Ursolic acid molecules dock MAPK1 to modulate gut microbiota diversity to reduce neuropathic pain.

To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.

[Progress of intraosseous basivertebral nerve ablation for symptomatic Modic alterations].

Chronic lumbar and back pain caused by degenerative vertebral endplates presents a challenging issue for patients and clinicians. As a new minimally invasive spinal treatment method, radiofrequency ablation of vertebral basal nerve in bone can denature the corresponding vertebral basal nerve through radiofrequency ablation of degenerative vertebral endplate. It blocks the nociceptive signal transmission of the vertebral base nerve, thereby alleviating the symptoms of low back pain caused by the degenerative vertebral endplate. At present, many foreign articles have reported the operation principle, operation method, clinical efficacy and related complications of radiofrequency ablation of the vertebral basal nerve. The main purpose of this paper is to conduct a comprehensive analysis of the current relevant research, and provide a reference for the follow-up clinical research.

Alteration of serotonin release response in the central nucleus of the amygdala to noxious and non-noxious mechanical stimulation in a neuropathic pain model rat.

Previously, we found that serotonin (5-HT) release in the central nucleus of the amygdala (CeA) of anesthetized rats decreases in response to innocuous stroking of the skin, irrespective of stimulus laterality, but increases in response to noxious pinching applied to a hindlimb contralateral to the 5-HT measurement site. The aim of the present study was to determine whether intra-CeA 5-HT release responses to cutaneous stimulation were altered in an animal model of neuropathic pain induced by ligation of the left L5 spinal nerve. In anesthetized neuropathic pain model rats, stroking of the left hindlimb increased 5-HT release in the CeA, whereas stroking of the right hindlimb decreased it. Meanwhile, pinching of the left hindlimb increased intra-CeA 5-HT release irrespective of stimulus laterality. In conclusion, the present study demonstrated that intra-CeA 5-HT release responses to cutaneous stimulation are altered in an animal model of neuropathic pain.

Spinal nerve transection-induced upregulation of SAP97 via promoting membrane trafficking of GluA1-containing AMPA receptors in the dorsal horn contributes to the pathogenesis of neuropathic pain.

Emerging evidence has implicated an important role of synapse-associated protein-97 (SAP97)-regulated GluA1-containing AMPARs membrane trafficking in cocaine restate and in contextual episodic memory of schizophrenia. Herein, we investigated the role of SAP97 in neuropathic pain following lumbar 5 spinal nerve transection (SNT) in rats. Our results showed that SNT led to upregulation of SAP97, enhanced the interaction between SAP97 and GluA1, and increased GluA1-containing AMPARs membrane trafficking in the dorsal horn. Microinjection of AAV-EGFP-SAP97 shRNA in lumbar 5 spinal dorsal horn inhibited SAP97 production, decreased SAP97-GluA1 interaction, reduced the membrane trafficking of GluA1-containing AMPARs, and partially attenuated neuropathic pain following SNT. Intrathecal injections of SAP97 siRNA or NASPM, an antagonist of GluA1-containing AMPARs, also partially reversed neuropathic pain on day 7, but not on day 14, after SNT. Spinal overexpression of SAP97 by AAV-EGFP-SAP97 enhanced SAP97-GluA1 interaction, increased the membrane insertion of GluA1-containing AMPARs, and induced abnormal pain in naïve rats. In addition, treatment with SAP97 siRNA or NASPM i.t. injection alleviated SNT-induced allodynia and hyperalgesia and exhibited a longer effect in female rats. Together, our results indicate that the SNT-induced upregulation of SAP97 via promoting GluA1-containing AMPARs membrane trafficking in the dorsal horn contributes to the pathogenesis of neuropathic pain. Targeting spinal SAP97 might be a promising therapeutic strategy to treatment of chronic pain.

Identification and decompression of superior cluneal nerve implicated in low back pain.

