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The article presents a medical research on neurofilament-immunoreactive afferents in the substantia gelatinosa induced by compression of the dorsal root ganglion (DRG). Allodynia was demonstrated by a decrease of mechanical withdrawal threshold and c-Fos expression in the superficial dorsal horn induced by non-noxious stimulation. It revealed that the changes may be related to alloydynia induced by DRG compression.

Study Design: We conducted a retrospective review of data from patients who underwent surgical treatment for lumbosacral radiculopathy., Objective: To assess the effectiveness of the foot tapping test (FTT) in evaluating lower limb motor function in patients with lumbosacral radiculopathy pre- and post-surgery., Summary of Background Data: Lumbosacral radiculopathy is becoming increasingly common in aging populations. Despite standard treatments, paralysis often leads to incomplete postoperative recovery, necessitating early detection and interventions., Methods: We enrolled individuals who underwent surgery for lumbosacral radiculopathy at our facility between 2009 and 2020. Patients with a history of lumbar surgeries, dialysis, rheumatoid arthritis, and transitional vertebrae were excluded. The FTT score was measured by having the sole of the foot tap as many times as possible for 10 s while keeping the heel in contact with the floor. The L4, L5, and S1 groups were assigned using the scores on the side of the radiculopathy, and the control group was assigned using the scores on the intact side. Data were analyzed using Dunnett's test for group comparisons and paired t-tests for pre-post-surgery comparisons., Results: Of the 522 eligible patients, 80 (159 nerve roots, one patient with hemi-prosthetic leg) were analyzed. The preoperative FTT scores in the L4 and L5 groups were significantly lower than those in the control group, indicating functional impairment. One year post-surgery, all groups showed improvements in FTT scores, with the L5 group exhibiting significant improvements compared to the control; this was supported by the results of sensitivity analyses considering the effects of paralysis and pain., Conclusion: The FTT is a valuable tool for the early detection of lower limb motor dysfunction in lumbosacral radiculopathy, particularly for L5 nerve root impairment, where it aids in timely surgical intervention and may improve postoperative outcomes and quality of life., Competing Interests: Conflict of Interest and Source of Funding: The authors have no relevant financial relationships to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: In chronic low back pain (CLBP) patients, study of altered brain metabolites in the anterior cingulate cortex (ACC) using magnetic resonance spectroscopy (MRS) could reveal the detailed pathology of CLBP and depression. The aim was to detect the central difference between CLBP and controls by means of measuring the metabolites in the ACC, and to analyze the correlations between depression and metabolites in ACC., Materials and Methods: MRS was performed in CLBP (n=60) and control participants (n=56) to evaluate the effects of CLBP on metabolites in the ACC and to analyze the correlations between metabolites and questionnaire scores in a cross-sectional study., Results: Adjusting for age and sex, a negative effect of CLBP on the N-acetylaspartate (NAA) level (estimated regression slope coefficient [B]=-0.685, P<0.001) and positive effects on the glutamate +glutamine (Glx)/creatine (B=0.136, P=0.016) and Glx/myoinositol (B=0.140, P<0.048) ratios in the ACC were found. The correlation analysis demonstrated that there was a significant moderate correlation between some questionnaire scores of emotional disorders and metabolites in the ACC of CLBP participants (absolute r>0.4, P<0.05)., Discussion: Lower NAA levels and higher Glx/creatine and Glx/myoinositol ratios in the ACC of CLBP participants compared with controls were revealed. The result suggests the hypothesis that excessive Glx leads to neuronal dysfunction and/or death, which was reflected as a low NAA level in the ACC of individuals with CLBP. Measurement of these metabolites using MRS potentially helps evaluate CLBP patients' condition and psychological status objectively.

Study Design: An experimental animal study., Objective: To investigate the relationship between pain-related behavior and the expression of neurotrophic factors in the dorsal root ganglion (DRG) and spinal cord (SC) using a nucleus pulposus (NP) rat model., Summary of Background Data: Neurotrophic factors are released from activated glial cells and are associated with pain-related behavior. Nerve growth factor (NGF) is a neurotrophic factor that is induced by inflammation., Methods: Rats were divided into an NP group (n = 94) and a sham-operated group (n = 46). NP harvested from the tail was applied to the left L5 DRG. Rats in the NP group were then divided into five subgroups: one non-treatment and four treatment groups. In the treatment groups, a dose of anti-NGF antibody or phosphate-buffered saline was administered into the DRG. Behavioral testing was performed to investigate the mechanical withdrawal threshold of the left hind paw for all groups. Immunohistochemical localization of NGF, phosphorylated p38 (p38), and brain-derived neurotrophic factor (BDNF) in the DRGs and SCs was performed, and the numbers of immunoreactive (IR) cells were counted., Results: The withdrawal threshold in the nontreatment NP group was significantly decreased for 35 days, and that of the middle- and high-dose treatment rats was significantly higher than the phosphate-buffered saline group values. In the DRG, NGF-IR, p38-IR, and BDNF-IR cells were increased for days 21. In the SC, BDNF-IR, and p38-IR cells were increased from days 7 to 21., Conclusion: In the DRG, NGF expression increased, mechanical thresholds were reduced, and p38 and BDNF expression was increased in the NP group. p38 and BDNF expression was increased in SC neurons during the same period. Inhibition of NGF may be a potential treatment for neuropathic pain due to lumbar disc herniation., Level of Evidence: 5.

