Butyrate promotes visceral hypersensitivity in IBS model via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.

Emerging evidence indicates that gut dysbiosis is involved in the pathogenesis of visceral hypersensitivity (VH). However, how gut microbiota contributes to the development of VH is unknown. Here, we sought to examine the signal transduction pathways from gut to dorsal root ganglion (DRG) responsible for this. Therefore, abdominal withdrawal reflex (AWR) scores, fecal output, fecal water content, and total gastrointestinal transit time (TGITT) were assessed in Con rats, VH rats, rats treated with NaB, and VH rats treated with VSL#3. Fecal microbiota and its metabolite (short-chain fatty acids, SCFAs), mast cell degranulation in colon, lincRNA-01028, miR-143, and protease kinase C (PKC) and TRPV1 expression in DRGs were further detected. VH rats showed an increased fecal water content, a shortened TGITT, an increased abundance of Clostridium sensu stricto 1 and increased butyrate in fecal samples, an increased mast cell degranulation, an increased expression of lincRNA-01028, PKC, and TRPV1, and a decreased expression of miR-143 in DRGs compared with control rats, which could be restored by the application of probiotic VSL#3. The above-mentioned detection in rats treated with butyrate was similar to that of VH rats. We further confirm whether butyrate sensitized DRG neurons by a lincRNA-01028, miR-143, and PKC-dependent mechanism via mast cell in vitro. In co-cultures, MCs treated with butyrate elicited a higher TRPV1 current, a higher expression of lincRNA-01028, PKC, and a lower expression of miR-143 in DRG neurons, which could be inhibited by a lincRNA-01028 inhibitor. These findings indicate that butyrate promotes visceral hypersensitivity via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.IMPORTANCEIrritable bowel syndrome (IBS), characterized by visceral hypersensitivity, is a common gastrointestinal dysfunction syndrome. Although the gut microbiota plays a role in the pathogenesis and treatment of irritable bowel syndrome (IBS), the possible underlying mechanisms are unclear. Therefore, it is of critical importance to determine the signal transduction pathways from gut to DRG responsible for this in vitro and in vivo assay. This study demonstrated that butyrate sensitized TRPV1 in DRG neurons via mast cells in vivo and in vitro by a lincRNA-01028, miR-143, and PKC-dependent mechanism. VH rats similarly showed an increased abundance of Clostridium sensu stricto 1, an increased fecal butyrate, an increased mast cell degranulation, and increased expression of TRPV1 compared with control rats, which could be restored by the application of VSL#3. In conclusion, butyrate produced by the altered intestinal microbiota is associated with increased VH.

Fibroblast growth factor 3 contributes to neuropathic pain through Akt/mTOR signaling in mouse primary sensory neurons.

Neuropathic pain (NP), a severe chronic pain condition, remains a substantial clinical challenge due to its complex pathophysiology and limited effective treatments. An association between the members of the Fibroblast Growth Factors (FGFs), particularly Fgf3, and the development of NP has become evident. In this study, utilizing a mouse model of NP, we observed a time-dependent increase in Fgf3 expression at both mRNA and protein levels within the dorsal root ganglia (DRG). Functional studies revealed that blocking Fgf3 expression mitigated nerve injury induced nociceptive hypersensitivity, suggesting its pivotal role in pain modulation. Moreover, our findings elucidate that Fgf3 contributes to pain hypersensitivity through the activation of the Akt/mTOR signaling in injured DRG neurons. These results not only shed light on the involvement of Fgf3 in nerve injury-induced NP but also highlight its potential as a promising therapeutic target for pain management. This study thereby advances our understanding of the molecular mechanisms underlying NP and opens new avenues for the development of effective treatment strategies.

