbent assays (ELISA). We compared the amounts of TNF-α and IL-6 with severity of pain (low back and leg pain), walking ability, and severity of stenosis (cross-sectional area of dural space). The concentration of IL-6 was significantly higher in LSS patients than in controls, but TNF-α levels were beneath the limit of detection. There was no correlation between IL-6 levels and severity of pain or walking ability (p > 0.05). However, there was a significant correlation between IL-6 levels and severity of stenosis (p < 0.05). The current study showed that the increased CSF IL-6 levels in LSS patients with radicular pain were not correlated with pain severity; although not proven in this study, the increase in CSF IL-6 concentration could indicate pathological nerve damage or degeneration of lumbar radiculopathy represented by the severity of stenosis.

The iliac crest bone grafting (ICBG) technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone is available for fusion surgery, but its reliability as a graft has not been fully reported. In the current study, we examined single-level instrumented posterolateral fusion with a local bone graft versus an ICBG in a prospective randomized study. Eighty-two patients diagnosed with L4 degenerated spondylolisthesis were divided into two groups at random. Forty-two patients underwent instrumented posterolateral fusion with a local bone graft (L4-L5 level), and 40 patients underwent instrumented posterolateral fusion with an ICBG (L4-L5 level). Rate and duration of bone union, visual analog scale (VAS) score, Japanese orthopedic association score (JOAS), Oswestry Disability Index (ODI), and complications were evaluated before and 2 years after therapy. VAS score, JOAS, and ODI were not significantly different between the two groups before and after surgery (P > 0.05). Rate and average duration of bone union were 90% and 8.5 months in the local bone graft group, and 85% and 7.7 months in the ICBG group, but without significant difference (P > 0.05). Prolonged surgical time and complications such as donor site pain (8 patients) and sensory disturbance (6 patients) were observed in the ICBG group. If single-level posterolateral fusion was performed, local bone graft technique has the same bone union rate compared with ICBG, requires less surgical time, and has fewer complications.

A 62-year-old patient presented with a 12-month history of severe sciatica. The patient showed tenderness of Valleix and lateral lower leg pain on his left side. MRI, myelogram, and radiculography revealed extraforaminal stenosis at the level of L5/S1. His symptoms disappeared after injection of lidocaine onto the L5 spinal nerve. The symptoms did not improve after conservative treatment, and surgery was performed under a diagnosis of neuropathy from far-out syndrome. For release of L5 spinal nerve compression, decompression and instrumented fusion surgery were performed. His symptoms disappeared immediately after surgery. Far-out syndrome itself is rare; however, it is important to consider this disease in cases of sciatica.

STUDY DESIGN: A retrospective observational study of healthy volunteers and patients with degenerative and infectious endplate abnormalities in the lumbar spine. OBJECTIVES: Our purpose was to evaluate the usefulness of diffusion-weighted imaging (DWI) for the differentiation of degenerative and infectious endplate abnormalities using 1.5-T magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: DWI can provide valuable structural information about tissues that may be useful for clinical applications in differentiation between degenerative and infectious endplate abnormalities. METHODS: Sixteen consecutive patients with endplate abnormalities that was detected by MRI of the lumbar spine, and 15 healthy volunteers were studied. DWI was performed using whole-body imaging with background body signal suppression with a b value of 1000 s/mm2. Apparent diffusion coefficient values of normal and abnormal vertebral bone marrow were calculated. RESULTS: Twenty-nine vertebral abnormalities were found in 16 patients. Nine vertebral abnormalities in 5 patients were because of infections and 20 vertebral abnormalities in 11 patients were because of degenerative changes; 7 levels were classified as Modic type 1, 7 levels as type 2, and 6 levels as type 3. DWI showed hyperintensity in all patients with infection, similar to that used in positron emission tomography, but not in the intervertebral spaces of any patients with degenerative disease. Apparent diffusion coefficient values of infectious bone marrow were significantly higher than normal and degenerative bone marrow. CONCLUSION: DWI is useful for differentiation of degenerative and infectious endplate abnormalities. Moreover, MRI is widely used clinically because of the lack of ionizing radiation, low cost, and fast imaging time as compared with positron emission tomography. Therefore, DWI has the potential to be used as a screening tool.

