Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

OBJECTIVE: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. METHODS: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI. RESULTS: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively. CONCLUSIONS: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

For whom the disc tolls: intervertebral disc degeneration, back pain and toll-like receptors.

Intervertebral disc (IVD) degeneration is characterised by catabolic and inflammatory processes that contribute largely to tissue degradation and chronic back pain. The disc cells are responsible for the pathological production of pro-inflammatory cytokines and catabolic enzymes leading to degeneration. However, this phenotypical change is poorly understood. Growing evidence in animal and human studies implicates Toll-like receptors (TLR) and their activation through danger-associated alarmins, found increasingly in degenerating IVDs. TLR signalling results in the release of pro-inflammatory cytokines and proteolytic enzymes that can directly cause IVD degeneration and back pain. This review aims to summarise the current literature on TLR activation in IVD degeneration and discuss potential treatment modalities to alleviate the inflammatory phenotype of disc cells in order to arrest IVD degeneration and back pain.

Overexpression of TIMP3 inhibits discogenic pain by suppressing angiogenesis and the expression of substance P in nucleus pulposus.

Approximately 50% of the cases of low back pain (LBP) are attributed to discogenic origin. The causes of discogenic pain are complicated and consist of a complex biochemical cascade. Neovascularization of intervertebral discs (IVDs) is believed to be associated with discogenic pain. The anti­angiogenesis ability of tissue inhibitor of metalloproteinase­3 (TIMP3) has been reported in many tumors, yet whether TIMP3 is associated with neovascularization of IVDs remains unknown. In the present study, both in vitro and in vivo models were used to investigate the association between discogenic pain and TIMP3 expression in nucleus pulposus (NP). PCR results demonstrated that inflammation induced downregulation of TIMP3 expression in NP cells. By using an adenovirus system to upregulate TIMP3 expression, the effect of TIMP3 on angiogenesis was measured by endothelial cell migration and tube formation assays. The results demonstrated that overexpression of TIMP3 suppressed angiogenesis in NP without the regulation of vascular endothelial growth factor (VEGF) expression. TNF­α converting enzyme (TACE) expression was downregulated by TIMP3, thus inhibiting the TACE­induced activation of TNF­α in NP cells. Immunohistochemical staining of IVDs also confirmed that TIMP3 inhibited the expression of substance P in NP. Taken together, the present results indicated the expression of TIMP3 in NP may have a key role in the development of discogenic pain.

Differential regulation of TRP channel gene and protein expression by intervertebral disc degeneration and back pain.

Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies.

Finite element and deformation analyses predict pattern of bone failure in loaded zebrafish spines.

The spine is the central skeletal support structure in vertebrates consisting of repeated units of bone, the vertebrae, separated by intervertebral discs (IVDs) that enable the movement of the spine. Spinal pathologies such as idiopathic back pain, vertebral compression fractures and IVD failure affect millions of people worldwide. Animal models can help us to understand the disease process, and zebrafish are increasingly used as they are highly genetically tractable, their spines are axially loaded like humans, and they show similar pathologies to humans during ageing. However, biomechanical models for the zebrafish are largely lacking. Here, we describe the results of loading intact zebrafish spinal motion segments on a material testing stage within a micro-computed tomography machine. We show that vertebrae and their arches show predictable patterns of deformation prior to their ultimate failure, in a pattern dependent on their position within the segment. We further show using geometric morphometrics which regions of the vertebra deform the most during loading, and that finite-element models of the trunk subjected reflect the real patterns of deformation and strain seen during loading and can therefore be used as a predictive model for biomechanical performance.

SFKs/p38 Pathway is Involved in Radicular Pain by Promoting Spinal Expression of Pro-Inflammatory Cytokines in a Rat Model of Lumbar Disc Herniation.