Study Design: A controlled, interventional animal study., Objective: The aim of this study was to evaluate the effect of diabetes mellitus (DM) on radiculopathy due to lumbar disc herniation (LDH), by investigating pain-related behavior and the expression of tumor necrosis factor-alpha (TNF-α) and growth-associated protein 43 (GAP43) in type 2 diabetic rats following application of nucleus pulposus (NP) to the dorsal root ganglion (DRG)., Summary of Background Data: Previous clinical studies suggested negative effects of DM on radiculopathy due to LDH, and that inflammation and nerve regeneration could interact with DM and radiculopathy., Methods: We applied autologous NP to the left L5 DRG of adult male Wistar rats and Goto-Kakizaki rats. Behavioral testing measured the mechanical withdrawal threshold of rats. We immunohistochemically evaluated the localization of ionized calcium-binding adapter molecule-1 (Iba-1), receptor of advanced glycation end products (RAGE), and TNF-α in DRGs. TNF-α and GAP43 expression levels in DRG were determined by quantitative real-time PCR and western blotting., Results: The mechanical withdrawal threshold significantly declined in the non-DM NP group compared with the non-DM sham group for 28 days, whereas the decline in threshold extended to 35 days in the DM NP group compared with the DM sham group. RAGE and TNF-α expression in DRGs was colocalized in Iba-1 positive cells. The non-DM NP rats had higher TNF-α protein expression levels versus the non-DM sham rats on day 7, and the DM NP group had higher levels versus the DM sham group on days 7 and 14. The non-DM NP group had higher GAP43 mRNA expression than the non-DM sham group for 28 days, while the DM NP group had a higher level than the DM sham group for 35 days., Conclusion: DM prolongs the pain-related behavior caused by NP. The prolonged inflammation and nerve regeneration could elucidate the pathogenesis of continuous pain of radiculopathy initiated by LDH., Level of Evidence: N /A.

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 (β 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.

Study Design: Controlled, interventional animal study., Objective: To examine the effect of an inhibitor of acid-sensing ion channel 3 (ASIC3) on pain-related behavior induced by application of the nucleus pulposus (NP) onto the dorsal root ganglion (DRG) in rats., Summary of Background Data: ASIC3 is associated with acidosis pain in inflamed or ischemic tissues and is expressed in sensory neurons and NP cells. The ASIC3 inhibitor, APETx2, increases the mechanical threshold of pain in models of knee osteoarthritis or postoperative pain. However, the efficacy of APETx2 for pain relief in the NP application model remains unknown., Methods: Autologous NP was applied to the left L5 nerve root of 183 adult female Sprague-Dawley rats. The DRGs were treated with NP plus one of the following four treatments: saline solution (SM), low (0.01 μg: LD), medium (0.1 μg: MD), or high dose (1.0 μg: HD) of APETx2. Behavioral testing was performed to investigate the mechanical withdrawal threshold using von Frey hairs. Expression of nerve growth factor, hypoxia-inducible factor-1α (HIF1α), activating transcription factor-3, and ionized calcium-binding adaptor molecule-1 was evaluated using immunohistochemistry. Statistical differences among multiple groups were assessed using the Steel test, the Tukey-Kramer test, and the Dunnett test. P < 0.05 were considered significant., Results: The thresholds in the HD group were higher than those in the SM group at Days 14 and 21 (P < 0.05). In the MD group, the threshold was higher than in the SM group at Day 14 (P < 0.05). High doses of APETx2 reduced the expression of HIF1α after Day 14 compared with the SM group (P < 0.05)., Conclusion: APETx2 significantly improved pain-related behavior in a dose-dependent manner. APETx2 may inhibit ASIC3 and partly inhibit Nav1.8 channels. This ASIC3 channel inhibitor may be a potential therapeutic agent in early-stage lumbar disc herniation., Level of Evidence: N/A.

