Compression Of Dorsal Root Ganglion Research Articles

Retracted: Effects of Ozone on Hippocampus BDNF and Fos Expressions in Rats with Chronic Compression of Dorsal Root Ganglia.

[This retracts the article DOI: 10.1155/2021/5572915.].

Baimai Ointment relieves chronic pain induced by chronic compression of dorsal root ganglion in rats by regulating neuroactive ligand-receptor interaction and HIF-1 signaling pathway

The Baimai Ointment with the effect of relaxing sinew and activating collaterals demonstrates a definite effect on Baimai disease with pain, spasm, stiffness and other symptoms, while the pharmacodynamic characteristics and mechanism of this agent remain unclear. In this study, a rat model of chronic compression of L4 dorsal root ganglion(CCD) was established by lumbar disc herniation, and the efficacy and mechanism of Baimai Ointment in the treatment of CCD were preliminarily explored by behavioral tests, side effect evaluation, network analysis, antagonist and molecular biology verification. The pharmacodynamic experiment indicated that Baimai Ointment significantly improved the pain thresholds(mechanical pain, thermal pain, and cold pain) and gait behavior of CCD model rats without causing tolerance or obvious toxic and side effects. Baimai Ointment inhibited the second-phase nociceptive response of mice in the formalin test, increased the hot plate threshold of normal mice, and down-regulated the expression of inflammatory cytokines in the spinal cord. Network analysis showed that Baimai Ointment had synergistic effect in the treatment of CCD and was related to descending inhibition/facilitation system and neuroinflammation. Furthermore, behavioral tests, Western blot, and immunofluorescence assay revealed that the pain-relieving effect of Baimai Ointment on CCD may be related to the regulation of the interaction between neuroactive ligand and receptors(neuroligands) such as CHRNA7, ADRA2A, and ADRB2, and the down-regulation of the expression of NOS2/pERK/PI3K, the core regulatory element of HIF-1 signaling pathway in spinal microglia. The findings preliminarily reveal the mechanism of relaxing sinew and activating collaterals of Baimai Ointment in the treatment of Baimai disease, providing a reference for the rational drug use and further research of this agent.

Analgesic Effect of Tuina on Rat Models with Compression of the Dorsal Root Ganglion Pain.

Neuropathic pain is a prevalent condition that affects 6.9%-10% of the population and results from nerve damage due to various etiologies, such as lumbar disc herniation, spinal canal stenosis, and intervertebral foramen stenosis. Although Tuina, a traditional Chinese manual therapy, has shown analgesic effects in clinical practice for the treatment of neuropathic pain, its underlying neurobiological mechanisms remain unclear. Animal models are essential for elucidating the basic principles of Tuina. In this study, we propose a standardized Tuina protocol for rats with compression of the dorsal root ganglion (DRG), which involves inducing DRG compression by inserting a stainless steel rod into the intervertebral foramen, performing Tuina manipulation with specific parameters of location, intensity, and frequency in a controlled environment, and assessing the behavioral and histopathological outcomes of Tuina treatment. This article also discusses the potential clinical implications and limitations of the study and suggests directions for future research on Tuina.

Lysine-specific demethylase 1 in primary sensory neurons participates in chronic compression of dorsal root ganglion–induced neuropathic pain

Low back and radicular pain syndromes, usually caused by local inflammation and irritation to the nerve root and dorsal root ganglion (DRG), are common throughout medical practice, but sufficient pain relief is scarce. In this study, we employed a chronic compression of DRG (CCD)–induced radicular pain model in rats to explore whether lysine-specific demethylase 1 (LSD1), a histone demethylase and transcriptional co-repressor, is involved in the pathological process of radicular pain. We found that LSD1 was expressed in various-sized DRG neurons by immunohistochemistry. CCD induced the upregulation of LSD1 in compressed L4–L5 DRGs. Moreover, either LSD1 small interfering RNAs or LSD1 inhibitor attenuated CCD–induced pain hypersensitivities. LSD1 was also upregulated in the injured lumbar 4 (L4) DRG in a spinal nerve ligation (SNL)–induced neuropathic pain mouse model. Nevertheless, LSD1 was not altered in L3–L5 DRGs in complete Freund’s adjuvant–induced inflammatory pain mouse model, paclitaxel– or streptozotocin–induced neuropathic pain models. Furthermore, knockdown of LSD1 in the injured L4 DRG reversed SNL–induced pain hypersensitivities in mice. Therefore, we speculate that nerve injury induced the upregulation of LSD1 in the injured DRGs, which contributes to neuropathic pain hypersensitivities; thus, LSD1 may serve as a potential target for the treatment of radicular pain and neuropathic pain.