INTRODUCTION: Low back pain (LBP) can be attributable to entrapment of the superior cluneal nerve (SCN) around the iliac crest. Surgical decompression is a useful treatment; however, finding all entrapped SCNs involved in patients with LBP can be difficult. We performed a retrospective study to help identify entrapped SCNs in the narrow surgical field. METHODS: We enrolled 20 LBP patient (22 sides) with SCN entrapment. They were 9 males and 11 females; their mean age was 72.5 years. We developed a 3-step procedure for successful SCN decompression surgery. In step 1, the thoracolumbar fascia is exposed and the SCN penetrating the fascia is released. In step 2, the fascia is opened and the SCN is released. In step 3, the fascia above the iliac crest is opened and the SCN is released. RESULTS: We successfully released 66 nerves; the average was 3.0 ± 0.8 (1-4) per patient. Step 1 detected 18 nerves (27.3%), step 2 identified 35 (53.0%), and in step 3, 13 (19.7%) were recognized. By tracing the thin nerves branching off the SCN, we found 7 nerves (10.6%). We performed 22 operations; step 1 identified 16 SCNs (72.7%), step 2 identified 21 (95.5%), and step 3 found 12 nerves (54.5%). CONCLUSIONS: The SCN is most readily identified upon opening of the thoracolumbar fascia. To identify as many SCN branches as possible, our 3-step method may be useful.

Long noncoding RNA small nucleolar RNA host gene 5 facilitates neuropathic pain in spinal nerve injury by promoting SCN9A expression via CDK9.

This study aims to explore the functions and mechanisms of long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) in chronic constriction injury (CCI)-induced neuropathic pain (NP). An NP rat model was established using the CCI method and the NP severity was evaluated by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The expression of SNHG5, CDK9, and SCN9A was quantified in rat dorsal root ganglion, in addition to the detections of apoptosis, pathological changes, neuron number, and the co-localization of Nav1.7 and cleaved caspase-3 with NeuN. In ND7/23 cells, the apoptosis and lactate dehydrogenase concentration were assessed, as well as the relationship between SNHG5, CDK9, and SCN9A. In the dorsal root ganglion of CCI-treated rats, SNHG5 and SCN9A were upregulated and downregulation of SNHG5 suppressed SCN9A expression, increased the PWT and PWL, blocked neuroinflammation and neuronal apoptosis, and alleviated NP. Mechanistically, SNHG5 recruited CDK9 to enhance SCN9A-encoded Nav1.7 expression and promoted peripheral neuronal apoptosis and injury. In addition, SCN9A overexpression nullified the alleviative effects of SNHG5 deficiency on NP and neuron loss in CCI rats. In conclusion, SNHG5 promotes SCN9A-encoded Nav1.7 expression by recruiting CDK9, thereby facilitating neuron loss and NP after spinal nerve injury, which may offer a promising target for the management of NP.

The triangular area between the greater, lesser, and third occipital nerves and its possible clinical significance.

PURPOSE: Occipital Neuralgia (ON) is defined as a unilateral or bilateral pain in the posterior area of the scalp occurring in the distribution area or areas of the greater occipital nerve (GON), lesser occipital nerve (LON), and/or third occipital nerve (TON). In the present study, the purpose was to show the possible importance of the triangular area (TA) in nerve block applied in ON by measuring the TA between GON, TON, and LON. METHODS: A total of 24 cadavers (14 males, 10 females) were used in the present study. The suboccipital region was dissected, revealing the points where the GON and TON pierced the trapezius muscle and superficial area, and the point where the LON left the sternocleidomastoid muscle from its posterior edge and was photographed. The area of the triangle between the superficial points of these three nerves and the center of gravity of the triangle (CGT) were determined by using the Image J Software and the results were analyzed statistically. RESULTS: The mean TA values were 952.82 ± 313.36 mm2 and 667.55 ± 273.82 mm2, respectively in male and female cadavers. Although no statistically significant differences were detected between the sides (p > 0.05), a statistically significant difference was detected between the genders (p < 0.05). The mean CGT value was located approximately 5 cm below and 3-3.5 cm laterally from the external occipital protuberance in both genders and sides. CONCLUSION: In ON that has more than one occipital nerve involvement, all occipital nerves can be blocked by targeting TA with a single occipital nerve block, and thus, the side effects that may arise from additional blocks can be reduced. The fact that there was a statistically significant difference according to the genders in the TA suggests that different block amounts can be applied according to gender.

Segmental infralesional pathological spontaneous activity in subacute traumatic spinal cord injury.