Study Design: A cross-sectional study., Objective: The aim of this study was to evaluate activity of the nucleus accumbens (NAc) in response to lumbar mechanical stimulation in patients with chronic low back pain (cLBP) using functional magnetic resonance imaging (fMRI)., Summary of Background Data: Although a modified activity of the NAc was characterized in cLBP patients, its pathological significance has yet to be determined. We hypothesized that NAc activation in response to pain might differ depending on the extent of psychiatric problems, which might be associated with the affective/motivational background of chronic pain., Methods: Twenty-one patients with cLBP (four men, 17 women) were recruited. Subjects were divided into two groups on the basis of scores on the patient version of the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) scores: ≥17 (High Score, HiS group) and <17 (non-High Score, non-HiS group). Each subject was placed in the prone position on a 3-Tesla magnetic resonance imaging (MRI) scanner and stimulated by mechanical stimulation on the left lower back. Three blocks of 30-second pain stimulus calibrated at either 3 or 5 on an 11-grade numerical rating scale (NRS) were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. Functional images were analyzed using a multisubject general linear model with Bonferroni multiple comparisons., Results: Subjects in the HiS group had more intense daily pain and lower quality of life than those in the non-HiS group (P < 0.05). Catastrophic thinking in relation to pain experience did not differ between the groups. Activation at the NAc was smaller in the HiS group than in the non-HiS group (P < 0.001)., Conclusion: The presence of psychiatric problems was associated with attenuated activity of the NAc in cLBP patients. Dysfunction of the NAc might potentially be involved in the affective/motivational factors in the chronification of LBP., Level of Evidence: N/A.

Study Design: A cross-sectional study of 1804 consecutive patients., Objective: The aim of this study was to investigate the prevalence of pathological pain and its distribution features in patients with chronic lumbar spinal disorders., Summary of Background Data: Clinical spinal disorders can involve pathological neuropathic pain (NeP) as well as physiological nociceptive pain (NocP), as they have varied pathology, including spinal cord injury, stenosis, and compression. A study conducted by the Japanese Society for Spine Surgery and Related Research (JSSR) has determined a prevalence of 29.4% for NeP in patients with lumbar spinal disorder. However, the data did not include information on pain location., Methods: Patients aged 20 to 79 years with chronic lower back pain (≥3 months, visual analog scale score ≥30) were recruited from 137 JSSR-related institutions. Patient data included an NeP screening questionnaire score and pain location (lower back, buttock, and legs). The association between the pain pathology and its location was analyzed statistically using the unpaired t test and Chi-square test followed by Fisher test. P < 0.05 was considered significant., Results: Low back pain subjects showed 31.9% of NeP prevalence, and the pain distribution showed [NocP(%)/NeP(%)] low back pain only cases: 44/22, while low back pain with leg pain cases showed a prevalence of 56/78. This indicates that low back pain alone can significantly induce NocP rather than NeP (P < 0.01). Buttock pain was revealed to significantly induce both lower back pain and leg pain with NeP properties (P < 0.01). Leg pain was revealed to be predominantly neuropathic, especially when it included peripheral pain (P < 0.01)., Conclusion: Low back pain with no buttock pain induces NocP rather than NeP. Buttock pain is significantly associated with NeP prevalence whether or not leg pain exists. Leg pain can increase the prevalence of NeP, especially when it contains a peripheral element., Level of Evidence: 3.

Study Design: A cohort study using data from the Locomotive Syndrome and Health Outcome in Aizu Cohort Study, a population-based prospective cohort study of residents of the towns of Tadami and Minamiaizu in Fukushima Prefecture, Japan., Objective: The aim of this study was to clarify the association between kyphotic posture and falls, and to investigate the presence or absence of sex differences., Summary of Background Data: In our literature review, we found no studies focusing on sex differences in the association between kyphotic posture and falls., Methods: We included subjects aged more than 40 years who participated in annual health check-ups from 2009 to 2010. We analyzed the effects of kyphotic posture, measured using the wall-occiput test (WOT), on falls, adjusting for potential confounders, such as age, body mass index, symptoms of depression, sedative medication, and other comorbidities., Results: We enrolled a total of 1418 subjects into primary analyses (593 men, 825 women; mean [standard deviation] age, 68.1 [7.7] yrs). We then stratified subjects into the following groups according to the degree of kyphotic posture: nonkyphotic posture (n = 1138, 80.3%), mild kyphotic posture (n = 172, 12.1%), and severe kyphotic posture (n = 108, 7.6%). We observed no significant difference in the severity of kyphotic posture between men and women (P = 0.18). Overall, 284 subjects (20.0%) experienced at least one fall during the one-year period. After adjustment for potential confounders using a logistic regression model, we observed a significant association between severe kyphotic posture and falls for men [odds ratio (OR) 2.14 (1.01-4.57); P = 0.048]. In contrast, we observed no significant association for women [OR for severe kyphotic posture 0.80 (0.43-1.50), OR for mild kyphotic posture 0.91 (0.53-1.57)]., Conclusion: We identified a sex difference in the association between kyphotic posture and falls in community-dwelling adults. In particular, severe kyphotic posture might only increase the incidence of falls in men., Level of Evidence: 3.

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.