STUDY DESIGN: A controlled, randomized, animal study. OBJECTIVE: The aim of this study was to investigate the role of src-family kinases/p38 pathway in a rat model of lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: LDH always generates radicular pain, and the mechanism remains unclear. We have reported that spinal src-family kinases (SFKs) may be involved in the process, but the downstream mechanism needs further investigation. METHODS: LDH was induced by implantation of autologous nucleus pulposus (NP), harvest from the tail, in lumbar 4/5 spinal nerve roots of rat. Von Frey filaments and radiant heat tests were performed to determine mechanical and thermal pain threshold respectively. Basso, Beattie, and Bresnahan (BBB) scale was assessed to test the locomotor function. The protein level of p-SFKs, t-SFKs, p-p38, t-p38 in spinal cord was examined by western blotting analysis. Cellular location of p-p38 was determined by immunochemistry staining. Spinal tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, and IL-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Rats with NP implantation showed persistent ipsilateral mechanical allodynia and thermal hyperalgesia, which manifested as obvious decrease of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). BBB scale indicated the locomotor function of hindpaws in rats with NP implantation kept intact. Western blotting and immunohistochemistry staining revealed that phosphorylated SFKs (p-SFKs) and phosphorylated p38 MAPK (p-p38) were sequentially upregulated in ipsilateral spinal dorsal horn, but not in contralateral side of rats with NP. Intrathecal delivery of SFKs inhibitor reduced spinal p-p38 expression. Both SFKs and p38 inhibitors alleviated pain behaviors in a dose-responsive manner without disturbing locomotor function and reduced spinal expression of TNF-α, IL-1ß, and IL-6 in rats with NP. CONCLUSION: Spinal SFKs contribute to radicular pain by activation of p38 MAPK and increasing pro-inflammatory cytokines expression in rats with NP implantation. Targeting SFKs/p38 pathway may be helpful for alleviating radicular pain. LEVEL OF EVIDENCE: N/A.

Immunomodulation of mesenchymal stem cells in discogenic pain.

BACKGROUND CONTEXT: Back pain is a highly prevalent health problem in the world today and has a great economic impact on health-care budgets. Intervertebral disc (IVD) degeneration has been identified as a main cause of back pain. Inflammatory cytokines produced by macrophages or disc cells in an inflammatory environment play an important role in painful progressive degeneration of IVD. Mesenchymal stem cells (MSCs) have shown to have immunosuppressive and anti-inflammatory properties. Mesenchymal stem cells express a variety of chemokines and cytokines receptors having tropism to inflammation sites. PURPOSE: This study aimed to develop an in vitro controlled and standardized model of inflammation and degeneration of IVD with rat cells and to evaluate the protective and immunomodulatory effect of conditioned medium (CM) from the culture of MSCs to improve the conditions presented in herniated disc and discogenic pain processes. STUDY DESIGN: This is an experimental study. METHODS: In this study, an in vitro model of inflammation and degeneration of IVD has been developed, as well as the effectiveness of CM from the culture of MSCs. RESULTS: Conditioned medium from MSCs downregulated the expression of various proinflammatory cytokines produced in the pathogenesis of discogenic pain such as interleukin (IL)-1ß, IL-6, IL-17, and tumor necrosis factor (TNF). CONCLUSION: Mesenchymal stem cells represent a promising alternative strategy in the treatment of IVD degeneration inasmuch as there is currently no treatment which leads to a complete remission of long-term pain in the absence of drugs.

Ankylosing Spondylitis and Axial Spondyloarthritis in Patients With Long-term Inflammatory Bowel Disease: Results From 20 Years of Follow-up in the IBSEN Study.