Transcriptome profiling of microRNAs reveals potential mechanisms of manual therapy alleviating neuropathic pain through microRNA-547-3p-mediated Map4k4/NF-κb signaling pathway

BackgroundLocal neuroinflammation secondary to spinal nerve compression in lumbar disk herniation (LDH) is a key driver contributing to neuropathic pain. Manual therapy (MT), a widely used nonsurgical therapy, can relieve LDH-mediated pain by reducing inflammation. MT has attracted extensive attention; however, its mechanism remains poorly understood. MicroRNAs (miRNAs) are important regulators of pain signaling transduction, but are rarely reported in the chronic compression of dorsal root ganglia (CCD) model, and further investigation is needed to decipher whether they mediate anti-inflammatory and analgesic effects of MT.MethodsWe used a combination of in vivo behavioral and molecular techniques to study MT intervention mechanisms. Neuropathic pain was induced in a CCD rat model and MT intervention was performed according to standard procedures. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory cytokine levels in dorsal root ganglia (DRG). Small RNA sequencing, immunofluorescence, Western blot, and qRT-PCR were performed to screen miRNAs and their target genes and determine core factors in the pathway possibly regulated by miRNA-mediated target gene in DRG of MT-treated CCD rats.ResultsCompared with naive rats, small RNA sequencing detected 22 differentially expressed miRNAs in DRG of CCD rats, and compared with CCD rats, MT-treated rats presented 19 differentially expressed miRNAs, which were functionally associated with nerve injury and inflammation. Among these, miR-547-3p was screened as a key miRNA mediating neuroinflammation and participating in neuropathic pain. We confirmed in vitro that its function is achieved by directly regulating its target gene Map4k4. Intrathecal injection of miR-547-3p agomir or MT intervention significantly reduced Map4k4 expression and the expression and phosphorylation of IκBα and p65 in the NF-κB pathway, thus reducing the inflammatory cytokine levels and exerting an analgesic effect, whereas intrathecal injection of miR-547-3p antagomir led to opposite effects.ConclusionsIn rats, CCD-induced neuropathic pain leads to variation in miRNA expression in DRG, and MT can intervene the transcription and translation of inflammation-related genes through miRNAs to improve neuroinflammation and alleviate neuropathic pain. MiR-547-3p may be a key target of MT for anti-inflammatory and analgesia effects, which is achieved by mediating the Map4k4/NF-κB pathway to regulate downstream inflammatory cytokines.

Differential Activation of pERK1/2 and c-Fos Following Injury to Different Regions of Primary Sensory Neuron.

Nerve injury causes hyperexcitability of the dorsal root ganglion (DRG) and spinal dorsal horn (DH) neurons, which results in neuropathic pain. We have previously demonstrated that partial dorsal rhizotomy (PDR) produced less severe pain-like behavior than chronic constriction injury (CCI) or chronic compression of DRG (CCD) and did not enhance DRG neuronal excitability. However, the mechanisms underlying such discrepancy remain unclear. This study was designed to compare the activation of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) in DRG and DH, and c-Fos in DH following treatments of CCI, CCD, and PDR. We confirmed that thermal hyperalgesia produced by PDR was less severe than that produced by CCI or CCD. We showed that pERK1/2 in DRG and DH was greatly activated by CCI or CCD, whereas PDR produced only transient and mild pERK1/2 activation. CCI, CCD, and PDR induced robust c-Fos expression in DH; nevertheless, c-Fos+ neurons following PDR were much fewer than that following CCI or CCD. Blocking retrograde axonal transport by colchicine proximal to the CCI injury site diminished thermal hyperalgesia and inhibited pERK1/2 and c-Fos activation. These findings demonstrate that less severe pain-like behavior produced by PDR than CCI or CCD attributes to less activation of pERK1/2 and c-Fos. Such neurochemical activation partially relies on retrograde axonal transport of certain “injury signals” from the peripheral injured site to DRG somata.