Study Design: The effect of an EP1 receptor antagonist on pain-related behavior induced by nucleus pulposus (NP) applied to the dorsal root ganglion (DRG) in rats was investigated., Objective: We investigated pain-related behavior, the amount of prostaglandin E2 (PGE2), and neural damage to the DRG after application of NP to the DRG after administration of an EP1 receptor antagonist., Summary of Background Data: PGE2 induces mechanical allodynia and hyperalgesia, which are mediated by PGE2 receptors. EP1 is one of the PGE2 receptor subtypes. An EP1 antagonist reduces hyperalgesia, allodynia, and c-fos expression in the rat chronic nerve constriction model., Methods: Sprague-Dawley rats (n = 103) were used. Animals receiving NP were divided into three experimental groups (n = 12 in each group): saline, high-dose (5 mg/kg) EP1 receptor antagonist (RA), and low-dose (2.5 mg/kg) EP1-RA (orally once daily for 5 days). Animals in the sham group did not receive NP. Von Frey tests were used for pain-behavior testing. The amount of PGE2 in DRG and the number of activating transcription factor-3 (ATF3) immunoreactive positive cells were compared among groups., Results: The mechanical thresholds in the three groups decreased 7 days after surgery (just before treatment). The threshold in both the high- and low-dose EP1-RA groups increased at 11 days (5 days after treatment) and continued for 14 days. The thresholds in both the low- and high-dose EP1-RA groups increased significantly compared with the saline group (P < 0.05). The amount of PGE2 was significantly increased in the NP group compared with the sham and naïve animals after application of NP. ATF3 expression was increased by NP but was not increased after administration of the EP1-RA., Conclusion: An EP1 receptor antagonist improves pain-related behavior in the rat model and might be a potential agent to improve pain-related behavior in patients with lumbar disc herniation.

Study Design: Controlled, interventional, animal study., Objective: To examine the involvement of high-mobility group box 1 (HMGB1) in the neuropathic pain state induced by the application of nucleus pulposus onto the dorsal root ganglion (DRG) and to investigate the effect of HMGB1 neutralization antibody in the pathogenesis., Summary of Background Data: HMGB1 is a potent proinflammatory mediator when present extracellularly, and anti-HMGB1 neutralization antibody inhibits inflammation, cytokine expression, and macrophage activation., Methods: Thirty-nine adult female Sprague-Dawley rats (200-300 g) were used. The left L5/6 facet joint was removed, and the L5 DRG was exposed. Nucleus pulposus harvested from the tail was applied to the left L5 DRG. Then, 400 μg of anti-HMGB1 neutralization antibody was administered intraperitoneally after surgery. Behavioral testing using von Frey hairs was performed to investigate the mechanical withdrawal threshold. Neuronal damage was investigated by counting the number of activating transcription factor 3 (ATF3) neurons. The expressions of tumor necrosis factor-α (TNF-α) and HMGB1 were measured by double-labeled immunohistochemistry and immunoblotting., Results: Immunoblotting of harvested nucleus pulposus revealed HMGB1 in the nucleus pulposus. Double-labeled immunohistochemistry revealed that macrophages in the applied nucleus pulposus expressed HMGB1 and TNF-α. Administration of anti-HMGB1 neutralization antibody significantly reduced the TNF-α expression in the DRG and improved the pain-related behavior from day 2 to day 14., Conclusion: HMGB1 appears to play an important role in the development of pain-related behavior induced by the application of nucleus pulposus onto the DRG. HMGB1 from applied nucleus pulposus and actively secreted from macrophages would act as a proinflammatory mediator together with proinflammatory cytokines. HMGB1 blocking therapy might become a new treatment method for neuropathic pain.

Study Design: this study was designed to examine the neuroprotective effects of asialo-erythropoietin (A-EPO) in a rat model of lumbar disc herniation., Objective: to investigate the effects of A-EPO on pain-related behavior, the expression of phosphorylated-p38 (p-p38) mitogen activated kinase, and the expression of tumor necrosis factor alpha (TNF-α) induced by nucleus pulposus (NP) application on the nerve root., Summary of Background Data: erythropoietin (EPO) has neuroprotective effects in a variety of models of central and peripheral nerve injuries. However, EPO is a hematopoietic growth factor and can therefore cause significant side effects such as thicker blood and promotion of blood clotting. A-EPO is a neuroprotective derivative of EPO that is not hematopoietic., Methods: female Sprague-Dawley rats (n = 149) were used in this study. NP harvested from the tail was applied to the left L5 nerve root and the rats were then divided into four groups: NP + nontreatment group, no further treatment; NP + A-EPO group, 13.4 microg/kg A-EPO; NP + EPO group, 13.4 microg/kg EPO; and NP + vehicle group, received vehicle. The substances were administered subcutaneously 1 day before surgery and daily for 2 weeks. In the sham group of animals, the L5 nerve root was exposed and NP was not applied. Withdrawal thresholds were determined by the von-Frey test 28 days after surgery. The expressions of p-p38 and TNF-α were assessed by immunohistochemical and immunoblotting analysis. Data were analyzed by unpaired Student t test and Dunnett t test (significance level, P < 0.05)., Results: in the NP + nontreatment and NP + vehicle groups, withdrawal thresholds were decreased significantly for 28 days compared with the sham group (P < 0.05). In the NP + A-EPO group, the thresholds were significantly increased on day 28, and in the NP + EPO group, the thresholds were significantly increased on days 21 and 28 (P < 0.05) compared with the NP + nontreatment and NP + vehicle groups. The expression of p-p38 in the NP + A-EPO group was significantly lower than that in the NP + vehicle group on day 1 (P < 0.05). The expression of TNF in the NP + A-EPO and NP + EPO groups was significantly lower than that in the NP + vehicle group on days 1 and 7 (P < 0.05)., Conclusions: A-EPO improved pain-related behavior and reduced the expression of p-p38 and TNF-α. The effect of A-EPO may be related to the inhibitory action of p-p38 and TNF-α in the dorsal root ganglion.