INTRODUCTION/AIMS: There is a dearth of knowledge regarding the status of infralesional lower motor neurons (LMNs) in individuals with traumatic cervical spinal cord injury (SCI), yet there is a growing need to understand how the spinal lesion impacts LMNs caudal to the lesion epicenter, especially in the context of nerve transfer surgery to restore several key upper limb functions. Our objective was to determine the frequency of pathological spontaneous activity (PSA) at, and below, the level of spinal injury, to gain an understanding of LMN health below the spinal lesion. METHODS: Ninety-one limbs in 57 individuals (53 males, mean age = 44.4 ± 16.9 years, mean duration from injury = 3.4 ± 1.4 months, 32 with motor complete injuries), were analyzed. Analysis was stratified by injury level as (1) C4 and above, (2) C5, and (3) C6-7. Needle electromyography was performed on representative muscles innervated by the C5-6, C6-7, C7-8, and C8-T1 nerve roots. PSA was dichotomized as present or absent. Data were pooled for the most caudal infralesional segment (C8-T1). RESULTS: A high frequency of PSA was seen in all infralesional segments. The pooled frequency of PSA for all injury levels at C8-T1 was 68.7% of the limbs tested. There was also evidence of PSA at the rostral border of the neurological level of injury, with 58.3% of C5-6 muscles in those with C5-level injuries. DISCUSSION: These data support a high prevalence of infralesional LMN abnormalities following SCI, which has implications to nerve transfer candidacy, timing of the intervention, and donor nerve options.

Tibetan medicine Ruyi Zhenbao Pill ameliorates neuropathic pain by inhibiting the CXCL10-CXCR3 pathway in spinal cord of spinal nerve ligation model.

ETHNOPHARMACOLOGICAL RELEVANCE: Ruyi Zhenbao Pill (RYZBP) is a traditional Tibetan medicine that has been used for over 300 years in China to treat neurological diseases, specifically neuropathic pain (NP). However, its characteristics and mechanism of action in treating NP remains unclear. AIM OF THE STUDY: Based on animal experiments and transcriptomics to evaluate the characteristics and mechanism of RYZBP in treating NP. METHODS: Mice were divided into six groups using random assignment: sham-operation group, spinal nerve ligation (SNL) group, RYZBP low (0.65 g kg-1), medium (1.30 g kg-1), high (2.60 g kg-1) doses groups, and positive drug pregabalin (PGB, 0.05 g kg-1) group. Mice received intragastrical administered for 14 consecutive days. SNL and intrathecal injection models were employed. The analgesic effects were assessed using the Von Frey test, Acetone test, and Hot Plate test. L5 spinal dorsal horns were collected for transcriptomics on day 15. The potential signaling pathways and Hub genes of RYZBP to ameliorate NP were obtained through transcriptomics and network pharmacology. Molecular docking was utilized to evaluate the binding ability of candidate active ingredients with the Hub genes. Finally, western blot (WB) and immunofluorescence (IF) were used to validate the predicted targets. RESULTS: RYZBP demonstrated a dose-dependent alleviation of mechanical allodynia, cold and heat stimulus-induced pain in SNL mice. Transcriptomics analysis identified 24 differentially expressed genes, and pathway enrichment analysis revealed that the CXCL10-CXCR3 signal axis may be the primary biological pathway through which RYZBP relieve NP. Molecular docking test indicated that the active ingredient in RYZBP exhibit a strong affinity for the target protein CXCL10. WB and IF tests showed that RYZBP can significantly inhibit CXCL10 and CXCR3 and its downstream molecules expression in the spinal dorsal horn of SNL mice. Additionally, intrathecal injection of rmCXCL10 worsened pain hypersensitivity, while RYZBP was able to suppress the pain hypersensitivity response induced by rmCXCL10 and reduce the expression levels of CXCL10 and CXCR3 and its downstream molecules. CONCLUSION: RYZBP had a significant analgesic effect on NP model, and this effect may be related to inhibiting the CXCL10-CXCR3 pathway in the spinal dorsal horn.

Metformin Alleviates Pain States by Regulating the Balance of Spinal Synaptic Transmission.