T-type Ca2+ channels play a dual role in modulating the excitability of dorsal root ganglia neurons.

A subgroup of low-threshold dorsal root ganglia (DRG) neurons discharge action potentials (APs) with an afterdepolarizing potential (ADP). The ADP is formed by T-type Ca2+ currents. It is known that T-type Ca2+ currents contribute to neuropathic pain. However, the change in ADP-firing of injured DRG neurons has not been widely studied yet. Here we applied patch clamp to record ADP-firing and T-type Ca2+ currents in intact and chronically compressed DRG (CCD) neurons and examined T-type Ca2+ channel proteins expression with western blotting. After CCD injury, the incidences of both ADP firing and non-ADP burst firing increased, and T-type Ca2+ channels contributed to both of these firing patterns. The neurons discharging large-amplitude-ADP firing were TTX-insensitive, implying that high-density T-type Ca2+ channels might cooperate with TTX-insensitive Na+ channels to reduce the AP threshold. By contrast, the neurons displaying non-ADP burst firing were TTX-sensitive, implying that low density T-type Ca2+ channels may cooperate with TTX-sensitive Na+ channels to increase AP number. In DRG neurons, T-type Ca2+ currents density varied widely, ranging between 100 pA/pF and 5 pA/pF. After injury, the proportion of DRG neurons with large T-type Ca2+ currents increased in parallel with the increase in the incidence of large-amplitude-ADP firing. And in addition to Cav3.2, Cav3.3 channels are also likely to contribute to low-threshold firing. The data revealed that T-type Ca2+ channels may play a dual role in modulating the injured neurons’ high excitability through a cooperative process with Na+ channels, thereby contributing to neuropathic pain.

Implantable, Programmable, and Wireless Device for Electrical Stimulation of the Dorsal Root Ganglion in Freely-Moving Rats: A Proof of Concept Study.

ObjectiveThis was a proof of concept study, based on systematic reviews of the efficacy and safety of the dorsal root ganglion (DRG) stimulation. The main objective was to develop an implantable, programmable, and wireless device for electrical stimulation of DRG and a methodology that can be used in translational research, especially to understand the mechanism of neuromodulation and to test new treatment modalities in animal models of pain.MethodsWe developed and tested a stimulator that uses a battery-powered microelectronic circuit, to generate constant current square biphasic or monophasic pulsed waveform of variable amplitudes and duration. It is controlled by software and an external controller that allows radio frequency communication with the stimulator. The stimulator was implanted in Sprague–Dawley (SD) rats. The lead was positioned at the L5 DRG level, while the stimulator was placed in the skin pocket at the ipsilateral side. Forty-five animals were used and divided into six groups: spinal nerve ligation (SNL), chronic compression injury of the DRG (CCD), SNL + active DRG stimulation, intact control group, group with the implanted sham stimulator, and sham lead. Behavioral testing was performed on the day preceding surgery and three times postoperatively (1st, 3rd, and 7th day).ResultsIn animals with SNL, neurostimulation reduced pain-related behavior, tested with pinprick hyperalgesia, pinprick withdrawal test, and cold test, while the leads per se did not cause DRG compression. The rats well tolerated the stimulator. It did not hinder animal movement, and it enabled the animals to be housed under regular conditions.ConclusionA proof-of-concept experiment with our stimulator verified the usability of the device. The stimulator enables a wide range of research applications from adjusting stimulation parameters for different pain conditions, studying new stimulation methods with different frequencies and waveforms to obtain knowledge about analgesic mechanisms of DRG stimulation.

Effects of Ozone on Hippocampus BDNF and Fos Expressions in Rats with Chronic Compression of Dorsal Root Ganglia.