STUDY DESIGN: retrograde neurotracing and immunohistochemistry were used to investigate the effect of the tumor necrosis factor (TNF)-α inhibitor, etanercept, on calcitonin gene-related peptide (CGRP) expression in dorsal root ganglion (DRG) neurons innervating intervertebral discs in rats. OBJECTIVE: to clarify the action of a TNF-α inhibitor on a sensory neuropeptide in DRG neurons innervating intervertebral discs. SUMMARY OF BACKGROUND DATA: degeneration of lumbar intervertebral discs is a cause of low back pain. TNF-α in the intervertebral disc is a major contributor to discogenie pain. Effects of TNF-α inhibition on CGRP expression in DRG neurons were evaluated. METHODS: the neurotracer FluoroGold was applied to the surfaces of L4/5 discs to label their innervating DRG neurons (n = 30). Of 30 rats, 10 were in a nonpunctured disc sham surgery control group, whereas the other 20 were in experimental groups in which intervertebral discs were punctured with a 23-gauge needle. Etanercept or saline was applied into the punctured discs (n = 10 each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP. The proportion of FluoroGold-labeled CGRP-immunoreactive DRG neurons was evaluated in all groups. RESULTS: FluoroGold-labeled neurons innervating the L4/5 disc were distributed throughout L1-L6 DRGs in all groups. Of the FluoroGold-labeled neurons, the proportion of CGRP-immunoreactive neurons was 21% ± 4% in the sham surgery control group, 32% ± 7% in the puncture + saline group, and 23% ± 4% in the puncture + etanercept group. The proportion of CGRP-immunoreactive neurons was significantly greater in the puncture + saline group compared with the sham control and puncture + etanercept groups (P < 0.01). CONCLUSION: in this model, CGRP was upregulated in DRG neurons innervating damaged discs. However, direct intradiscal application of etanercept immediately after disc puncture suppressed CGRP expression in DRG neurons innervating injured discs. This finding may further elucidate the mechanism for the effectiveness of etanercept in upregulation of neuropeptide in DRG neurons innervating intervertebral discs.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To examine the utility of 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) to diagnose pyogenic spondylitis in patients showing Modic change. SUMMARY OF BACKGROUND DATA: Vertebral bone marrow infection may appear as Modic type 1 signal on magnetic resonance imaging, so it is difficult to distinguish between common Modic change and infection. In the current study, we aimed to examine the utility of 18F-FDG-PET to diagnose pyogenic spondylitis in patients showing Modic change. METHODS: In a prospective assessment of 312 patients showing low back pain, 18 patients were suspected of having pyogenic vertebral osteomyelitis because of their symptoms, biopsy results, blood analysis, x-ray examination, magnetic resonance imaging, and FDG-PET during a 1-year follow-up. RESULTS: Observers ultimately diagnosed 11 patients with pyogenic spondylitis (group 1 observers). FDG-PET evaluation by 2 radiologists (group 2 observers) showed isotope accumulation in the lumbar spine in 11 patients, and no accumulation in 7 patients. The evaluation by group 1 observers, who did not see the FDG-PET findings, was compared with the evaluation by group 2 observers. No patients were evaluated differently by group 1 and group 2 observers. CONCLUSION: In conclusion, the rate of detecting spondylodiscitis infection was very high if FDG-PET was additionally used. FDG-PET is recommended to distinguish between common Modic change and spinal infection.

Nerve growth factor (NGF) and its dual structurally unrelated receptors, tropomyosin-related kinase A (TrkA) or p75 neurotrophin receptor (p75(NTR)), cause the pathogenesis of discogenic pain. To investigate the sensory innervation of injured rat lumbar intervertebral disc (IVD), we examined the expression of neuropeptides such as calcitonin gene-related peptide (CGRP) at dorsal root ganglia (DRG) by inhibiting NGF or its dual receptors. Sprague-Dawley rats with multiply punctured L5-L6 IVD were used. Six experimental groups were prepared: naïve, sham control, and four agent-treated groups with punctured IVD (vehicle, anti-NGF antibody, anti-TrkA antibody, and anti-p75(NTR) antibody). Retrograde neurotracer Fluoro-Gold (FG) was applied together except for the naïve group. Their lumbar DRG were harvested and immunolabeled for CGRP. FG-labeled DRG neurons were most prevalent at L1 and L2 DRG, and the proportion of FG-labeled CGRP-immunoreactive DRG neurons in the vehicle group was significantly elevated (p < 0.05) compared with the sham group, while those of antibody-treated groups, especially in the anti-p75(NTR) group, significantly decreased compared with the vehicle group (p < 0.05). Direct intradiscal application of antibody to NGF or its receptors suppressed CGRP expression, and p75(NTR) antagonism induced the most profound suppression.