Artemisia argyi volatile oil ameliorates allergic contact dermatitis via modulating TRPA1/CGRP signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Artemisia argyi Levl.et Vant. have a long history of being used to treat skin diseases such as pruritus and dermatitis in China, but the therapeutic effect on allergic contact dermatitis (ACD) is still unclear. AIM OF THE STUDY: To investigate the effect and molecular mechanisms of the volatile oil of A. argyi leaves (abbreviated as 'AO') in the treatment of ACD. MATERIALS AND METHODS: The main components in AO were analyzed using GC-MS. The effect of AO on channel currents in hTRPA1-transfected HEK293T cells was studied by whole-cell patch clamp. Subsequently, chloroquine-evoked acute itch and squaraine dibutyl ester (SADBE)-induced ACD chronic itch model was established to evaluate the antipruritic effect through counting scratching behavior, and the anti-inflammatory effects on ACD mice were measured using histological analysis. Meanwhile, the changes of CGRP, the infiltration of nerve fibers and the recruitment of dendritic cells, the expression of Il-23 and Il-17 mRNA in skin lesions, the phosphorylation of ERK and p38 in dorsal root ganglion (DRG), were evaluated by molecular biological methods. Then the inhibitory effect of AO on AITC- or SADBE-activated TRPA1 channels in primary DRG neurons of C57BL/6, Trpa1-/- or Trpv1-/- mice was elucidated by Ca2+ imaging and immunofluorescence. RESULTS: AO treatment inhibited the activation of TRPA1 in HEK293T cells and alleviated acute itch caused by chloroquine, but this effect was lacking in Trpa1-/- mice. Furthermore, administration of AO attenuated scratching behavior in SADBE-induced ACD mice. AO also inhibited the increase of nerve fibers and recruitment of dendritic cells, and down-regulated the expression of CGRP and the levels of Il-23 and Il-17 mRNA. Meanwhile, AO reduced the expression of p-p38 and p-ERK in the lesioned skin and DRG of SADBE-induced ACD mice. Additionally, AO blocked the activation of TRPA1 channels and decreased the levels of CGRP, p-p38, and p-ERK in DRG neurons. CONCLUSION: AO could inhibit TRPA1 channels in sensory neurons, thereby reducing the release of CGRP and exerting anti-pruritic and anti-inflammatory effect. These findings also provide a new strategy for exploring the role of A. argyi in treating ACD.

Efficacy of Mind-Regulating and Depression-Reliving Acupuncture in combination with Radiofrequency Thermocoagulation of Dorsal Root Ganglion for Post-herpetic Neuralgia.

PURPOSE: This study is aimed at evaluating the efficacy of Mind-Regulating and Depression-Relieving Acupuncture in combination with radiofrequency thermocoagulation of DRG for PHN. METHODS: PHN patients who presented to the Pain Department of Affiliated Hospital of Jiaxing University from November 2021 to June 2023 were included. The participants were assigned into two groups using a random number table: Acupuncture + RFTC (Group H, n = 44) group and RFTC (Group C, n = 44) group. The pain numerical rating score (NRS), visual analogue scale scores (VAS), IL-6 , Gal-3, oral dose of tramadol and gabapentin capsules levels were recorded before and after 1, 2, 4, 8 and 12 w of the treatment. RESULTS: After treatment, NRS scores in both groups were significantly lower than pretreatment scores at each time point. Compared with before treatment, the VAS scores at all time points after treatment was increased in both groups. Compared with before treatment, the doses of oral gabapentin capsules and tramadol were reduced in both groups after treatment. Compared with group C, the doses of oral gabapentin capsules and tramadol after the end of the treatment course were significantly reduced in group H. Compared with before treatment, the blood levels of Gal-3 and IL-6 were reduced at all points after treatment in both groups. Compared with group C, the blood Gal-3 and IL-6 levels were significantly reduced in group H. CONCLUSION: Compared with RFTC alone, acupuncture combined with RFTC of DRG has a better therapeutic effect for PHN.

Eugenol and lidocaine inhibit voltage-gated Na+ channels from dorsal root ganglion neurons with different mechanisms.