The effects of ozone on hippocampal expression levels of brain-derived neurotrophic factor (BDNF) and c-fos protein (Fos) were evaluated in rats with chronic compression of dorsal root ganglia (CCD). Forty-eight adult female Sprague-Dawley rats were randomly divided into the following 4 groups (n = 12): sham operation (sham group), CCD group, CCD with 20 μg/ml of ozone (CCD + AO3 group), and CCD with 40 μg/ml of ozone (CCD + BO3 group). Except the sham group, unilateral L5 dorsal root ganglion (DRG) compression was performed on all other groups. On days 1, 2, and 4 after the operation, the CCD + AO3 and CCD + BO3 groups were injected with 100 μl of ozone with concentrations of 20 and 40 μg/ml, respectively. Thermal withdrawal latencies (TWLs) and mechanical withdrawal thresholds (MWTs) were measured at various time points before and after the operation. BDNF and Fos expressions were examined in the extracted hippocampi using immunohistochemistry. The TWLs and MWTs of CCD model rats that received ozone were lower with decreased BDNF and increased Fos expression levels, on day 21 after the operation, compared to those of the sham group (P < 0.05). The TWLs and MWTs of the CCD + AO3 and CCD + BO3 groups were higher with increased BDNF and decreased Fos expression levels, on day 21 after the operation, compared to those of the CCD group (P < 0.05). The TWLs were longer and the MWTs were higher in the CCD + BO3 group at each time point with increased BDNF and decreased Fos expression levels, on day 21 after the operation, compared to those of the CCD + AO3 group (P < 0.05). Our results revealed that ozone can relieve the neuropathic pain caused by the pathological neuralgia resulting from DRG compression in rats. The mechanism of action for ozone is likely associated with changes in BDNF and Fos expression levels in the hippocampus.

Intervertebral foramen injection of plerixafor attenuates neuropathic pain after chronic compression of the dorsal root ganglion: Possible involvement of the down-regulation of Nav1.8 and Nav1.9

Neuropathic pain is a common chronic pain condition with major impact on quality of life. However, its physiopathologic mechanism remains unknown and pain management is still a challenge. Accumulating evidence indicated that C-X-C chemokine receptor type 4 (CXCR4) played a critical role in the process of pain. Thus, the present study aimed to investigate whether intervertebral foramen injection of CXCR4 antagonist, plerixafor, was able to relieve neuropathic pain and explore the possible underlying mechanism. Chronic compression of the dorsal root ganglion (CCD) was established as a typical model of neuropathic pain. The results indicated that CCD induced multiple pain-related behaviors and the expression of CXCR4, Nav1.8 and Nav1.9 was significantly increased in compressed dorsal root ganglion (DRG) neurons. Knocking down CXCR4 expression could significantly reduce neuropathic pain and intervertebral foramen plerixafor injection (IVFP) dramatically decreased the up-regulation of Nav1.8 and Nav1.9 and attenuated neuropathic pain. The analgesic duration of IVFP was maintained at least for 24 h which was much longer than intervertebral foramen injection of Nav1.8 blocker and local anesthetics. Therefore, our study provided evidence that IVFP could reduce the expression of Nav1.8 and Nav1.9 in DRG neurons which might contribute to, at least in part, the analgesic effect of plerixafor on CCD-induced neuropathic pain. It is concluded that IVFP was an effective and applicable treatment approach for neuropathic pain.

Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.

The role of pruriceptors in enhancing sensitivity to pruritogens in a murine chronic compression model of dorsal root ganglion

Chronic pruritus is a symptom that commonly observed in neurological diseases. It has been hypothesized that the chronic pruritus may result from sensitization of itch-signaling pathways but the mechanisms remain obscure. In this study, we established a mouse model of chronic compression of dorsal root ganglion (CCD) and injected various pruritogenic and algogenic agents intradermally to the calf skin ipsilateral to the compressed dorsal root ganglion (DRG). Compared to the naïve mice, a significant increase in itch-related behaviors was observed in the CCD mice after the injection of pruritogens including histamine and BAM8-22, but not after the injection of capsaicin, although all the above agents evoked enhanced pain-related behaviors toward the injected site. In addition, we investigated if pruritogen-evoked activities of DRG neurons were enhanced in this model. In vivo calcium imaging revealed that compressed DRG neurons exhibited enhanced responses to histamine and BAM8-22. Immunoflorescent staining also showed that the histamine receptor H1 and the capsaicin receptor TRPV1 were significantly upregulated in DRG neurons. Our findings indicated that the sensitization of primary pruriceptive neurons may underlie the enhanced itch sensation after chronic compression of DRG in the mice, and may play a role in chronic pruritus in neurological diseases.

