CGRP Regulates Nucleus Pulposus Cell Apoptosis and Inflammation via the MAPK/NF-κB Signaling Pathways during Intervertebral Disc Degeneration

Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF-κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand-new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.

The Role of Diagnostic Injections in Spinal Disorders: A Narrative Review

Neck and back pain is increasingly prevalent, and has increased exponentially in recent years. As more resources are dedicated to the diagnosis of pain conditions, it is increasingly important that the diagnostic techniques used are as precise and accurate as possible. Traditional diagnostic methods rely heavily upon patient history and physical examination to determine the most appropriate treatments and/or imaging studies. Though traditional means of diagnosis remain a necessity, in many cases, correlation with positive or negative responses to injections may further enhance diagnostic specificity, and improve outcomes by preventing unnecessary treatments or surgeries. This narrative review aims to present the most recent literature describing the diagnostic validity of precision injections, as well as their impact on surgical planning and outcomes. Diagnostic injections are discussed in terms of facet arthropathy, lumbar radiculopathy, discogenic pain and discography, and sacroiliac joint dysfunction. There is a growing body of evidence supporting the use of diagnostic local anesthetic injections or nerve blocks to aid in diagnosis. Spinal injections add valuable objective information that can potentially improve diagnostic precision, guide treatment strategies, and aid in patient selection for invasive surgical interventions.

Intradiscal quantitative chemical exchange saturation transfer MRI signal correlates with discogenic pain in human patients

Low back pain (LBP) is often a result of a degenerative process in the intervertebral disc. The precise origin of discogenic pain is diagnosed by the invasive procedure of provocative discography (PD). Previously, we developed quantitative chemical exchange saturation transfer (qCEST) magnetic resonance imaging (MRI) to detect pH as a biomarker for discogenic pain. Based on these findings we initiated a clinical study with the goal to evaluate the correlation between qCEST values and PD results in LBP patients. Twenty five volunteers with chronic low back pain were subjected to T2-weighted (T2w) and qCEST MRI scans followed by PD. A total of 72 discs were analyzed. The average qCEST signal value of painful discs was significantly higher than non-painful discs (p = 0.012). The ratio between qCEST and normalized T2w was found to be significantly higher in painful discs compared to non-painful discs (p = 0.0022). A receiver operating characteristics (ROC) analysis indicated that qCEST/T2w ratio could be used to differentiate between painful and non-painful discs with 78% sensitivity and 81% specificity. The results of the study suggest that qCEST could be used for the diagnosis of discogenic pain, in conjunction with the commonly used T2w scan.

NF-kB decoy oligodeoxynucleotide preserves disc height in a rabbit anular-puncture model and reduces pain induction in a rat xenograft-radiculopathy model

While it is known that the degenerated intervertebral disc (IVD) is one of the primary reasons for low-back pain and subsequent need for medical care, there are currently no established effective methods for direct treatment. Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes’ expression, among which are inflammatory cytokines, in many tissues including the IVD. NF-κB decoy is an oligodeoxynucleotide containing the NF-κB binding site that entraps NF-κB subunits, resulting in suppression of NF-κB activity. In the present preclinical study, NF-κB decoy was injected into degenerated IVDs using the rabbit anular-puncture model. In terms of distribution, NF-κB decoy persisted in the IVDs up to at least 4 weeks after injection. The remaining amount of NF-κB decoy indicated that it fit a double-exponential-decay equation. Investigation of puncture-caused degeneration of IVDs showed that NF-κB decoy injection recovered, dose-dependently, the reduced disc height that was associated with reparative cell cloning and morphological changes, as assessed through histology. Gene expression, by quantitative real-time polymerase chain reaction (qRT-PCR), showed that NF-κB decoy attenuated inflammatory gene expression, such as that of interleukin-1 and tumor necrosis factor-α, in rabbit degenerated IVDs. NF-κB decoy also reduced the pain response as seen using the “pain sensor” nude rat xenograft-radiculopathy model. This is the first report demonstrating that NF-κB decoy suppresses the inflammatory response in degenerated IVDs and restores IVD disc height loss. Therefore, the intradiscal injection of NF-κB decoy may have the potential as an effective therapeutic strategy for discogenic pain associated with degenerated IVDs.