Diffusion-weighted imaging (DWI) can provide valuable structural information about tissues that may be useful for clinical applications in evaluating lumbar foraminal nerve root entrapment. Our purpose was to visualize the lumbar nerve root and to analyze its morphology, and to measure its apparent diffusion coefficient (ADC) in healthy volunteers and patients with lumbar foraminal stenosis using 1.5-T magnetic resonance imaging. Fourteen patients with lumbar foraminal stenosis and 14 healthy volunteers were studied. Regions of interest were placed at the fourth and fifth lumbar root at dorsal root ganglia and distal spinal nerves (at L4 and L5) and the first sacral root and distal spinal nerve (S1) on DWI to quantify mean ADC values. The anatomic parameters of the spinal nerve roots can also be determined by neurography. In patients, mean ADC values were significantly higher in entrapped roots and distal spinal nerve than in intact ones. Neurography also showed abnormalities such as nerve indentation, swelling and running transversely in their course through the foramen. In all patients, leg pain was ameliorated after selective decompression (n = 9) or nerve block (n = 5). We demonstrated the first use of DWI and neurography of human lumbar nerves to visualize and quantitatively evaluate lumbar nerve entrapment with foraminal stenosis. We believe that DWI is a potential tool for diagnosis of lumbar nerve entrapment.

BACKGROUND: It has been reported that rat L5/6 lumbar discs are innervated mainly by L2 dorsal root ganglion neurons. We previously reported that L2 spinal nerve infiltration was effective for discogenic low back pain (DLBP) patients, although the diagnosis was based only on the results of physical examination, plain films, and magnetic resonance imaging (MRI). The purpose of the current study was to evaluate L2 spinal nerve block for DLBP patients retrospectively based on MRI findings and surgical results. METHODS: A total of 62 patients with only LBP and no accompanying radicular pain were investigated. Patients had only one level of disc degeneration on MRI. When pain was provoked during discography, we performed surgery at the next stage (40 patients). In all, 22 patients were excluded owing to negative discography results. Of the 40 patients, we evaluated 25 strictly selected patients suffering from DLBP. DLBP was diagnosed when the patient experienced pain relief at least 2 years after anterior lumbar interbody fusion. Fifteen patients who did not show pain relief after surgery were used for the non-DLBP group. L2 spinal nerve infiltration using 1.5 ml of lidocaine was performed in all 40 patients before surgery. The visual analogue scale (VAS) score after L2 spinal nerve infiltration was recorded, and an association of L2 spinal nerve infiltration and DLBP was explored. RESULTS: Low back pain scores assessed using the VAS score, the Japanese Orthopedic Association score, and the Oswestry Disability Index score in the two groups were not significantly different. L 2 spinal nerve infiltration was effective for 27 patients but not effective for 13 patients; the VAS score after 15 min and 2 h improved in the DLBP group compared with that of the non-DLBP group (P < 0. 05). L2 spinal nerve infiltration was more effective in DLBP patients (21 patients, 84%) than in the non-DLBP group (6 patients, 40%) (P < 0.05). CONCLUSIONS: In the current study, L2 spinal nerve infiltration was effective in 84% of selected DLBP patients and is thought to be a useful tool for diagnosing DLBP. However, we should take into consideration that the L2 spinal nerve infiltration was effective in 40% of non-DLBP patients as well.