BACKGROUND: Patients with inflammatory bowel disease [IBD] often suffer from rheumatic manifestations, including inflammatory back disorders. The prevalence of these disorders late in the course of IBD is poorly investigated. The aim of this study was to estimate the prevalence of inflammatory back disorders in patients with IBD 20 years after diagnosis, and to investigate possible associations with IBD severity, HLA-B27, and the NOD2 genotype. METHODS: A population-based cohort [the IBSEN study] was followed prospectively for 20 years. Information covering IBD activity and rheumatic diseases was collected at the regular follow-ups. HLA-B27 and NOD2 were analysed as present or absent. RESULTS: At 20 years, 599 members of the original cohort were alive, of whom 470 [78.5%] were investigated [314 ulcerative colitis and 156 Crohn's disease patients]. Ankylosing spondylitis was diagnosed in 21 patients [4.5%], axial spondyloarthritis was diagnosed in 36 patients [7.7%], and inflammatory back pain was diagnosed in 54 patients [11.5%]. Chronic back pain [back pain > 3 months] was present in 220 patients [46.8%]. HLA-B27 was associated with ankylosing spondylitis, axial spondyloarthritis, and inflammatory back pain, whereas no significant association was found for NOD2. A more chronic IBD course was associated with axial spondyloarthritis. CONCLUSIONS: Our data revealed a high prevalence of ankylosing spondylitis, axial spondyloarthritis, and inflammatory back pain 20 years after the IBD diagnosis. HLA-B27 but not NOD-2 was a predisposing factor for the inflammatory back disorders in IBD patients. Axial spondyloarthritis was associated with a more chronic active IBD disease course.

Link-N: The missing link towards intervertebral disc repair is species-specific.

INTRODUCTION: Degeneration of the intervertebral disc (IVD) is a frequent cause for back pain in humans and dogs. Link-N stabilizes proteoglycan aggregates in cartilaginous tissues and exerts growth factor-like effects. The human variant of Link-N facilitates IVD regeneration in several species in vitro by inducing Smad1 signaling, but it is not clear whether this is species specific. Dogs with IVD disease could possibly benefit from Link-N treatment, but Link-N has not been tested on canine IVD cells. If Link-N appears to be effective in canines, this would facilitate translation of Link-N into the clinic using the dog as an in vivo large animal model for human IVD degeneration. MATERIALS AND METHODS: This study's objective was to determine the effect of the human and canine variant of Link-N and short (s) Link-N on canine chondrocyte-like cells (CLCs) and compare this to those on already studied species, i.e. human and bovine CLCs. Extracellular matrix (ECM) production was determined by measuring glycosaminoglycan (GAG) content and histological evaluation. Additionally, the micro-aggregates' DNA content was measured. Phosphorylated (p) Smad1 and -2 levels were determined using ELISA. RESULTS: Human (s)Link-N induced GAG deposition in human and bovine CLCs, as expected. In contrast, canine (s)Link-N did not affect ECM production in human CLCs, while it mainly induced collagen type I and II deposition in bovine CLCs. In canine CLCs, both canine and human (s)Link-N induced negligible GAG deposition. Surprisingly, human and canine (s)Link-N did not induce Smad signaling in human and bovine CLCs. Human and canine (s)Link-N only mildly increased pSmad1 and Smad2 levels in canine CLCs. CONCLUSIONS: Human and canine (s)Link-N exerted species-specific effects on CLCs from early degenerated IVDs. Both variants, however, lacked the potency as canine IVD regeneration agent. While these studies demonstrate the challenges of translational studies in large animal models, (s)Link-N still holds a regenerative potential for humans.

Carbonic anhydrase XII functions in health and disease.

Human CAXII was initially identified as a cancer marker in different cancers and tumors. Expression of CAXII is regulated by hypoxia and estrogen receptors. CAXII expression has been also detected in several tissues, whereas in cancer and tumor tissues its expression is several fold higher. In brain tumors, an alternatively spliced form of CAXII is expressed. Higher expression of CAXII in breast cancer is indicative of lower grade disease. CAXII plays a key role in several physiological functions. Mutation in the CAXII gene causes cystic fibrosis-like syndrome and salt wasting disease. CAXII is also seen in nuclear pulposus cells of the vertebrae. Aging dependent stiffness or degeneration of backbone correlates with CAXII expression level. This finding suggests a possible implication of CAXII as a biomarker for chronic back pain and a pharmacological target for possible treatment of chronic back pain.

Histomorphometry and Bone Matrix Mineralization Before and After Bisphosphonate Treatment in Boys With Duchenne Muscular Dystrophy: A Paired Transiliac Biopsy Study.