Eugenol (EUG) is a bioactive monoterpenoid used as an analgesic, preservative, and flavoring agent. Our new data show EUG as a voltage-gated Na+ channel (VGSC) inhibitor, comparable but not identical to lidocaine (LID). EUG inhibits both total and only TTX-R voltage-activated Na+ currents (INa) recorded from VGSCs naturally expressed on dorsal root ganglion sensory neurons in rats. Inhibition is quick, fully reversible, and dose-dependent. Our biophysical and pharmacological analyses showed that EUG and LID inhibit VGSCs with different mechanisms. EUG inhibits VGSCs with a dose-response relationship characterized by a Hill coefficient of 2, while this parameter for the inhibition by LID is 1. Furthermore, in a different way from LID, EUG modified the voltage dependence of both the VGSC activation and inactivation processes and the recovery from fast inactivated states and the entry to slow inactivated states. In addition, we suggest that EUG, but not LID, interacts with VGSC pre-open-closed states, according to our data.

Neph1 is required for neurite branching and is negatively regulated by the PRRXL1 homeodomain factor in the developing spinal cord dorsal horn.

The cell-adhesion molecule NEPH1 is required for maintaining the structural integrity and function of the glomerulus in the kidneys. In the nervous system of Drosophila and C. elegans, it is involved in synaptogenesis and axon branching, which are essential for establishing functional circuits. In the mammalian nervous system, the expression regulation and function of Neph1 has barely been explored. In this study, we provide a spatiotemporal characterization of Neph1 expression in mouse dorsal root ganglia (DRGs) and spinal cord. After the neurogenic phase, Neph1 is broadly expressed in the DRGs and in their putative targets at the dorsal horn of the spinal cord, comprising both GABAergic and glutamatergic neurons. Interestingly, we found that PRRXL1, a homeodomain transcription factor that is required for proper establishment of the DRG-spinal cord circuit, prevents a premature expression of Neph1 in the superficial laminae of the dorsal spinal cord at E14.5, but has no regulatory effect on the DRGs or on either structure at E16.5. By chromatin immunoprecipitation analysis of the dorsal spinal cord, we identified four PRRXL1-bound regions within the Neph1 introns, suggesting that PRRXL1 directly regulates Neph1 transcription. We also showed that Neph1 is required for branching, especially at distal neurites. Together, our work showed that Prrxl1 prevents the early expression of Neph1 in the superficial dorsal horn, suggesting that Neph1 might function as a downstream effector gene for proper assembly of the DRG-spinal nociceptive circuit.

Unveiling the role of dorsal root ganglia in spasticity reduction: Insights from contralateral seventh cervical nerve cross transfer surgery.

BACKGROUND: Central nervous system (CNS) disorders, such as stroke, often lead to spasticity, which result in limb deformities and significant reduction in quality of life. Spasticity arises from disruptions in the normal functioning of cortical and descending inhibitory pathways in the brainstem, leading to abnormal muscle contractions. Contralateral seventh cervical nerve cross transfer (CC7) surgery has been proven to effectively reduce spasticity, but the specific mechanism for its effectiveness is unclear. METHODS: This study aimed to investigate the changes in the dorsal root ganglia (DRG) following CC7 surgery. A comprehensive anatomical analysis was conducted through cadaveric study and magnetic resonance imaging (MRI) study, to accurately measure the regional anatomy of the C7 DRG. DRG perfusion changes were quantitatively assessed by comparing pre- and postoperative dynamic contrast-enhanced (DCE) MRI. RESULTS: In CC7 surgery, the C7 nerve root on the affected side is cut close to the DRG (3.6 ± 1.0 mm), while the C7 nerve root on the healthy side is cut further away from the DRG (65.0 ± 10.0 mm). MRI studies revealed that after C7 proximal neurotomy on the affected side, there was an increase in DRG volume, vascular permeability, and perfusion; after C7 distal neurotomy on the healthy side, there was a decrease in DRG volume, with no significant changes in vascular permeability and perfusion. CONCLUSION: This study provides preliminary insights into the mechanisms of spasticity reduction following CC7 surgery, indicating that changes in the DRG, such as increased vascular permeability and perfusion, could disrupt abnormal spinal γ-circuits. The resulting high-perfusion state of DRG, possibly due to heightened neuronal activity and metabolic demands, necessitating further research to verify this hypothesis.