STUDY DESIGN: Investigation of sensory innervation of rat osteoporotic lumbar vertebrae using in vitro and in vivo models. OBJECTIVE: To investigate (1) sensory innervation of osteoporotic rat vertebrae, (2) effects of risedronate on sensory neurons, (3) effects of osteoporosis treatment on bone mineral densities (BMDs) and the sensory innervation. SUMMARY OF BACKGROUND DATA: Osteoporotic patients without fractures sometimes experience vague low back pain of unknown origin. The mechanisms of osteoporosis treatments against the pain are unclear. METHODS: (1) The expression of calcitonin gene-related peptide (CGRP) immunoreactive (-ir) or transient receptor potential vanilloid 1 (TRPV1)-ir nerve fibers in vertebrae and dorsal root ganglions (DRG) innervating L3 vertebrae of Sprague Dawley rats labeled with neurotracer were examined in control, sham, and ovariectomized (OVX) rats. (2) Cultured rat neonate DRG neurons in media containing different concentrations of risedronate were immunostained for CGRP, and we measured its activity using axonal length and proportion of CGRP-ir neurons. (3) BMDs and CGRP expression in DRG neurons innervating L3 vertebrae were examined in the following 5 groups: sham (treated with saline), OVX (saline), OVX+EXE (treadmill exercise), OVX+RIS (risedronate), and OVX+RIS+EXE (risedronate and exercise). RESULTS: (1) A few CGRP-ir or TRPV1-ir nerve fibers were observed in the bone marrow. CGRP or TRPV1 expression in DRG was elevated in the OVX group (P < 0.05). (2) The axonal length and proportion of CGRP-ir neurons were dose-dependently suppressed (P < 0.05). (3) BMDs improved and the CGRP expression decreased in the risedronate-treated groups (P < 0.05), especially in the OVX+RIS+EXE group. CONCLUSION: Sensory innervation of osteoporotic rat vertebrae showed increased expression of CGRP and TRPV1 in DRG neurons. Risedronate suppressed activity of CGRP-ir neurons in vitro, improved BMD, and decreased CGRP expression, especially together with exercise in vivo.

Pathomechanisms of injured-nerve pain have not been fully elucidated. Radicular pain and chronic constriction injury models have been established; however, producing these models is complicated. A sciatic nerve-pinch injury is easy to produce but the reliability of this model for evaluating pain behavior has not been examined. The current study evaluated pain-related behavior and change in pain markers in the dorsal root ganglion (DRG) of rats in a simple, sciatic nerve-pinch injury model. In the model, the sciatic nerve was pinched for 2 s using forceps (n = 20), but not injured in sham-operated animals (n = 20). Mechanical and thermal hyperalgesia were measured every second day for 2 weeks using von Frey filaments and a Hargreaves device. Calcitonin gene-related peptide (CGRP), activating transcription factor-3 (ATF-3), phosphorylated p38 mitogen activated protein (Map) kinase (p-p38), and nuclear factor-kappa B (NF-κB; p65) expression in L5 DRGs were examined at 4 and 7 days after surgery using immunohistochemistry. The proportion of neurons immunoreactive for these markers was compared between the two groups. Mechanical (during 8 days) and thermal hyperalgesia (during 6 days) were found in the pinch group rats, but not in the sham-operated animals (p < 0.05); however, hyperalgesia was not significant from days 10 to 14. CGRP, ATF-3, p-p38, and NF-κB expression in L5 DRGs was upregulated in the nerve-injured rats compared with the sham-operated rats (p < 0.01). Our results indicate that a simple sciatic nerve pinch produced pain-related behavior. Upregulation of the pain-marker expression in the nerve-injury model suggested it could be used as a model of pain. However, it was not considered as suitable for long-term studies.

The relationship of Modic change to pain and inflammation remains to be unclear. Recently, some authors have reported that Modic type 1 signals are closely related to infection. However, if the patients do not have severe back pain, fever, or an abnormal blood profile, it is difficult to distinguish between common Modic change and infection. The purpose of this study was to examine the prevalence of pyogenic spondylitis in patients who showed Modic type 1 change without other signs of infection. Seventy-one patients with Modic type 1 change were evaluated (average age 55, 32 males and 39 females). X-ray and magnetic resonance imaging (MRI) were performed to investigate low-back pain and leg pain. Body temperature was measured and blood analysis (including white blood cell count and level of C-reactive protein) was conducted for all patents. All 71 patients with Modic type 1 change, but without other signs of infection were followed for 2 years. Low-back pain, X-ray, and blood analyses were performed every 3 months; and MRI was performed every year. Severe low-back pain or abnormal signs developed in four patients during the follow-up. Pyogenic spondylitis was diagnosed in three patients by symptoms, blood results, and imaging, and confirmed by biopsy. Two of the three patients were diabetic. A total of 4.2% of patients with Modic type 1 change, but without other signs of infection were diagnosed as having pyogenic spondylitis during the 2-year follow-up, therefore, it is important to consider this before treating Modic type 1 change.