Study Design: An experimental rat study., Objective: To assess pain-related behavior and vascular endothelial growth factor (VEGF) expression induced by nucleus pulposus (NP) applied to nerve roots in rats., Summary of Background Data: Radiculopathy from disc herniation is caused by nerve compression and chemical inflammation. In experimental studies, a decrease in mechanical withdrawal threshold, blood flow, and nerve root dysfunction was reported when the NP was applied to nerve roots. However, neuron reproduction and changes in nerve root blood vessels have not been clearly understood., Methods: NP harvested from the tail was applied to the left L5 dorsal root ganglion (NP group; n = 77). As a control, sham-operated animals were used (n = 77). Behavioral testing with von Frey hairs was performed for 35 days. Immunoreactivity (IR) for VEGF, activating transcription factor-3, growth-associated protein-43 (GAP-43), factor VIII, and hypoxia-inducible factor-1[alpha] (HIF-1 a) were studied by immunohistochemistry. Western blot analyses of VEGF and GAP-43 were also performed., Results: The mechanical withdrawal threshold significantly decreased from 7 to 28 days in the NP group versus the sham group (P < 0.05). In the NP group, activating transcription factor-3-IR cells increased from 3 to 14 days (P < 0.05), hypoxia-inducible factor-1[alpha]-IR cells increased at 14 days (P < 0.05), and blood vessels with Factor VII-IR cells increased at 28 days (P < 0.05) compared with the sham group. The expression levels of VEGF and GAP-43 in the NP group significantly increased at 14 and 28 days (P < 0.05)., Conclusion: Neuron damage induced by NP applied to the nerve root at the early stage, and axon extension occurred from 14 days. VEGF increased at 14 and 28 days, and the numbers of blood vessels increased 28 days after surgery. The mechanical withdrawal threshold improved at 35 days. Regeneration and vascularization by VEGF might be associated with pain-related behavior.

Study Design: The association between intramuscular pressure and low back pain was investigated by measuring intramuscular pressure and blood flow, assessing histologic appearance, and performing immunohistochemical testing in rats., Objective: To develop an experimental rat model of increased intramuscular pressure (IMP) in the lumbar paraspinal muscles accompanied by reduced intramuscular blood flow (IMBF). The expression of neuropeptides in the dorsal root ganglion of the experimental model was also investigated., Summary of Background Data: Studies have reported that IMP in the lumbar paraspinal muscles is one of the causes of chronic low back pain. However, the pathology of low back pain accompanied by IMP has not been sufficiently clarified., Methods: A balloon was inflated below the vertebral fascia of rats (balloon group) and intramuscular pressure and blood flow in the lumbar paraspinal muscles were measured. Intramuscular pressure was measured using a pressure transducer, whereas IMBF was measured using a contact-type laser Doppler flowmeter. Compared with the sham operation group, intramuscular pressure was higher and IMBF was lower for the balloon group at 1 hour and 1 day after insertion. In addition, at 1 hour and 1 day after insertion, IMBF and pressure were continuously measured while rats were positioned in flexion for 1 hour., Results: Intramuscular pressure was significantly higher and IMBF was significantly lower in the balloon group at 1 day after insertion (P < 0.05). Expression of substance P, a neuropeptide, was also observed in the dorsal root ganglion of the first lumbar vertebra., Conclusion: These findings suggest that IMP and decreased IMBF in the lumbar paraspinal muscles induce inflammation and pain in the lower back.