Proteomic Analysis of Dorsal Root Ganglia in a Mouse Model of Paclitaxel-Induced Neuropathic Pain.

Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 60%) of chemotherapy induced peripheral neuropathy. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients.

TFAP2A is involved in neuropathic pain by regulating Grin1 expression in glial cells of the dorsal root ganglion.

Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A-Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics.

Tonic Stimulation of Dorsal Root Ganglion Results in Progressive Decline in Recruitment of Aα/ß-Fibers in Rats.

OBJECTIVES: In this study, we aimed to characterize the recruitment and maintenance of action potential firing in Aα/ß-fibers generated during tonic dorsal root ganglion stimulation (DRGS) applied over a range of clinically relevant stimulation parameters. MATERIALS AND METHODS: We delivered electrical stimulation to the L5 dorsal root ganglion and recorded antidromic evoked compound action potentials (ECAPs) in the sciatic nerve during DRGS in Sprague Dawley rats. We measured charge thresholds to elicit ECAPs in Aα/ß-fibers during DRGS applied at multiple pulse widths (50, 150, 300, 500 µs) and frequencies (5, 20, 50, 100 Hz). We measured the peak-to-peak amplitudes, latencies, and widths of ECAPs generated during 180 seconds of DRGS, and excitation threshold changes to investigate potential mechanisms of ECAP suppression. RESULTS: Tonic DRGS produced ECAPs in Aα/ß-fibers at charge thresholds below the motor threshold. Increasing the pulse width of DRGS led to a significant increase in the charge required to elicit ECAPs in Aα/ß-fibers, while varying DRGS frequency did not influence ECAP thresholds. Over the course of 180 seconds, ECAP peak-to-peak amplitude decreased progressively in a frequency-dependent manner, where 5- and 100-Hz DRGS resulted in 22% and 87% amplitude reductions, respectively, and ECAP latencies increased from baseline measurements during DRGS at 10, 20, 50, and 100 Hz. Regardless of DRGS frequency, ECAP amplitudes recovered within 120 seconds after turning DRGS off. We determined that ECAP suppression may be attributed to increasing excitation thresholds for individual fibers during DRGS. Following 180 seconds of DRGS, an average of 7.33% increase in stimulation amplitude was required to restore the ECAP to baseline amplitude. CONCLUSIONS: DRGS produces a progressive and frequency-dependent reduction in ECAP amplitude that occurs within and above the frequency range used clinically to relieve pain. If DRGS-mediated analgesia relies on Aß-fiber activation, then the frequency or duty cycle of stimulation should be set to the lowest effective level to maintain sufficient activation of Aß-fibers.

Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability.

Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K+ channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K+ channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K+ channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures.

EFFECTIVENESS OF DORSAL ROOT GANGLION STIMULATION IN CHRONIC PAIN MANAGEMENT: A SYSTEMATIC REVIEW.

OBJECTIVE: This systematic review aims to determine the effectiveness of Dorsal Root Ganglion Stimulation (DRGS) in chronic pain management. MATERIALS AND METHODS: In 2023, a comprehensive systematic review was undertaken utilizing various electronic databases, employing MeSH terms and free search terms tailored to the study's aims. This review included primary research such as cohorts, case-control studies, and clinical trials, all focusing on the efficacy of DRGS in treating various chronic pain conditions. Non-human or animal studies were omitted from the selection process. A review of study quality was conducted, followed by meticulous analysis of the findings to synthesize the evidence. This review represents the most current research, with updates extending to 2024. A total of 400 articles were reviewed. 29 articles were included in our review after meticulous screening. RESULTS: Twenty-nine articles published in the last five years meeting selection criteria were identified, encompassing patients with various diagnoses warranting the use of DRGS beyond CRPS. Additionally, the analysis includes different outcome measurement tools, emphasizing improvements in pain management, functionality, and quality of life. Finally, common complications such as surgical site infection and issues with electrodes are highlighted. CONCLUSIONS: This systematic review affirms the effectiveness of DRGS therapy in managing diverse chronic pain conditions, highlighting improvements in quality of life, functionality, and mood states, making it a viable alternative for patients unresponsive to traditional treatments.