STUDY DESIGN: We examined the sensory innervation of the coccygeal (Co) 5/6 intervertebral disc in rats using a retrograde neurotracing method and immunohistochemistry. OBJECTIVE: To investigate the properties of the sensory innervation of the rat coccygeal disc. SUMMARY OF BACKGROUND DATA: Developing a rat disease model for degenerative intervertebral disc compression using lumbar discs is technically impractical because of their location. Coccygeal intervertebral discs are more readily accessible and several reports of morphologic evaluation of degenerative coccygeal intervertebral discs using compression devices exist. However, their sensory innervation and properties have not yet been characterized. METHODS: FluoroGold neurotracer was applied to the Co5/6 intervertebral discs of intraperitoneally anesthetized Sprague Dawley rats (n = 10). Subsequently, the discs and the L1-S4 dorsal root ganglions (DRGs) were resected and sectioned. The discs were double-stained for immunoreactivity to the neuronal marker beta-tubulin (Tuj-1) and biotin-labeled isolectinB4 (IB4), a neuropathic pain marker, or Tuj-1 and calcitonin gene-related peptide (CGRP), an inflammatory pain marker. The DRGs were double-stained for IB4-binding and CGRP immunoreactivity (IR). The proportions of IB4-binding or CGRP-IR DRG neurons were assessed by cell counting and compared. RESULTS: The disc immunohistochemistry showed evidence of sensory nerve fibers lying in the outermost layer of the anulus fibrosus. FluoroGold labeled DRG neurons mainly derived from S1 to S3 DRGs, especially S2 and S3. No labeled neurons were observed in the S4 DRG. The histochemistry of the DRGs showed a predominance of CGRP-IR DRG neurons (3.5 +/- 1.7% IB4-binding and 15.4 +/- 5.6% CGRP-IR on average). CONCLUSION: This study showed evidence for nerve fibers in the discs and predominant innervation by CGRP-IR DRG neurons. The neurons innervating the discs mostly derived from S1 to S3 DRGs, especially S2 and S3. These findings may be useful in developing rat models of disease involving degenerative intervertebral disc compression.

The number of patients showing lumbar degenerative scoliosis, including disc wedging, has increased, and examination of the mechanism of spinal nerve compression due to lateral and rotational mobility of the lumbar spine is necessary. Thirty-two patients with L4-L5 disc wedging but without antero- or retrospondylolisthesis and ten age-matched controls were examined. The angle of disc wedging and change in the angle between left and right bending were evaluated by anterior-posterior X-ray images of patients while they were in a standing position. The degree of disc degeneration and existence of vacuum phenomena were evaluated at the L4-L5 discs. Rotational mobility between maximal right and left rotation was examined by computed tomography (CT). Rotational mobility was measured using the spinal transverse processes of L4 and L5. The relationship between these factors was statistically evaluated using multivariate analysis and Spearman's correlation test. There was a significant increase in the average rotational mobility of the L4-L5 disc-wedging group. In the L4-L5 disc-wedging group, the increased angle of disc wedging and change in the angle between left and right bending correlated with increased rotational mobility. The degree of disc degeneration did not affect rotational mobility. However, existence of vacuum phenomena increased the rotational mobility of the L4-L5 disc-wedging group. This is the first study to evaluate the rotational hypermobility of L4-L5 disc wedging in patients without antero- or retrospondylolisthesis using kinematic CT. Increases in the wedging angle and abnormal instability of lateral bending correlated with increased rotational mobility. For surgical planning of degenerative L4-L5 disc wedging, it is important to consider rotational hypermobility using kinematic CT or X-ray imaging findings of lateral bending.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To examine the relationship between low back pain after discectomy for disc herniation and Modic type 1 change. SUMMARY OF BACKGROUND DATA: Lumbar vertebral bone marrow change is divided into Modic types. Some reports indicate that Modic type 1 is related to low back pain, but the reliability of this assertion is unclear. The current study examines changes in low back pain in patients with lumbar disc herniation and Modic type 1 change after lumbar discectomy without fusion surgery. METHODS: Forty-five patients with lumbar disc herniation showing normal or Modic type 1 signals in their bone marrow were selected (mean age 35 years). All patients suffered low back and leg pain because of lumbar disc herniation, and underwent a discectomy without fusion. We evaluated change in low back pain [Visual analogue scale (VAS) score, Japanese Orthopedic Association score (JOAS), and Oswestry Disability Index (ODI)] before, 12 and 24 months after surgery. RESULTS: Twenty-three patients showed Modic type 1 signals and 22 patients showed normal intensity before surgery. VAS score, JOAS, and ODI were not significantly different between the normal and Modic type 1 groups. VAS score, JOAS, and ODI improved after surgery in both groups (P>0.05). Low back pain after surgery evaluated from the 3 scores was not significantly different in the 2 groups 12 or 24 months after surgery (P>0.05). CONCLUSION: Discectomy improved low back pain in patients suffering from lumbar disc herniation. Patients with or without Modic type 1 change showed a similar improvement of low back pain score. Low back pain in patients with disc herniation appears to mainly originate from disc or nerve root compression, and decompression surgery without fusion is an option for these patients, even those with Modic type 1 changes.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To examine the change of Modic Type 1 to Type 2 after posterolateral fusion surgery. SUMMARY OF BACKGROUND DATA: Lumbar vertebral bone marrow change is divided into Modic types. Magnetic resonance imaging reveals Modic Type 1 and 2 signals. Some reports indicate that with time, Type 1 signals (intervertebral instability) change to Type 2 (restabilization), but the reliability of this assertion is unclear. The current study examines the change of Modic Type 1 signals to Type 2 after posterolateral fusion surgery. METHODS: Patients with Modic Type 1 and 2 signals were selected (mean age, 65 years). All patients suffered low back pain and leg pain due to lumbar spinal canal stenosis, and underwent decompression and posterolateral fusion surgery. We evaluated change in Modic signal and severity of low back pain (Visual analogue scale score, Japanese Orthopedic Association score, and Oswestry Disability Index before and 24 months after surgery. RESULTS: Of 21 patients with Modic Type 1 signals before surgery, 2 cases changed to normal bone marrow, 9 to Type 2, and 12 remained Type 1. Of 12 patients with Type 2 signals, none changed to Type 1, 2 changed to normal bone marrow, and 10 remained Type 2. Visual analogue scale score, Japanese Orthopedic Association score, and Oswestry Disability Index improved after surgery; however, low back pain was not significantly associated with signal change after surgery (P > 0.05). CONCLUSION: In the current study, Modic Type 1 signals changed to Type 2; however, Type 2 did not change to Type 1, suggesting that Type 2 signals indicate a stabilized stage. For Modic Type 1 and 2 signals, there were changes to normal bone marrow signals in 4 cases. Therefore, degenerated bone marrow may be able to regenerate after surgical stabilization. We did not show a significant difference between low back pain and signal type.