BACKGROUND: Metformin has been shown to have potent analgesic effects; however, the underlying mechanism of synaptic plasticity mediating analgesia remained ambiguous. METHODS: In this study, animal behavioral tests, whole-cell patch­clamp recording, immunofluorescence staining, and network pharmacology techniques were applied to elucidate the mechanisms and potential targets of metformin-induced analgesia. RESULTS: Single or consecutive injections of metformin significantly inhibited spinal nerve ligation (SNL)-induced neuropathic pain, and formalin-induced acute inflammatory pain. Network pharmacology analysis of metformin action targets in pain database-related targets revealed 25 targets, including five hub targets (nitric oxide synthase 1 (NOS1), NOS2, NOS3, epidermal growth factor receptor (EGFR), and plasminogen (PLG)). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that metformin-induced analgesia was markedly correlated with calcium signaling and synaptic transmission. Intrathecal injection of metformin significantly reversed nerve injury-induced c-Fos (neural activity biomarker) mRNA and protein expression in neuropathic rats by regulating NOS2 expression. In addition, whole-cell recordings of isolated spinal neurons demonstrated that metformin dose-dependently inhibited the enhanced frequency and amplitude of miniature excitatory synaptic currents (mEPSCs) but did not affect those of miniature inhibitory synaptic currents (mIPSCs) in neuropathic pain. CONCLUSIONS: This study further demonstrated that metformin might inhibit spinal glutamatergic transmission and abnormal nociceptive circuit transduction by monitoring synaptic transmission in pain. Results of this work provide an in-depth understanding of metformin analgesia via synaptic plasticity.

Anatomical Study of Cross-Transfer of the Contralateral C7 Nerve Through the Posterior Epidural Pathway of the Cervical Spine for the Treatment of Spastic Paralysis of the Upper Limbs.

BACKGROUND: This study explored the safety and feasibility of surgical treatment of spastic paralysis of the central upper extremity by contralateral cervical 7 nerve transfer via the posterior epidural pathway of the cervical spine. METHODS: Five fresh head and neck anatomical specimens were employed to simulate contralateral cervical 7 nerve transfer through the posterior epidural pathway of the cervical spine. The relevant anatomical landmarks and surrounding anatomical relationships were observed under a microscope, and the relevant anatomical data were measured and analysed. RESULTS: The posterior cervical incision revealed the cervical 6 and 7 laminae, and lateral exploration revealed the cervical 7 nerve. The length of the cervical 7 nerve outside the intervertebral foramen was measured to be 6.4 ± 0.5 cm. The cervical 6 and cervical 7 laminae were opened with a milling cutter. The cervical 7 nerve was extracted from the inner mouth of the intervertebral foramen, and its length was 7.8 ± 0.3 cm. The shortest distance of the cervical 7 nerve transfer via the posterior epidural pathway of the cervical spine was 3.3 ± 0.3 cm. CONCLUSIONS: Cross-transfer surgery of the contralateral cervical 7 nerve via the posterior epidural pathway of the cervical spine can effectively avoid the risk of nerve and blood vessel damage in anterior cervical nerve 7 transfer surgery; the nerve transfer distance is short, and nerve transplantation is not required. This approach may become a safe and effective procedure for the treatment of central upper limb spastic paralysis.

Correspondence: Morphological features of the greater occipital nerve and its possible importance for interventional procedures.

This response applauds Saglam et al.'s (2023) recent study on the greater occipital nerve's anatomy while urging readers to consider earlier pivotal studies overlooked. It emphasizes how prior research has significantly shaped headache treatments and provides valuable insights for future practices and discussions.

Picroside â ¡ attenuates neuropathic pain by regulating inflammation and spinal excitatory synaptic transmission.

Nerve injury induced microglia activation, which released inflammatory mediators and developed neuropathic pain. Picroside Ⅱ (PⅡ) attenuated neuropathic pain by inhibiting the neuroinflammation of the spinal dorsal horn; however, how it engaged in the cross talk between microglia and neurons remained ambiguous. This study aimed to investigate PⅡ in the modulation of spinal synaptic transmission mechanisms on pain hypersensitivity in neuropathic rats. We investigated the analgesia of PⅡ in mechanical and thermal hyperalgesia using the spinal nerve ligation (SNL)-induced neuropathic pain model and formalin-induced tonic pain model, respectively. RNA sequencing and network pharmacology were employed to screen core targets and signaling pathways. Immunofluorescence staining and qPCR were performed to explore the expression level of microglia and inflammatory mediator mRNA. The whole-cell patch-clamp recordings were utilized to record miniature excitatory postsynaptic currents in excitatory synaptic transmission. Our results demonstrated that the analgesic of PⅡ was significant in both pain models, and the underlying mechanism may involve inflammatory signaling pathways. PⅡ reversed the SNL-induced overexpression of microglia and inflammatory factors. Moreover, PⅡ dose dependently inhibited excessive glutamate transmission. Thus, this study suggested that PⅡ attenuated neuropathic pain by inhibiting excitatory glutamate transmission of spinal synapses, induced by an inflammatory response on microglia.

Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy.

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer's disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick's disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick's disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

Morphological features of the greater occipital nerve and its possible importance for interventional procedures.

Being one of the most prevalent neurological symptoms, headaches are burdensome and costly. Blocks and decompression surgeries of the greater occipital nerve (GON) have been frequently used for migraine, cervicogenic headache, and occipital neuralgia which are classified under headache by International Headache Society. Knowledge of complex anatomy of GON is crucial for its decompression surgery and block. This study was performed to elucidate anatomical features of this nerve in detail. Forty-one cadavers were dissected bilaterally. According to its morphological features, GON was classified into four main types that included 18 subtypes. Moreover, potential compression points of the nerve were defined. The number of branches of the GON up to semispinalis capitis muscle and the number of its branches that were sent to this muscle were recorded. The most common variant was that the GON pierced the aponeurosis of the trapezius muscle, curved around the lower edge of the obliquus capitis inferior muscle, and was loosely attached to the obliquus capitis inferior muscle (Type 2; 61 sides, 74.4%). In the subtypes, the most common form was Type 2-A (44 sides, 53.6%), in which the GON pierced the aponeurosis of each of the trapezius muscle and fibers of semispinalis muscle at one point and there was a single crossing of the GON and occipital artery. Six potential compression points of the GON were detected. The first point was where the nerve crossed the lower border of the obliquus capitis inferior muscle. The second and third points were at its piercing of the semispinalis capitis muscle and the muscle fibers/aponeurosis of the trapezius, respectively. Fourth, fifth, and sixth compression points of GON were located where the GON and occipital artery crossed each other for the first, second, and third times, respectively. On 69 sides, 1-4 branches of the GON up to the semispinalis capitis muscle were observed (median = 1), while 1-4 branches of GON were sent to the semispinalis capitis muscle on 67 sides (median = 1). The novel anatomical findings described in this study may play a significant role in increasing the success rate of invasive interventions related with the GON.

Neuromodulation and Functional Gastrointestinal Disease.

INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are common, and they severely impair an individual's quality of life. The mechanism of pathogenesis and the effective treatments for FGIDs remain elusive. Neuromodulation-a relatively new treatment-has exhibited a good therapeutic effect on FGIDs, although there are different methods for different symptoms of FGIDs. MATERIALS AND METHODS: We used PubMed to review the history of neuromodulation for the treatment of FGIDs and to review several recently proposed neuromodulation approaches with improved effects on FGIDs. CONCLUSION: Electroacupuncture, transcutaneous electroacupuncture, transcutaneous auricular vagal nerve stimulation, sacral nerve stimulation (SNS) (which relies on vagal nerve stimulation), and gastric electrical stimulation (which works through the modulation of slow waves generated by the interstitial cells of Cajal), in addition to the noninvasive neurostimulation alternative approach method of SNS-tibial nerve stimulation and transcutaneous electrical stimulation (which is still in its infancy), are some of the proposed neuromodulation approaches with improved effects on FGIDs. This review has discussed some critical issues related to the selection of stimulation parameters and the underlying mechanism and attempts to outline future research directions backed by the existing literature.

HSP27 Modulates Neuropathic Pain by Inhibiting P2X3 Degradation.

The role of heat shock protein 27 (HSP27), a chaperone, in neuropathic pain after nerve injury has not been systematically surveyed despite its neuroprotective and regeneration-promoting effects. In this study, we found that HSP27 expression in sensory neurons of the dorsal root ganglia (DRG) mediated nerve injury-induced neuropathic pain. Neuropathic pain behaviors were alleviated by silencing HSP27 in the DRG of a rat spinal nerve ligation (SNL) model. Local injection of an HSP27-overexpression construct into the DRG of naïve rats elicited neuropathic pain behaviors. HSP27 interacted with a purinergic receptor, P2X3, and their expression patterns corroborated the induction and reversal of neuropathic pain according to two lines of evidence: colocalization immunohistochemically and immunoprecipitation biochemically. In a cell model cotransfected with HSP27 and P2X3, the degradation rate of P2X3 was reduced in the presence of HSP27. Such an alteration was mediated by reducing P2X3 ubiquitination in SNL rats and was reversed after silencing HSP27 in the DRGs of SNL rats. In summary, the interaction of HSP27 with P2X3 provides a new mechanism of injury-induced neuropathic pain that could serve as an alternative therapeutic target.