Study Design: Cerebral activation by lumbar mechanical stimulus was investigated by functional magnetic resonance imaging in healthy subjects and patients with chronic low back pain (LBP)., Objectives: To characterize the cerebral substrates of LBP, and to explore a possible pathologic pattern of cerebral activation in chronic LBP patients., Summary of Background Data: The cerebral substrates of LBP have been poorly defined in contrast to those of cutaneous somatic pain., Methods: Eight healthy volunteers and 6 patients with idiopathic, chronic LBP were recruited. Each subject was placed in the prone position on a 3 Tesla MRI scanner, and stimulated by manual pressure with the tail of an air-filled, 20-mL syringe at 5 cm left of the fourth-fifth lumbar spinal interspace. Three blocks of 30-second painful stimulus, calibrated at either 3 or 5 on the 10-cm visual analog scale (VAS), were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. VAS of pain intensity and unpleasantness were evaluated after each session. Functional imaging was analyzed using a multisubject general linear model with Bonferroni multiple comparisons at P < 0.05., Results: Pain thresholds were smaller (P < 0.05) and VAS of unpleasantness was larger in LBP patients than in healthy subjects. Activation was observed at the prefrontal, insular, posterior cingulate cortices (PCC), supplementary motor, and premotor areas predominantly in the right hemisphere, but not at the somatosensory cortices. LBP patients showed augmented activation compared with healthy volunteers specifically at the right insula, supplementary motor, and PCC., Conclusion: Chronic LBP patients showed increased tenderness at the lower back, higher aversive reaction to pain, and augmented LBP-related cerebral activation. The LBP-related activation is characterized by the absence of sensory-discriminative component and the involvement of PCC.

Study Design: An analysis of pain behavior and neuronal apoptosis in the dorsal root ganglion (DRG) following crush injury to the L5 nerve root, with or without surgical sympathectomy., Objectives: To determine whether sympathectomy prevents pain behavior and to compare pain behavior with expression of tumor necrosis factor (TNF)-alpha and apoptosis in the DRG., Summary of Background Data: Sympathetic block is used to relieve symptoms in radiculopathy patients. One effect of the block is improvement of blood flow to the nerve. However, this beneficial effect continues longer than the expected duration of local anesthesia, suggesting an unknown neuroprotective effect involving interference with sympathetic activity., Methods: Sprague-Dawley rats (n = 102) were used and divided into 4 experimental groups. In the crush group, animals received a crush injury to the L5 nerve root. In the sympathectomy group, animals received sympathectomy (Syx) on the left side. In the Syx + crush group, both sympathectomy and crush injury were performed. In the sham group, the surgical procedure was the same, but neither sympathectomy nor crush injury took place. Mechanical allodynia was determined in 4 groups. Expression of TNF-alpha was compared in rats with crush injury, with and without sympathectomy. Using immunostaining for caspase 3, NeuN, and GFAP, localization of apoptotic cells was observed. In addition, we compared the percentage of neurons undergoing apoptosis in the DRG., Results: Sympathectomy prevented mechanical allodynia throughout the 14-day experimental period. TNF-alpha expression was increased in the DRG following crush-only injury, whereas it was decreased in animals undergoing sympathectomy after the crush injury. DRG apoptosis in the crush group was significantly higher than in the sympathectomy group at day 7 (P < 0.05)., Conclusion: Surgical sympathectomy reduced mechanical allodynia for 14 days after nerve root crush injury, and that DRG apoptosis was decreased in injured animals that underwent sympathectomy. Sympathetic block may not only cause an increase in nerve blood flow, but may also prevent the development of significant TNF-alpha elevation, DRG apoptosis, and neuropathic pain.

Study Design: Experimental animal study., Objective: To determine whether corticosteroids produce additional benefit to nerve root infiltration (NRI) for experimental lumbar disc herniation., Summary of Background Data: NRI is used for nonsurgical treatment of radicular symptoms caused by lumbar disc herniation or lumbar spinal canal stenosis. Various studies have shown that NRI using local anesthetic or combinations of local anesthetic and corticosteroid can provide both short- and long-term pain relief. However, whether corticosteroids produce additional benefit to NRI remains controversial., Methods: A total of 174 adult female Sprague-Dawley rats were used in this study. The left L5 nerve root and dorsal root ganglion (DRG) were exposed. For the nontreatment group, autologous nucleus pulposus was harvested from the tail and applied to the DRG. For treatment groups, 1% lidocaine (Lido group), 0.4% dexamethasone (Dexa group), 1% lidocaine + 0.4% dexamethasone (Lido + Dexa group), or saline (Saline group) was injected into the underlayer of epineurium just distal to the nucleus pulposus. At 2, 7, 14, and 21 days after surgery, withdrawal threshold was determined using the von Frey test for mechanical allodynia. Expression of tumor necrosis factor (TNF)-alpha in the DRG was examined by immunohistochemical analyses and immunoblotting., Results: Withdrawal threshold decreased in the nontreatment group from day 2 to day 14. Conversely, Lido, Dexa, and Lido + Dexa groups showed no decreases in withdrawal thresholds, and no significant differences were observed among these 3 groups. Immunohistochemical analyses showed that TNF-alpha was localized in DRG neurons in all groups. Immunoblotting showed that expression of TNF-alpha in the DRG was lower in Lido, Dexa, and Lido + Dexa groups than in the nontreatment group. No significant differences were observed among these 3 groups., Conclusion: NRI prevented mechanical allodynia. However, no additional benefit from using corticosteroid was identified, suggesting that corticosteroid may be unnecessary for NRI.