Feasibility of Using Intraoperative Neuromonitoring in the Prophylaxis of Dysesthesia in Transforaminal Endoscopic Discectomies of the Lumbar Spine.

(1) Background: Postoperative nerve root injury with dysesthesia is the most frequent sequela following lumbar endoscopic transforaminal discectomy. At times, it may be accompanied by transient and rarely by permanent motor weakness. The authors hypothesized that direct compression of the exiting nerve root and its dorsal root ganglion (DRG) by manipulating the working cannula or endoscopic instruments may play a role. (2) Objective: To assess whether intraoperative neurophysiological monitoring can help prevent nerve root injury by identifying neurophysiological events during the initial placement of the endoscopic working cannula and the directly visualized video endoscopic procedure. (3) Methods: The authors performed a retrospective chart review of 65 (35 female and 30 male) patients who underwent transforaminal endoscopic decompression for failed non-operative treatment of lumbar disc herniation from 2012 to 2020. The patients’ age ranged from 22 to 86 years, with an average of 51.75 years. Patients in the experimental group (32 patients) had intraoperative neurophysiological monitoring recordings using sensory evoked (SSEP), and transcranial motor evoked potentials (TCEP), those in the control group (32 patients) did not. The SSEP and TCMEP data were analyzed and correlated to the postoperative course, including dysesthesia and clinical outcomes using modified Macnab criteria, Oswestry disability index (ODI), visual analog scale (VAS) for leg and back pain. (4) Results: The surgical levels were L4/L5 in 44.6%, L5/S1 in 23.1%, and L3/L4 in 9.2%. Of the 65 patients, 56.9% (37/65) had surgery on the left, 36.9% (24/65) on the right, and the remaining 6.2% (4/65) underwent bilateral decompression. Postoperative dysesthesia occurred in 2 patients in the experimental and six patients in the control group. In the experimental neuromonitoring group, there was electrodiagnostic evidence of compression of the exiting nerve root’s DRG in 24 (72.7%) of the 32 patients after initial transforaminal placement of the working cannula. A 5% or more decrease and a 50% or more decrease in amplitude of SSEPs and TCEPs recordings of the exiting nerve root were resolved by repositioning the working cannula or by pausing the root manipulation until recovery to baseline, which typically occurred within an average of 1.15 min. In 15 of the 24 patients with such latency and amplitude changes, a foraminoplasty was performed before advancing the endoscopic working cannula via the transforaminal approach into the neuroforamen to avoid an impeding nerve root injury and postoperative dysesthesia. (5) Conclusion: Neuromonitoring enabled the intraoperative diagnosis of DRG compression during the initial transforaminal placement of the endoscopic working cannula. Future studies with more statistical power will have to investigate whether employing neuromonitoring to avoid intraoperative compression of the exiting nerve root is predictive of lower postoperative dysesthesia rates in patients undergoing videoendoscopic transforaminal discectomy.

Optical Modulation on the Nucleus Accumbens Core in the Alleviation of Neuropathic Pain in Chronic Dorsal Root Ganglion Compression Rat Model

The role of the nucleus accumbens (NAc) in chronic neuropathic pain has been suggested, but the role of the NAc in dorsal root ganglion (DRG) neuropathic pain remains unclear. The objective of this study was to determine whether optogenetic stimulation of the NAc influences DRG compression-induced neuropathic pain. We established sham or DRG lesions in female Sprague-Dawley rats by L4-5 DRG root compression, and the animals received unilateral injections of optogenetic virus in the NAc core. We employed reflexive pain tests to assess the alterations between the groups at the light on/off states. To determine thalamic firing, we performed single-unit in vivo extracellular recording. For statistical analysis, we used one- or two-way repeated-measures analysis of variance. Compared to sham-operated rats, chronic compressed DRG rats showed elevated behavioral sensitivity and sustained neuronal hyperexcitability in the thalamus. NAc optic stimulation improved pain behaviors and lowered thalamic discharge from ventral posterolateral thalamic nuclei. The NAc core impacts the reward and motivational aspects of chronic neuropathic pain influenced by limbic behaviors to thalamic discharge. Increased thalamic firing activity may result in chronic compressed DRG-induced neuropathic pain, and optogenetic neuromodulation of the NAc can ease chronic pain and thalamic discharge.