BACKGROUND: Clinically, the origin of low back pain is unknown. The pain may originate from the lumbar muscles directly, or it may be referred pain from the spine. Dorsal root ganglion (DRG) neurons with dichotomizing axons have been reported in several species and are thought to be related to referred pain. However, these neurons, which have dichotomizing axons to the lumbar facet joints and to the lumbar muscle, have not been fully investigated. METHODS: Two neurotracers - 1,1'-dioctadecyl-3,3,3',3'- tetramethyl-indocarbocyanine perchlorate (DiI) and fluorogold (FG) - were used in the present double-labeling study. DiI crystals were placed in the right L5/6 facet joint, and FG was applied to right multifidus muscles at the L5 level in 10 rats. Two weeks later, bilateral DRGs from L1 through L6 were harvested, sectioned, and observed under a fluorescence microscope. RESULTS: DiI-labeled DRG neurons innervating the L5/6 facet joint (5.17% of the total DRG neurons) were distributed from L1 to L6. FG-labeled DRG neurons innervating the lower back muscle (15.9% of the total) were also distributed from L1 to L6. Double-labeled DRG neurons were found from L1 to L6. The ratio of total double-labeled/total DiI-labeled DRG neurons was 17% and that of total double-labeled/total FG-labeled DRG neurons was 7%. Approximately 17% of all DRG neurons innervating the facet joints had other axons that extended to the lower back muscle. CONCLUSIONS: This finding provides a possible neuroanatomical explanation for referred low back muscle pain from the lower facet joints.