Study Design: We investigated involvement of EphB/ephrinB system in neuropathic pain., Objective: Using immunoblotting, immunohistochemistry, and RNA interference techniques, we examined the expression levels of EphB receptors and ephrinB ligands in neuropathic pain. We also explored the effect of ephrinB siRNA for neuropathic pain., Summary of Background Data: It has been reported that EphB2 regulates the development of synaptic plasticity in the hippocampus by interacting with N-methyl-D-aspartate (NMDA) receptors. In acute pain models, it has been clear that EphB1/ephrinB2 interactions via the NMDA receptor modulates synaptic efficacy in spinal cord., Methods: Adult female Sprague-Dawley rats were used in this study. A crush injury model was prepared by crushing the left L5 spinal nerve distal to dorsal root ganglions (DRG) under deep anesthesia. The sham operation was subjected as control. Expression of ephrinB2 and EphB1 were examined by immunoblotting and immunohistochemical analyses with anti-EphB and anti-ephrinB antibodies. To assess involvement of ephrinB in neuropathic pain, we examined the effect of small interference RNA (siRNA) on mechanical allodynia., Results: Among EphB and ephrinB isoforms tested, ephrinB2 and EphB1 were predominant in DRG and spinal cord. Results showed that the expression of ephrinB2 was enhanced in neurons in DRG and spinal cord by the injury in a time-dependent manner. EphB1 was expressed in neurons of spinal cord. Administration of ephrinB2 siRNA reduced the expression of ephrinB2 and mechanical allodynia., Conclusion: Expression of ephrinB2 is enhanced by nerve injury in neurons in DRG and spinal cord, while its receptor EphB1 is expressed in spinal cord. These results suggest that induction of ephrinB2 might activate EphB1/ephrinB2 signaling pathway to regulate synaptic plasticity and reorganization, and that ephrinB2 siRNA could be a potential therapeutic agent for neuropathic pain.

Study Design: An experimental animal study., Objective: To study if antitumor necrosis factor-alpha (TNF-alpha) antibody, which is administered at different times, reduces the pain behavior induced by application of nucleus pulposus (NP) to the nerve root., Summary of Background Data: Treatment with TNF-alpha inhibitor reduces the pain-related behavior induced by epidural application of NP in rats., Methods: Left L5 partial laminectomy was performed and NP was applied to the L5 nerve root in 24 rats. The rats were divided into 4 groups. In 3 groups, anti-rat TNF-alpha antibody was intravenously administered immediately after, or 6 or 20 days after NP application. The fourth group was not treated with anti-rat TNF-alpha antibody (untreated rats). The withdrawal threshold of the plantar surface was determined 1 day before up through 28 days after NP application., Results: The withdrawal threshold of rats that had been treated with anti-rat TNF-alpha antibody immediately after or 6 days after, but not 20 days after, NP application, was significantly higher than that of the untreated rats., Conclusions: Anti-TNF-alpha antibody reduced allodynia only when it was administered soon after the onset of allodynia. Late administration of anti-TNF-alpha antibody did not have an antiallodynic effect.

Study Design: The association between lumbar facet joint inflammation and radiculopathy was investigated using behavioral, histologic, and immunohistochemical testing in rats., Objectives: To develop a rat model of lumbar facet joint inflammation and ascertain whether facet joint inflammation induces radiculopathy using this model., Summary of Background Data: Both mechanical and chemical factors have been identified as important for inducing radiculopathy. In lumbar spondylosis, facet joint osteophytes may contribute to nerve root compression, which may induce radiculopathy. Furthermore, inflammation may occur in the facet joint, as in other synovial joints. Inflamed synovium may thus release inflammatory cytokines and induce nerve root injury with subsequent radiculopathy., Methods: A piece of gelatin sponge containing complete adjuvant was inserted into the L5-L6 facet joint in rats (arthritis group). Saline was used in the control group. Mechanical allodynia was determined using the von Frey test. Inflammatory cells infiltrating the epidural space were counted, and changes in cartilage were assessed histologically. Tumor necrosis factor (TNF)-alpha-immunoreactive cells in the L5 dorsal root ganglion were counted., Results: Mechanical allodynia was observed in the arthritis group from day 3, gradually recovering during the observation period. Significantly larger numbers of inflammatory cells had infiltrated the epidural space by days 3 and 7 in the arthritis group than in controls. Numbers of TNF-alpha-immunoreactive cells were significantly increased at days 1 and 3 in the arthritis group compared with controls. Predominantly small nociceptive neurons were stained., Conclusions: When inflammation was induced in a facet joint, inflammatory reactions spread to nerve roots, and leg symptoms were induced by chemical factors. These results support the possibility that facet joint inflammation induces radiculopathy.