Pain modulation effect on motor cortex after optogenetic stimulation in shPKCγ knockdown dorsal root ganglion-compressed Sprague-Dawley rat model.

Neuropathic pain can be generated by chronic compression of dorsal root ganglion (CCD). Stimulation of primary motor cortex can disrupt the nociceptive sensory signal at dorsal root ganglion level and reduce pain behaviors. But the mechanism behind it is still implicit. Protein kinase C gamma is known as an essential enzyme for the development of neuropathic pain, and specific inhibitor of protein kinase C gamma can disrupt the sensory signal and reduce pain behaviors. Optogenetic stimulation has been emerged as a new and promising conducive method for refractory neuropathic pain. The aim of this study was to provide evidence whether optical stimulation of primary motor cortex can modulate chronic neuropathic pain in CCD rat model. Animals were randomly divided into CCD group, sham group, and control group. Dorsal root ganglion-compressed neuropathic pain model was established in animals, and knocking down of protein kinase C gamma was also accomplished. Pain behavioral scores were significantly improved in the short hairpin Protein Kinase C gamma knockdown CCD animals during optic stimulation. Ventral posterolateral thalamic firing inhibition was also observed during light stimulation on motor cortex in CCD animal. We assessed alteration of pain behaviors in pre-light off, stimulation-light on, and post-light off state. In vivo extracellular recording of the ventral posterolateral thalamus, viral expression in the primary motor cortex, and protein kinase C gamma expression in dorsal root ganglion were investigated. So, optical cortico-thalamic inhibition by motor cortex stimulation can improve neuropathic pain behaviors in CCD animal, and knocking down of protein kinase C gamma plays a conducive role in the process. This study provides feasibility for in vivo optogenetic stimulation on primary motor cortex of dorsal root ganglion-initiated neuropathic pain.

Tau protein function: The mechanical exploration of axonal transport disorder caused by persistent pressure in dorsal root ganglia.

ObjectiveWe analyzed the function of Tau protein to explore the underlying mechanism of axonal transport disorder caused by persistent pressure in the dorsal root ganglia (DRG).MethodsWistar rats were divided into the sham operated group, the control group and the experimental group. The Wistar rat model of continuous compression of DRG was used for further investigation. DRG neurons were extracted and cultured, and the protein content was detected using bicinchoninic acid method. Western blotting and immunofluorescence assays were performed to detect the protein content. Intraperitoneal injection of lithium chloride was performed for interaction with Tau. The results were then analyzed statistically.ResultsAfter 2 weeks of sustained pressure, the expression level of Tau396 increased by 33%, while Tau404 increased by 25% in the DRG of the experimental group (p < 0.05). The expression level of PSD‐95 in the DRG decreased by 15% (p < 0.05), while the expression of vGluT1, vGluT3 and vAchT decreased significantly in the DRG of the experimental group (p < 0.05). There was no significant difference in the expression of vGluT2 and vGAT among the three groups (p > 0.05). After intervention with lithium chloride, the expression of phosphorylated Tau at the above sites decreased in varying degrees compared with the model group. The expression level of Tau404 was reduced by 55%, and that of Tau199 by 60% in the DRG of the experimental group.ConclusionChronic compression of DRG and hypoxia caused phosphorylation of Tau in axons and inhibition of PSD‐95, and the function of the synaptic glutamic acid vesicle is defective in the synapse. This process is crucial in the development and progression of axonal transport dysfunction induced by chronic DRG compression, and phosphorylation of Tau plays a substantial role in this process.