Duchenne muscular dystrophy (DMD) is a genetic disorder causing progressive muscle weakness. To prolong independent ambulation, DMD patients are treated with glucocorticoids, which, in turn, can increase bone fragility. In a cohort with vertebral fractures, intravenous bisphosphonate (iv BP) therapy stabilized vertebrae and reduced back pain. To characterize the effects of glucocorticoid therapy and bisphosphonate treatment on bone tissue and material properties, paired transiliac biopsy samples (before and after on average 2.4 years of iv BP) from 9 boys with DMD were studied for histomorphometry and bone mineralization density distribution (BMDD) and compared to reference values. Before iv BP, the boys had low cancellous bone volume (BV/TV) and cortical thickness (Ct.Wi) (both on average 56% of the healthy average, p < 0.001 versus reference), and mineralizing surface (MS/BS) in the lower normal range (on average 74% of the healthy average). The average degree of mineralization of cancellous (Cn.CaMean) and cortical compartments (Ct.CaMean) was 21.48 (20.70, 21.90) wt% and 20.42 (19.32, 21.64) wt%, respectively (median [25th, 75th percentiles]), which was not different from reference. After iv BP, BV/TV and Ct.Wi were, on average, unchanged. However, at the individual patient level, BV/TV Z-scores increased in 2, remained unchanged in 4, and declined in 3 patients. Additionally, on average, MS/BS decreased (-85%, p < 0.001), Cn.CaMean (+2.7%) increased, whereas the heterogeneity of cancellous (Cn.CaWidth -19%) and cortical bone mineralization (Ct.CaWidth -8%, all p < 0.05) decreased versus baseline. The changes in bone mineralization are consistent with the antiresorptive action of iv BP. At the same time, our observations point to the need for novel therapies with less or absent bone turnover suppression, including the fact that bone turnover was low even before bisphosphonate therapy, that bone turnover declined further (as expected) with treatment, and that declines in trabecular bone volume were observed in some boys despite bisphosphonate therapy. © 2015 American Society for Bone and Mineral Research.

Intervertebral Disc Cells Produce Interleukins Found in Patients with Back Pain.

OBJECTIVE: To examine the link between cytokines in intervertebral disc (IVD) tissues and axial back pain. DESIGN: In vitro study with human IVD cells cultured from cadaveric donors and annulus fibrosus (AF) tissues from patients. RESULTS: Cultured nucleus pulposus (NP) and AF cells were stimulated with interleukin (IL)-1ß. IL-8 and IL-7 gene expression was analyzed using real-time polymerase chain reaction. IL-8 protein was quantified by enzyme-linked immunosorbent assay. After IL-1ß stimulation, IL-8 gene expression increased 26,541 fold in NP cells and 22,429 fold in AF cells, whereas protein released by the NP and AF cells increased 2,389- and 1,784-fold, respectively. IL-7 gene expression increased 3.3-fold in NP cells (P < 0.05).Cytokine profiles in AF tissues collected from patients undergoing surgery for back pain (painful group) or scoliosis (controls) were compared by cytokine array. IL-8 protein in the AF tissues from patients with back pain was 1.81-fold of that in controls. IL-7 and IL-10 in AF tissues from the painful group were 6.87 and 4.63 times greater than the corresponding values in controls, respectively (P < 0.05). CONCLUSION: Inflammatory mediators found in AF tissues from patients with discogenic back pain are likely produced by IVD cells and may play a key role in back pain.

Increased 99mTc MDP activity in the costovertebral and costotransverse joints on SPECT-CT: is it predictive of associated back pain or response to percutaneous treatment?