BACKGROUND: Recent studies have revealed that the low-affinity nerve growth factor receptor, p75 neurotrophin receptor (p75NTR), is important in inflammatory pain. Moreover, p75NTR immunoreactive sensory nerve and dorsal root ganglion (DRG) neurons have been found to innervate lumbar intervertebral discs. The purpose of the current study was to investigate the effect of p75NTR saporin, a toxin used to destroy p75NTR, on calcitonin gene-related peptide (CGRP), an inflammatory neuropeptide associated with pain, in DRG neurons innervating punctured intervertebral discs in rats. METHODS: The neurotracer fluorogold (FG) was applied to the surfaces of L5/6 discs to label their innervating DRG neurons (n = 30). Of 30 rats, 10 were in a nonpunctured disc sham surgery control group (nonpuncture group), and the other 20 were in experimental groups in which intervertebral discs were punctured with a 23-gauge needle. p75NTR saporin was applied to the discs of 10 rats (puncture + p75NTR saporin group) and the other 10 received the same volume of saline (puncture + saline group). At 14 days after surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP, and the proportions of CGRP-immunoreactive DRG neurons was evaluated. RESULTS: Of the FG-labeled neurons innervating the L5/6 disc, the proportion of CGRP-immunoreactive neurons was 32% +/- 6% (mean +/- SE) in the nonpuncture group, 47.2% +/- 8% in the puncture + saline group, and 34.6% +/- 9% in the puncture + p75NTR saporin group. The proportion of CGRP-immunoreactive neurons was significantly greater in the puncture + saline group compared with the nonpuncture and puncture + p75NTR saporin groups (P < 0.01). CONCLUSIONS: Half of the DRG neurons innervating the discs were positive for CGRP in the puncture + saline group. CGRP is important for mediating inflammatory and nerve-injured pain and may be important in discogenic pain. However, p75NTR saporin suppressed CGRP expression in DRG neurons. Therefore, p75NTR may be an important receptor for mediating discogenic pain via CGRP expression.

Degeneration of lumbar intervertebral discs is thought to be a cause of low back pain. Studies have found that a cause of discogenic low back pain is intervertebral disc inflammation and axonal growth of afferent fibers innervating the disc. Lumbar spine fusion for chronic discogenic low back pain is considered an effective procedure. However, no study has investigated the mechanism of pain relief. We did this by applying Fluoro-Gold (FG) to the ventral aspect of the L4-L5 intervertebral discs of 40 rats. We exposed the nucleus pulposus to the annulus fibrosus in a disc punctured model. Rats were divided into 4 groups. Group A: Punctured intervertebral disc with sham posterolateral fusion (PLF) (n = 10), Group B: Punctured intervertebral disc with PLF (n = 15), Group C: Normal intervertebral disc (no puncture) with PLF (n = 10), and Group D: Normal disc (no disc puncture) with sham PLF (n = 5). Four weeks after surgery, bilateral L1-L5 dorsal root ganglia (DRGs) were stained with growth-associated protein 43 (GAP43), a marker of axonal growth, and calcitonin gene-related peptide (CGRP), a neuropeptide marker of pain. Bone union was evaluated using X-ray imaging. Of the FG-labeled neurons, the proportions of GAP43- and CGRP-immunoreactive (IR) neurons in Group A were significantly higher than in Group D (P < 0.05). The proportions of GAP43- and CGRP-IR neurons in bone union rats in Group B were significantly lower than in nonunion rats in Group B and in the rats in Group A (P < 0.05). No significant differences in GAP43- and CGRP-IR neurons were observed between bone union and nonunion rats in Group C and the rats in Group D (P > 0.05). PLF is strongly related to the downregulation of GAP43 and CGRP expression. Therefore, PLF may suppress the increase of inflammatory neuropeptides and the process of axonal growth. Moreover, these results may explain, in part, the mechanism of pain relief following lumbar spinal fusion for chronic discogenic low back pain in humans.

Nerve growth factor (NGF) and its low-affinity receptor, p75 neurotrophin receptor (p75 NTR), are important mediators of pain. To explore further the mechanisms involved, we examined suppression of pain behavior and expression of neuropeptides such as calcitonin gene-related peptide (CGRP) using a p75 NTR inhibitory antibody, in a mouse sciatic nerve crush model. In the nerve-injured model, 150 microg of a p75 NTR inhibitory antibody or 10 microl of saline were applied. The sciatic nerve in the sham-operated group was uninjured. Mechanical allodynia was measured for 2 weeks. CGRP and p75 NTR expression in L5 dorsal root ganglions (DRGs) was examined immunohistochemically. Mechanical allodynia was found in the two nerve injured groups, but not in the sham-operated group (p < 0.05). However, the magnitude of the mechanical allodynia was significantly decreased after application of p75 NTR inhibitory antibody (p < 0.05). CGRP and p75 NTR immunoreactivity in the L5 DRG neurons was upregulated in the injured nerve groups compared with the sham-operated group; however, p75 NTR inhibitory antibody decreased the CGRP and p75 NTR expression (p < 0.01). Application of the p75 NTR inhibitory antibody to the pinched sciatic nerve suppressed CGRP and p75 NTR expression and pain behavior.