Role of NaV1.6 and NaVβ4 Sodium Channel Subunits in a Rat Model of Low Back Pain Induced by Compression of the Dorsal Root Ganglia

Low back pain is a common cause of chronic pain and disability. It is modeled in rodents by chronically compressing the lumbar dorsal root ganglia (DRG) with small metal rods, resulting in ipsilateral mechanical and cold hypersensitivity, and hyperexcitability of sensory neurons. Sodium channels are implicated in this hyperexcitability, but the responsible isoforms are unknown. In this study, we used siRNA-mediated knockdown of the pore-forming NaV1.6 and regulatory NaVβ4 sodium channel isoforms that have been previously implicated in a different model of low back pain caused by locally inflaming the L5 DRG. Knockdown of either subunit markedly reduced spontaneous pain and mechanical and cold hypersensitivity induced by DRG compression, and reduced spontaneous activity and hyperexcitability of sensory neurons with action potentials <1.5 msec (predominately cells with myelinated axons, based on conduction velocities measured in a subset of cells) 4 days after DRG compression. These results were similar to those previously obtained in the DRG inflammation model and some neuropathic pain models, in which sensory neurons other than nociceptors seem to play key roles. The cytokine profiles induced by DRG compression and DRG inflammation were also very similar, with upregulation of several type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines. Surprisingly, the cytokine profile was largely unaffected by NaVβ4 knockdown in either model. The NaV1.6 channel, and the NaVβ4 subunit that can regulate NaV1.6 to enhance repetitive firing, play key roles in both models of low back pain; targeting the abnormal spontaneous activity they generate may have therapeutic value.

Possible mechanism underlying analgesic effect of Tuina in rats may involve piezo mechanosensitive channels within dorsal root ganglia axon

OBJECTIVETo demonstrate the analgesic effect of Tuina mainly from mechanically sensitive ion channels in peripheral myelinated nerve fibers. METHODSA total of 40 healthy and pathogen-free adult male Sprague-Dawley rats were used in the study [weight: (220.0 ± 1.4) g, Shanghai Slac Laboratory Animal Co., Ltd., Shanghai, China; license No. Shanghai ICP 05033115]. The rats were housed in cages with free access to water and food in a temperature-controlled room [(22 ± 1) °C] and 12-h/12-h light-dark cycle. Thirty-two rats were randomly divided into five groups: naive, sham, chronic compression of dorsal root ganglion (CCD), Tuina (7 d) and Tuina (21 d). CCD rat model was established via unilateral DRG compression by “L” liked steel bar. Chinese Tuina treatment was accepted once per day. Behavior monitoring of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested. The expression of Piezo1 and Piezo2 in myelinated nerve fiber were analyzed by immunohistochemistry and Western-blotting. RESULTSThere was a high expression of Piezo2 and a low expression of Piezo1 in the naive and CCD groups. In contrast, the expression of Piezo2 was down regulated and Piezo1 was increased after a period of Tuina. There was significant difference (P ≤ 0.05) between the groups. CONCLUSIONOur findings suggest that Tuina therapy can increase the expression of Piezo2 and decrease the expression of Piezo1 in the test rats. The different changes in the expressions of Piezo1 and Piezo2 may play an important role in alleviating CCD-induced allodynia and hyperalgesia.

Friday, September 28, 2018 3:00 PM–4:00 PM abstracts: optimizing lumbar disc surgery: 215. Patients presenting with a lumbar far-lateral herniated nucleus pulposus can expect similar postoperative outcomes to those presenting with a central or paracentral herniation