PURPOSE: Pain related to costovertebral and costotransverse joints is likely an underrecognized and potentially important cause of thoracic back pain. On combined single-photon emission computed tomography and computed tomography (SPECT-CT), increased technetium-99m methylene diphosphonate (99mTc MDP) activity at these articulations is not uncommon. We evaluated whether this activity corresponds with thoracic back pain and whether it predicts response to percutaneous injection. METHODS: All 99mTc MDP SPECT-CT spine examinations completed at our institution from March 2008 to March 2014 were retrospectively reviewed to identify those with increased 99mTc MDP activity in the costovertebral or costotransverse joints. The presence of corresponding thoracic back pain, percutaneous injection performed at the relevant joint(s), and response to injection were recorded. RESULTS: A total of 724 99mTc MDP SPECT-CT examinations were identified. Increased 99mTc MDP activity at costovertebral or costotransverse joints was reported in the examinations of 55 patients (8%). Of these, 25 (45%) had corresponding thoracic back pain, and nine of 25 patients (36%) underwent percutaneous injection of the joint(s) with increased activity. At clinical follow-up two days to 12 weeks after injection, one patient (11%) had complete pain relief, two (22%) had partial pain relief, and six (67%) had no pain relief. CONCLUSION: The findings suggest that increased activity in costovertebral and costotransverse joints on 99mTc MDP SPECT-CT is only variably associated with the presence and location of thoracic back pain; it does not predict pain response to percutaneous injection.

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat.

BACKGROUND: Whole-body vibration (WBV) is associated with back and neck pain in military personnel and civilians. However, the role of vibration frequency and the physiological mechanisms involved in pain symptoms are unknown. QUESTIONS/PURPOSES: This study asked the following questions: (1) What is the resonance frequency of the rat spine for WBV along the spinal axis, and how does frequency of WBV alter the extent of spinal compression/extension? (2) Does a single WBV exposure at resonance induce pain that is sustained? (3) Does WBV at resonance alter the protein kinase C epsilon (PKCε) response in the dorsal root ganglia (DRG)? (4) Does WBV at resonance alter expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn? (5) Does WBV at resonance alter the spinal neuroimmune responses that regulate pain? METHODS: Resonance of the rat (410 ± 34 g, n = 9) was measured by imposing WBV at frequencies from 3 to 15 Hz. Separate groups (317 ± 20 g, n = 10/treatment) underwent WBV at resonance (8 Hz) or at a nonresonant frequency (15 Hz). Behavioral sensitivity was assessed throughout to measure pain, and PKCε in the DRG was quantified as well as spinal CGRP, glial activation, and cytokine levels at Day 14. RESULTS: Accelerometer-based thoracic transmissibility peaks at 8 Hz (1.86 ± 0.19) and 9 Hz (1.95 ± 0.19, mean difference [MD] 0.290 ± 0.266, p < 0.03), whereas the video-based thoracic transmissibility peaks at 8 Hz (1.90 ± 0.27), 9 Hz (2.07 ± 0.20), and 10 Hz (1.80 ± 0.25, MD 0.359 ± 0.284, p < 0.01). WBV at 8 Hz produces more cervical extension (0.745 ± 0.582 mm, MD 0.242 ± 0.214, p < 0.03) and compression (0.870 ± 0.676 mm, MD 0.326 ± 0.261, p < 0.02) than 15 Hz (extension, 0.503 ± 0.279 mm; compression, 0.544 ± 0.400 mm). Pain is longer lasting (through Day 14) and more robust (p < 0.01) after WBV at the resonant frequency (8 Hz) compared with 15 Hz WBV. PKCε in the nociceptors of the DRG increases according to the severity of WBV with greatest increases after 8 Hz WBV (p < 0.03). However, spinal CGRP, cytokines, and glial activation are only evident after painful WBV at resonance. CONCLUSIONS: WBV at resonance produces long-lasting pain and widespread activation of a host of nociceptive and neuroimmune responses as compared with WBV at a nonresonance condition. Based on this work, future investigations into the temporal and regional neuroimmune response to resonant WBV in both genders would be useful. CLINICAL RELEVANCE: Although WBV is a major issue affecting the military population, there is little insight about its mechanisms of injury and pain. The neuroimmune responses produced by WBV are similar to other pain states, suggesting that pain from WBV may be mediated by similar mechanisms as other neuropathic pain conditions. This mechanistic insight suggests WBV-induced injury and pain may be tempered by antiinflammatory intervention.

Intervertebral discs from spinal nondeformity and deformity patients have different mechanical and matrix properties.