Prognostic Factors for Successful Percutaneous Disc Decompression Using the Navigable Device L’DISQ in Patients with Lumbar Discogenic Pain

The navigable percutaneous disc decompression (PDD) device L’DISQ is an effective and safe option for the treatment of lumbar discogenic pain. This retrospective study aimed to evaluate the prognostic factors associated with the successful outcome of PDD using the L’DISQ for treating lumbar discogenic pain by following up patients before and 1, 2, 3, and 6 months after the procedure. A successful outcome was defined as a ≥ 50% reduction in the numeric rating scale scores for pain and a ≥ 40% reduction in the Oswestry disability index scores at 6 months after the procedure. Clinical parameters and patient demographics, including pain duration, history of surgery, number of treatment levels, and radiographic findings of lumbar magnetic resonance imaging, were also examined. Of the 106 patients included, 80 (75.5%) had successful outcomes at 6 months. Multivariable logistic regression analysis revealed that the presence of high-intensity zones (HIZs) (P = 0.016) was an independent positive predictor of successful PDD outcomes; conversely, migration of the herniated disc (P = 0.017) and bilaterally herniated discs (P = 0.001) were negative predictors. Therefore, the presence of HIZs, absence of migration of herniated discs, and presence of unilaterally herniated discs are positive predictors of successful outcomes.

Abnormal Intrinsic Functional Interactions Within Pain Network in Cervical Discogenic Pain

Cervical discogenic pain (CDP) is mainly induced by cervical disc degeneration. However, how CDP modulates the functional interactions within the pain network remains unclear. In the current study, we studied the changed resting-state functional connectivities of pain network with 40 CDP patients and 40 age-, gender-matched healthy controls. We first defined the pain network with the seeds of the posterior insula (PI). Then, whole brain and seed-to-target functional connectivity analyses were performed to identify the differences in functional connectivity between CDP and healthy controls. Finally, correlation analyses were applied to reveal the associations between functional connectivities and clinical measures. Whole-brain functional connectivity analyses of PI identified increased functional connectivity between PI and thalamus (THA) and decreased functional connectivity between PI and middle cingulate cortex (MCC) in CDP patients. Functional connectivity analyses within the pain network further revealed increased functional connectivities between bilateral PI and bilateral THA, and decreased functional connectivities between left PI and MCC, between left postcentral gyrus (PoCG) and MCC in CDP patients. Moreover, we found that the functional connectivities between right PI and left THA, between left PoCG and MCC were negatively and positively correlated with the visual analog scale, respectively. Our findings provide direct evidence of how CDP modulates the pain network, which may facilitate understanding of the neural basis of CDP.

The Effect and Possible Mechanism of Intradiscal Injection of Simvastatin in the Treatment of Discogenic Pain in Rats

To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).

Effects on pain of percutaneous treatment of cervical disc herniations using DiscoGel: A retrospective analysis

Background and purpose Cervical discogenic pain originates from degenerated intervertebral discs and is a common condition in the middle-aged population. Cervical discs may herniate and give compressions to cervical nerves, with pain and functional limitation of the arms. DiscoGel is a device that can be useful in the treatment of cervical disc herniation, with very short operating time and low radiation dose. Material and methods Between March 2018 and April 2019 we performed this procedure on 38 patients with non-fissurated cervical herniation using 0.3–0.4 mL of DiscoGel injected under fluoroscopic guidance. The most common discs affected were C5–C6, C6–C7 and C4–C5. Outcomes were evaluated with Visual Analogue Scale (VAS) and Neuropathic Pain Symptom Inventory (NPSI) scores at 3, 6 and 12 months follow-up. A magnetic resonance imaging (MRI) scan of the cervical spine was performed 3 months after the procedure. Results Postoperative examinations showed: VAS 2.15 ± 1.34 and NPSI 2.29 ± 0.71. Postoperative MRI performed 3 months after the procedure showed a good improvement of cervical disc herniation or bulging or protrusion. The mean dose area product (DAP) was 2803 mGy/cm2 with a mean fluoroscopy time of 4 minutes 22 seconds. Conclusion DiscoGel is a suitable approach for non-fissurated cervical disc herniations, especially in patients that are not suitable for open surgery, with excellent postoperative results, fast recovery and a low radiation dose.