BACKGROUND CONTEXT A far lateral herniated nucleus pulposus (HNP) consists of 7%-12% of all disc herniations. 'Far lateral' is often used to describe a lumbar disc herniation that compresses the exiting nerve root at the same level, lateral to the neural foramen. The far lateral disc herniations have been described to elicit radicular leg pain that is more severe than a central or paracentral lumbar disc herniation due to direct compression of dorsal root ganglion, and are said to have a more acute onset in their clinical symptoms. However, literature does not provide much description of the comparative postoperative outcomes between those presenting with a far lateral HNP and those with a central or paracentral herniation. PURPOSE The goal of this study is to examine the pre- and postoperative outcomes between patients presenting with a central or paracentral versus a far lateral HNP. STUDY DESIGN/SETTING Retrospective cohort series. PATIENT SAMPLE We performed a retrospective cohort analysis of patients who underwent a primary lumbar microdiscectomy between 2009 and 2015 by one of two senior orthopaedic spine surgeons for lumbar spinal stenosis. Patients were excluded from analysis if they had any previous lumbar surgery, an unstable spondylolisthesis, were under 18 years of age at the time of surgery, or had postoperative follow up less than 3 months. Patients were divided into two groups based on the location of the HNP (central or paracentral versus far-lateral). OUTCOME MEASURES Patient reported outcomes were obtained in the form of Oswestry Disability Index (ODI) scores, Visual Analog Scales (VAS) scores for the back and leg, 12-Item Short Form Mental and Physical Survey (SF-12) scores, and the Veterans Rand 12-Item Health Mental and Physical Survey (VR-12) scores. METHODS Baseline patient characteristics were compared using chi-squared analysis and independent sample t-tests for categorical and continuous data, respectively. Bivariate and multivariate regressions were subsequently used to compare clinical outcomes between procedure groups. Multivariate analyses controlled for differences in baseline patient characteristics. RESULTS Overall, 212 consecutive patients who fulfilled our inclusion criteria were assessed. Average follow-up was 24.14 months (range 3–78 months). There were 191 patients who presented with a central or paracentral HNP, while 21 patients presented with a far-lateral HNP. There were no significant differences in the demographic variables between these two groups. Patients with a far lateral disc herniation presented with a trend towards a shorter duration of symptoms prior to surgery (24.5 vs. 31.5 months; p=.052). On multivariate analysis, patients with a far lateral disc herniation presented with significantly lower SF-12 mental (52.14±13.49 vs. 55.1±6.55; p=.034) and physical scores (24.76±7.5 vs. 36.9±11.1; p=.008). Similarly, the far-lateral disc herniation patients also presented with significantly lower VR-12 mental (47.2±12.8 vs. 56.9±7.0; p=.024) and physical scores (25.8±8.7 vs.39.38±11.8; p=.005). However, postoperatively, all patients have similar SF-12 and CR-12 survey scores. The improvement in ODI score was significantly lower in the patients presenting with a far lateral disc herniation (7.8±15.1 vs. 28.3±21.5; p=.002). No significant difference in re-operation rates was found (p=.236). CONCLUSIONS Patients presenting with far lateral disc herniations present with significantly lower SF-12 mental and physical scores as well as lower VR-12 mental and physical scores. However, at approximately 2 years following a lumbar microdecompression surgery, both groups of patients express similar successful outcomes, including SF-12 and VR-12 survey scores. Re-operation rates are similar between the two groups. Despite compression at the site of the dorsal root ganglion and the reported greater difficulty in addressing far lateral disc herniations, patients presenting with these far lateral disc herniations can expect similar outcomes to those patients present with herniations in the central or paracentral region.

Perturbing NR2B-PSD-95 interaction relieves neuropathic pain by inactivating CaMKII-CREB signaling.

Neuropathic pain is characterized by central sensitization. The interaction between N-methyl-D-aspartate receptors (NMDARs) and postsynaptic density protein-95 (PSD-95) plays a major role in central sensitization. Here, we aimed to investigate the analgesic effect of disruption of the interaction between NMDAR and PSD-95. Chronic dorsal root ganglia compression model rats were used to mimic sciatica. Thermal hyperalgesia and mechanical allodynia were evaluated. The expression of spinal phospho-NR2B, PSD-95, calcium/calmodulin-dependent protein kinase II (CaMKII), and cAMP response element binding protein (CREB) was measured using western blotting. A mimetic peptide Myr-NR2B9c was injected intrathecally to disrupt the interaction between PSD-95 and NR2B and detected by coimmunoprecipitation. Chronic dorsal root ganglia compression surgery induced thermal hyperalgesia and mechanical allodynia, and upregulated pain-related proteins such as phospho-NR2B, PSD-95, CaMKII, and CREB expressions in the spinal cord. Myr-NR2B9c disrupted the interaction between NR2B-containing NMDARs and PSD-95 in the spinal cord. Intrathecal administration of Myr-NR2B9c attenuated neuropathic pain behaviors and downregulated the expressions of phospho-NR2B, PSD-95, CaMKII, and CREB in the spinal cord. The present study indicates that dissociation of NR2B-containing NMDARs from PSD-95 inactivates CaMKII and CREB signaling and relieves pain.