Elderly postmenopausal women who have osteoporosis sometimes experience low back pain, however, the relationship between low back pain and osteoporosis in the absence of vertebral fractures remains unclear. We examined the relationship between bone mineral density (BMD), bone resorption and low back pain in elderly female patients who did not have osteoporotic vertebral fractures. The average BMD was 0.675 g/cm(2) when assessed by dual-energy X-ray absorptiometry (DEXA). Patients were excluded from the study if they had vertebral fractures revealed by radiography, CT scans or MRI. Bisphosphonate (risedronate) was administered for 4 months. The visual analogue scale (VAS) pain score, Roland Morris Disability Questionnaire (RDQ), Short Form-36 (SF-36) questionnaire, BMD and N-terminal telopeptide of type I collagen (NTx; a marker for bone resorption) were examined before and after treatment. DEXA did not increase significantly, but serum and urinary NTx were decreased (-51.4% and -62.0%, respectively) after 4 months of risedronate treatment (p<0.01). The assessment was repeated using the VAS score, RDQ and SF-36, which revealed an improvement after risedronate treatment (p<0.01). A decrease in serum and urinary NTx was associated with improvement of low back pain, suggesting that despite the absence of vertebral fractures, bone resorption due to osteoporosis may cause low back pain.

A 60-year-old patient presented with a six-month history of severe sciatica. The patient showed tenderness of Valleix and Friberg's sign, and his symptoms disappeared after injection of lidocaine both onto the sciatic nerve and onto the L spinal nerve. MRI revealed left extraforaminal disc herniation at the L/S1 level and thickness of the piriformis muscle. The symptoms did not improve after conservative treatment second stage surgery was performed under a diagnosis of double lesion neuropathy at the lumbar spine and at the piriformis muscle. For release of sciatic nerve compression, incision of the piriformis muscle was performed. The symptoms decreased however, they persisted. Surgical treatment for the lumbar lesion was performed. The symptoms disappeared immediately after surgical removal of the disc herniation and posterolateral fusion. It is important to consider double crush syndrome at lumbar lesion and piriformis levels.

STUDY DESIGN.: Immunohistological analysis of punctured disc after application of a p38 MAP kinase inhibitor. OBJECTIVE.: To examine effect of direct application on dorsal root ganglion (DRG) neurons innervating damaged rat discs. SUMMARY OF BACKGROUND DATA.: Degeneration of lumbar discs is one cause of low back pain. Pathogenesis may involve sensory nerve ingrowth into disc inner layers; tumor necrosis factor-alpha (TNF-alpha) is thought to be a major inducer of ingrowth. Because p38 mitogen-activated protein kinase (p38) upregulates TNF-alpha expression and may play a crucial role in pain sensation, we investigated the effect of one injection of inhibitor on expression of the pain-related neuropeptide calcitonin gene-related peptide (CGRP). METHODS.: The neuro-tracer fluoro-gold was applied to the surfaces of L4/5 discs to label the innervating DRG neurons (n = 30). Of 30 rats, 10 were controls, whereas the other 20 were the experimental model (i.e., discs were punctured with 23-gauge needle). P38 specific inhibitor or saline was applied simultaneously (n = 10 each, Puncture + inhibitor and puncture + saline groups). Fourteen days postsurgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP. Proportion of CGRP-immunoreactive DRG neurons was evaluated in all groups. RESULTS.: Fluoro-gold-labeled neurons innervating the L4/5 disc were distributed throughout L1 to L6 DRGs in all groups. Proportions of labeled neurons positive for CGRP were 15.2% +/- 8% (controls), 27.2% +/- 10% (puncture + saline), and 25.2% +/- 8% (puncture + inhibitor). Proportion of immunoreactive neurons was significantly increased in the puncture groups compared with controls. However, there was no significant difference between the 2 puncture groups (P > 0.1). CONCLUSION.: In this model, CGRP was upregulated in DRG neurons innervating the damaged disc. However, a direct single application of p38 inhibitor did not suppress CGRP expression in innervating DRG neurons. Future research with p38 inhibitor in this model should evaluate multiple or systemic administration of inhibitor.