Gene expression in the dorsal root ganglion and the cerebrospinal fluid metabolome in polyneuropathy and opioid tolerance in rats.

First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.

Advances in Spinal Neuromodulation for Chemotherapy-induced Peripheral Neuropathy.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) continues to be a major source of chronic morbidity in patients with cancer. Current treatment options and efficacy are limited; thus, there is a need to investigate more effective therapeutic options. Spinal neuromodulation including dorsal column spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S) are being explored for these patients. The purpose of this narrative review was to critically summarize and evaluate the advancements that have been made in utilizing SCS and DRG-S for CIPN. MATERIALS AND METHODS: A thorough literature search was conducted using PubMed for any research on patients with CIPN who underwent DRG-S or SCS. Studies involving patients with general cancer-related pain were not included. Only articles that were published in English, had original, extractable data, and were available on or before August 1, 2023, were included. RESULTS: This study evaluated twelve studies with a total of 13 patients that reported using SCS for CIPN and four studies with a total of 12 patients that reported using DRG-S for CIPN. Many of the studies demonstrated that DRG-S or SCS can assist in reducing opioid consumption, lowering pain scores, and improving sensory deficits. CONCLUSION: DRG-S and SCS have the potential to improve symptoms and lower medication usage in patients suffering from CIPN. Spinal neuromodulation could be considered as an alternative therapy for patients with persistent symptoms.

Lateral atlanto-axial joint access using the C2 pedicle.

BACKGROUND: Neck pain and headaches can arise from the lateral atlanto-axial joint (LAA joint). This pain can be diagnosed with intra-articular injections of local anesthetic. A widely used technique for access to the lateral atlanto-axial joint uses a posterior approach, but this approach can be hazardous because of the proximity of the vertebral artery, the dural sac, and the C2 spinal nerve and dorsal root ganglion. OBJECTIVE: The objective was to describe and test a new technique for accessing the LAA joint that avoids structures that lie behind the joint. INTERVENTIONS: The new technique was described, and tested for tolerance in 10 patients with unilateral suboccipital pain, and tenderness over the LAA joint, along with evidence of LAA joint arthropathy on SPECT CT. The technique requires inserting a needle along a trajectory tangential to the dorsal surface of the C2 lamina. It involves obtaining a declined view of the C2 lamina and C2 pedicle. CONCLUSIONS: In all cases, the C2 pedicle was easily identified and allowed the needle to pass asymptomatically underneath the neurovascular structures behind the joint. The tactile response of the lamina of C2 provided important feedback regarding needle depth caudal to the LAA joint.

Low-frequency dorsal root stimulation is effective for various pain etiologies and pain locations.

BACKGROUND: Dorsal root ganglion stimulation (DRG-S) has emerged as a novel therapeutic approach for managing chronic neuropathic pain. AIMS: This study aims to compare the effectiveness of 4-20 Hz DRG-S through a retrospective analysis of a cohort of 28 patients with various neuropathic pain etiologies and pain locations. MATERIALS AND METHODS: Patient responses to both stimulation frequencies were examined using the Numeric Rating Scale (NRS) and Patient Global Impression of Change (PGIC) assessments. Factors such as patient preference and satisfaction were also evaluated. RESULTS: The results indicate that 4 Hz DRG-S is not only as effective as 20 Hz stimulation but may also surpass it. Among the 28 patients, 26 assessed 4 Hz stimulation to be at least as effective as 20 Hz, with the majority (22 out of 26) considering 4 Hz stimulation superior. After trying 4 Hz stimulation, 24 out of 28 patients chose it over 20 Hz, while two patients opted for a combination of both settings. Only two patients reverted to their original 20 Hz stimulation program. A statistically significant pain reduction of 24% was observed when comparing the effects of 4 Hz versus 20 Hz. DISCUSSION: The study highlights the broader applicability of low-frequency DRG-S, extending its benefits beyond the realm of low back pain. Patients with diverse pain etiologies and locations experienced comparable positive outcomes, suggesting that the advantages of low-frequency stimulation are not confined to specific pain types or locations. CONCLUSION: This study emphasizes the potential of 4 Hz DRG-S as a valuable alternative to the standard 20 Hz stimulation. Although the exact mechanisms require further investigation, the observed clinical benefits and patient preferences for low-frequency stimulation suggest its viability across diverse pain indications and locations. Additional research is necessary to substantiate these findings and assess the durability and economic implications of low-frequency DRG-S.