Study Design: Vasodilatation was studied in a model of experimental chronic cauda equina compression using measurements of vessel diameter on video recordings., Objective: The vasodilative effect was compared between a prostaglandin E2 receptor (EP) subtype agonists (EP4 agonist) and a prostaglandin E1 (PGE1) derivate., Summary and Background Data: Reduction of blood flow is one important pathogenic factor of neurogenic intermittent claudication (NIC) for lumbar spinal canal stenosis. It is known that PGE1 improves the mean walking distance in patients with cauda equina compression type of NIC. There are four subtypes of EP: EP1, EP2, EP3, and EP4. EP4 is located in vessels of pigs and rabbits. A highly selective EP4 agonist, which has effects on dilatation of pig and rabbit vessels, has recently been developed. One may therefore assume that this agonist may improve blood flow in the chronically compressed cauda equina., Methods: A total of 25 dogs were used. A plastic balloon inflated to 10 mm Hg was placed under the lamina of the seventh lumbar vertebra for 1 week. OP-1206 cyclodextrin clathrate (OP-1206 CD: prostaglandin E1 derivate) and ONO-4819 CD (a highly selective EP4 agonist) were intravenously administrated. The following 5 experimental groups were assigned: animals in group OP (3) (n = 5) and Group OP (10) (n = 5) received 3 eta g/kg per minute and 10 eta g/kg per minute of OP-1206 CD, respectively; those in Group EP (3) (n = 5) and Group EP (10) (n = 5) received 3 eta g/kg per minute and 10 eta g/kg per minute of ONO-4819 CD, respectively; and those in the control group (n = 5) received saline. After 7 days, the cauda equina was exposed and blood vessels of the second or third sacral nerve root were identified using a specially designed operation microscope equipped with a video camera. The diameters of the observed blood vessels were measured on video-recordings every 10 minutes until 60 minutes after administrating OP-1206 CD or ONO-4819CD., Results: In the Groups OP (3), OP (10), and EP (10), the blood vessels were dilated and blood flow increased after injection of the agents. In the Group EP (10), the vessel diameter and blood flow increased significantly compared with that in the other four groups. In contrast, the blood vessels contracted and the blood flow was reduced in the Group EP (3)., Conclusions: Our results suggested that the EP4 agonist at high concentrations might be a potential therapeutic agent since it is expected to increase blood flow in nerve roots in patients with spinal canal stenosis.

Study Design: A cross-sectional and epidemiologic study investigated low back pain., Objective: To assess the correlation among outcome measures for low back pain, including sciatica, according to a proposed low back pain-related model., Summary of Background Data: Various outcome measures are used in low back pain research: pain, functional status, generic health status, and patient satisfaction. Correlation among these measures has been unclear., Methods: For this study, 816 subjects (369 men and 447 women; average age, 62 years) who underwent an adult medical examination. The patients were interviewed concerning their personal background, severity of low back pain and sciatica, functional status, general health perception, social participation, subjective happiness, and patient satisfaction. The correlation among these measures was analyzed systematically using path analysis based on a low back pain-related model hypothesizing that low back pain and sciatica worsen functional status and general health perception and then affect social participation, subjective happiness, and patient satisfaction., Results: Restriction of functional status was found to be the most closely correlated with severity of low back pain. A decrease in physical health was most closely correlated with restriction of function. Social participation, subjective happiness, and patient satisfaction were closely correlated with physical health status. There was a significant correlation among outcome measures concerning physical health, which was consistent with a low back pain-related model., Conclusions: The outcome measures concerning physical health in this study were found to be correlated significantly, consistent with the proposed low back pain-related model.

Study Design: The distribution of the lumbar plexus was analyzed using cadavers., Objective: To clarify the safety zone to prevent nerve injuries with respect to retroperitoneal endoscopic surgery., Summary of Background Data: Surgical approaches to the retroperitoneal space vary among surgeons. Recently, retroperitoneal endoscopic surgery has been applied to various spinal disorders. When the psoas major muscle is separated during retroperitoneal endoscopic surgery, there is a potential risk of injury to the lumbar plexus or nerve roots. However, there is sparse knowledge regarding the relationship between the greater psoas muscle and the lumbar plexus., Methods: A total of 30 cadavers were analyzed. Six lumbar spines of the cadavers were cut in parallel with the lumbar disc space. Each axial section was photographed and captured into a computer. The distribution of the lumbar plexus was analyzed using computer images. The positions where the genitofemoral nerve emerged on the abdominal surface of the psoas major muscle were analyzed using 24 cadavers., Results: L2/3 and above, all parts of the lumbar plexus, and nerve roots were located from the dorsal fourth of the vertebral body and dorsally. The genitofemoral nerve descends obliquely forward through the psoas major muscle, emerging on the abdominal surface between the cranial third of the L3 vertebra and the caudal third of the L4 vertebra. The safety zone of the psoas major muscle to prevent nerve injuries, excluding the genitofemoral nerve, is at L4/L5 and above., Conclusions: The safety zone, excluding the genitofemoral nerve, is at L4-L5 and above.