Effect of spirocyclopiperazinium salt compound LXM-15 on spinal nerve injury in rats.

BACKGROUND: Currently available therapies for neuropathic pain show limited efficacy. This study aimed to investigate the anti-nociceptive effect of the spirocyclopiperazinium salt compound LXM-15 in spinal nerve ligation (SNL) rats and to explore the potential mechanisms. METHODS: Mechanical allodynia and thermal hyperalgesia tests were used to evaluate the effects of LXM-15 in SNL rats. The expression of CaMKIIα, CREB, JAK2, STAT3, c-fos and TNF-α was detected by western blotting, ELISA or qRT-PCR analysis. Receptor blocking test was performed to explore possible target. RESULTS: Administration of LXM-15 (1, 0.5, 0.25 mg/kg, i.g.) dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in rats subjected to SNL (p < 0.01, p < 0.05), and the effects were completely blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonist (p > 0.05). LXM-15 significantly decreased the overexpression of phosphorylated CaMKIIα, CREB, JAK2 and STAT3 proteins and the mRNA levels of TNF-α and c-fos (p < 0.01, p < 05). All of the effects could be blocked by α7 or M4 receptor antagonist. Furthermore, LXM-15 reduced the protein expression of TNF-α and c-fos (p < 0.01, p < 0.05). No significant acute toxicity or abnormal hepatorenal function was observed. CONCLUSIONS: This is the first study to report that LXM-15 exerts significant anti-nociceptive effect on SNL rats. This effect may occur by activating peripheral α7 nicotinic and M4 muscarinic receptors, further inhibiting the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and finally inhibiting the expression of TNF-α and c-fos. SIGNIFICANCE: Existing treatments for neuropathic pain show limited efficacy with severe adverse reactions. This paper is the first to report that LXM-15, a new spirocyclopiperazinium salt compound, exerts a significant anti-nociception in SNL rats without obvious toxicity. The underlying mechanisms include activating peripheral α7 nicotinic and M4 muscarinic receptors, then inhibiting the signalling pathways of CaMKIIα/CREB and JAK2/STAT3 and the expressions of TNF-α and c-fos. This study sheds new light on the development of novel analgesic drugs with fewer side effects.

Anatomical Analysis of the S1 Neural Foramen Using Three-Dimensional Computed Tomography Imaging: Insights for Effective S1 Nerve Root Block.

OBJECTIVE: The first sacral nerve root block (S1 NRB) is used to diagnose and treat lumbosacral and radicular pain. This study aims to clarify the anatomy of the S1 neural foramen using three-dimensional (3D) computed tomography (CT) images and to establish the optimal fluoroscopic angle, localize the S1 neural foramen on fluoroscopy, and determine the safe puncture depth for S1 NRB. METHODS: In this single-center cohort study, 200 patients with lumbar degenerative disease who underwent preoperative CT were enrolled. Four distinct studies were conducted using the CT data. Study 1 examined the correlation of the sacral slope angle and the supine and prone positions. Study 2 analyzed the tunnel view angle (TVA) using 3D reconstruction. Study 3 ascertained the location of the S1 neural foramen in fluoroscopy images. Study 4 investigated the safe depth for performing S1 NRB. RESULTS: The regression analysis in Study 1 revealed a correlation of the sacral slope angle and the supine and prone positions. Study 2 determined an optimal fluoroscopic TVA of approximately 30° for the S1 NRB. Study 3 found that the S1 neural foramen was located caudal to the L5 pedicle 1.7 ± 0.2 times the distance between the L4 and L5 pedicles. Study 4 revealed that the depths of the S1 neural foramen and root were 27.0 ± 2.1 mm and 16.5 ± 2.0 mm, respectively. CONCLUSIONS: Our study suggests an optimal fluoroscopic angle, a simple method to locate the S1 neural foramen on fluoroscopy, and an ideal puncture depth for a safe and effective S1 NRB.