The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for Spinal Cord Stimulation Long-term Outcome Optimization and Salvage Therapy.

INTRODUCTION: The International Neuromodulation Society (INS) has recognized a need to establish best practices for optimizing implantable devices and salvage when ideal outcomes are not realized. This group has established the Neurostimulation Appropriateness Consensus Committee (NACC)® to offer guidance on matters needed for both our members and the broader community of those affected by neuromodulation devices. MATERIALS AND METHODS: The executive committee of the INS nominated faculty for this NACC® publication on the basis of expertise, publications, and career work on the issue. In addition, the faculty was chosen in consideration of diversity and inclusion of different career paths and demographic categories. Once chosen, the faculty was asked to grade current evidence and along with expert opinion create consensus recommendations to address the lapses in information on this topic. RESULTS: The NACC® group established informative and authoritative recommendations on the salvage and optimization of care for those with indwelling devices. The recommendations are based on evidence and expert opinion and will be expected to evolve as new data are generated for each topic. CONCLUSIONS: NACC® guidance should be considered for any patient with less-than-optimal outcomes with a stimulation device implanted for treating chronic pain. Consideration should be given to these consensus points to salvage a potentially failed device before explant.

Cannabinoid CB2 receptors in primary sensory neurons are implicated in CB2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB2 agonists show therapeutic efficacy without unwanted CB1-mediated side effects. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB2 receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB2f/f and CX3CR1CRE/+; CB2f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB2f/f mice, but not AdvillinCRE/+; CB2f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications.

Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain.

Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.

Nerve Growth Factor Signaling Modulates the Expression of Glutaminase in Dorsal Root Ganglion Neurons during Peripheral Inflammation.

Glutamate functions as the major excitatory neurotransmitter for primary sensory neurons and has a crucial role in sensitizing peripheral nociceptor terminals producing sensitization. Glutaminase (GLS) is the synthetic enzyme that converts glutamine to glutamate. GLS-immunoreactivity (-ir) and enzyme activity are elevated in dorsal root ganglion (DRG) neuronal cell bodies during chronic peripheral inflammation, but the mechanism for this GLS elevation is yet to be fully characterized. It has been well established that, after nerve growth factor (NGF) binds to its high-affinity receptor tropomyosin receptor kinase A (TrkA), a retrograde signaling endosome is formed. This endosome contains the late endosomal marker Rab7GTPase and is retrogradely transported via axons to the cell soma located in the DRG. This complex is responsible for regulating the transcription of several critical nociceptive genes. Here, we show that this retrograde NGF signaling mediates the expression of GLS in DRG neurons during the process of peripheral inflammation. We disrupted the normal NGF/TrkA signaling in adjuvant-induced arthritic (AIA) Sprague Dawley rats by the pharmacological inhibition of TrkA or blockade of Rab7GTPase, which significantly attenuated the expression of GLS in DRG cell bodies. The results indicate that NGF/TrkA signaling is crucial for the production of glutamate and has a vital role in the development of neurogenic inflammation. In addition, our pain behavioral data suggest that Rab7GTPase can be a potential target for attenuating peripheral inflammatory pain.