BACKGROUND CONTEXT: It is well-established that disc mechanical properties degrade with degeneration. However, prior studies utilized cadaveric tissues from donors with undefined back pain history. Disc degeneration may present with pain at the affected motion segment, or it may be present in the absence of back pain. The mechanical properties and matrix quantity of discs removed and diagnosed for degeneration with patient chronic pain may be distinct from those with other diagnoses, such as spinal deformity. PURPOSE: To test the hypothesis that discs from nondeformity segments have inferior mechanical properties than deformity discs owing to differences in matrix quality. STUDY DESIGN/SETTING: In vitro study comparing the mechanical and matrix properties of discs from surgery patients with spinal nondeformity and deformity. METHODS: We analyzed nucleus and annulus samples (8-11 specimens per group) from surgical discectomy patients as part of a fusion or disc replacement procedure. Tissues were divided into two cohorts: nondeformity and deformity. Dynamic indentation tests were used to determine energy dissipation, indentation modulus, and viscoelasticity. Tissue hydration at a physiologic pressure was assessed by equilibrium dialysis. Proteoglycan, collagen, and collagen cross-link content were quantified. Matrix structure was assessed by histology. RESULTS: We observed that energy dissipation was significantly higher in the nondeformity nucleus than in the deformity nucleus. Equilibrium dialysis experiments showed that annulus swelling was significantly lower in the nondeformity group. Consistent with this, we observed that the nondeformity annulus had lower proteoglycan and higher collagen contents. CONCLUSIONS: Our data suggest that discs from nondeformity discs have subtle differences in mechanical properties compared with deformity discs. These differences were partially explained by matrix biochemical composition for the annulus, but not for the nucleus. The results of this study suggest that compromised matrix quality and diminished mechanical properties are features that potentially accompany discs of patients undergoing segmental fusion or disc replacement for disc degeneration and chronic back pain. These features have previously been implicated in pain via instability or reduced motion segment stiffness.

Evaluation of behavior and expression of NaV1.7 in dorsal root ganglia after sciatic nerve compression and application of nucleus pulposus in rats.

PURPOSE: The pathomechanisms of pain resulting from lumbar disc herniation have not been fully elucidated. Prostaglandins and cytokines generated at the inflammatory site produce associated pain; however, non-steroidal anti-inflammatory drugs and steroids are sometimes ineffective in patients. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are related to sensory transmission in primary sensory nerves. The sodium channel NaV1.7 has emerged as an attractive analgesic target. The purpose of this study was to evaluate pain-related behavior and expression of NaV1.7 in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. METHODS: Rats were divided into three groups and underwent either sciatic nerve compression with NP for 2 s using forceps (n = 20), sham operation with neither compression nor NP (n = 20), or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for three weeks using von Frey filaments. NaV1.7 expression in L5 DRG was examined 7 and 14 days after surgery using immunohistochemistry. The number of neurons immunoreactive for NaV1.7 was compared among the three groups. RESULTS: Mechanical hyperalgesia was found over the 14-day observation in the nerve compression plus NP application group, but not in the sham-operated or control groups (P < 0.05). NaV1.7 expression in L5 DRG was up-regulated in the nerve compression plus NP application group, compared with sham-operated and control rats (P < 0.01). CONCLUSIONS: Our results indicate that nerve compression plus NP application produces pain-related behavior. We conclude that NaV1.7 expression in DRG neurons may play an important role in mediating pain from sciatic nerves after compression injury and exposure to NP.

Spinal transient receptor potential ankyrin 1 channel induces mechanical hypersensitivity, increases cutaneous blood flow, and mediates the pronociceptive action of dynorphin A.

We characterized pain behavior and cutaneous blood flow response induced by activation of the spinal transient receptor potential ankyrin 1 (TRPA1) channel using intrathecal drug administrations in the rat. Additionally, we assessed whether the pronociceptive actions induced by intrathecally administered dynorphin A, cholecystokinin or prostaglandin F(2α) are mediated by the spinal TRPA1 channel. Cinnamaldehyde, a TRPA1 agonist, produced a dose-related (3-10 µg) cutaneous blood flow increase and mechanical hypersensitivity effect. These effects at the currently used doses were of short duration and attenuated, although not completely, by pretreatment with A-967079, a TRPA1 antagonist. The cinnamaldehyde-induced hypersensitivity was also reduced by pretreatment with minocycline (an inhibitor of microglial activation), but not by carbenoxolone (a gap junction decoupler). In vitro study, however, indicated that minocycline only poorly blocks the TRPA1 channel. The mechanical hypersensitivity effect induced by dynorphin A, but not that by cholecystokinin or prostaglandin F(2α), was attenuated by a TRPA1 antagonist Chembridge-5861528 as well as A-967079. The cinnamaldehyde-induced cutaneous blood flow increase was not suppressed by MK-801, an NMDA receptor antagonist, or bicuculline, a GABA(A) receptor antagonist. The results indicate that spinal TRPA1 channels promote mechanical pain hypersensitivity and due to antidromic activation of nociceptive nerve fibers increase cutaneous blood flow. The attenuation of the cinnamaldehyde-induced hypersensitivity effect by minocycline may be explained by action other than block of the TRPA1 channel. Moreover, the spinal TRPA1 channel is involved in mediating the pronociceptive action of dynorphin A, but not that of the spinal cholecystokinin or prostaglandin F(2α).

Assessment of SpondyloArthritis International Society criteria for axial spondyloarthritis in chronic back pain patients with a high prevalence of HLA-B27.

OBJECTIVE: The Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (SpA) allow SpA classification of HLA-B27-positive patients if ≥2 specific clinical SpA features are present. We investigated the performance of these clinical ASAS criteria in a population with a high prevalence of HLA-B27. METHODS: A total of 807 persons reporting chronic back pain (CBP) lasting for >4 weeks during a population survey underwent a clinical, laboratory, and radiologic evaluation. The ASAS criteria for axial SpA were then used to determine classification status. RESULTS: Only 332 patients (41% of all CBP patients) fulfilled the prerequisite ASAS definitions for CBP (duration of ≥3 months and onset at age <45 years). In this ASAS-defined CBP cohort (51% women, CBP onset at age 27.2 years, 17% HLA-B27 positive), ASAS classification criteria for axial SpA were met by 8.4% of patients. Radiographic SpA by the modified New York criteria was present in 2.4%, while 6% fulfilled the clinical arm of the ASAS SpA criteria only. One-fifth of patients with clinical SpA developed radiographic evidence of SpA after a median of 8 years. CONCLUSION: Application of the clinical ASAS classification criteria in an area with a high prevalence of HLA-B27 leads to significant increases in the prevalence of axial SpA compared to radiologic SpA among CBP patients. This increase in the prevalence of disease is likely to have significant ramifications for patient management and health care systems.

Bone morphogenetic proteins and degenerative disk disease.

Bone morphogenetic proteins (BMPs) are involved not only in osteogenesis but also in chondrogenesis. They play an important role in the development and maintenance of the intervertebral disk (IVD). For this reason, an increasing amount of research has been performed to examine the relationship between BMPs and degenerative disk disease (DDD). Moreover, researchers are examining the safe use of BMPs as a potential treatment for diskogenic back pain. We performed a literature search using databases from the US National Library of Medicine and the National Institutes of Health to identify studies relating BMPs to DDD. According to in vitro and in vivo studies in different animal and human IVDs, BMP-2 and BMP-7 are upregulated with aging and with induced disk injury; this represents an anabolic response. Direct administration of BMP-2 to IVD cells results in increased production of components of the extracellular matrix. Upregulation of the BMP pathway via other agents, namely simvastatin and LIM mineralization protein-1, has resulted in similar outcomes. Adenoviruses loaded with BMPs, transfected either directly to IVD cells or via articular chondrocytic vectors, also resulted in reversal of the typical findings in DDD. We conclude that the use of BMPs to treat DDD has a promising future. Further studies are indicated to determine optimal delivery and efficacy in humans.