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Background/Objectives: Chronic neuropathic pain (CNP) stands as one of the most debilitating complications in patients with myelitis owing to its challenging management. Bright spotty lesions (BSLs) are frequently observed in neuromyelitis optica spectrum disorder (NMOSD), but few reports have discussed CNP in myelitis. We aim to demonstrate that BSLs could be one of the potential prognostic factors for CNP development in myelitis. Methods: We examined 63 patients diagnosed with myelitis. Patients were categorized into CNP and non-CNP groups. We assessed the severity of clinical symptoms and the oral steroid dose administered after pulse therapy. Spine magnetic resonance imaging (MRI) of each patient was reviewed to analyze the characteristics of myelitis. Serological and cerebrospinal fluid (CSF) findings were also examined to confirm the etiology. Results: CNP was observed in 27 patients (42.9%). The mean onset age of patients with CNP was 45.26 ± 14.16 years. The MRI lesions exhibited more enhanced features and bright spotty lesions (BSLs) in the CNP group (χ2 test, p < 0.05). Patients with CNP received a lower oral steroid dose during the first month after symptom onset (χ2 test, p < 0.05). Multivariate logistic regression analysis revealed that patients with CNP exhibited significant BSLs in their myelitis lesions on spine MRI (OR 4.965; 95% CI, 1.282 to 19.235, p = 0.02). Conclusions: Although the exact mechanism remains unknown, the presence of BSLs on spine MRI could serve as an independent prognostic factor for CNP development. Additionally, our study suggests that lower oral steroid doses administered immediately after symptom onset are associated with CNP development. Further investigation with a larger cohort is warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain‐induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel‐object recognition test and the Y‐maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro‐inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2‐AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti‐inflammatory functions. Additionally, SNI‐induced activation of the p‐ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno‐associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain‐induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway. [ABSTRACT FROM AUTHOR]

Peripheral neuropathic pain is common in patients with peripheral nerve injury and can significantly impact both their function and quality of life. There is a wide variety of non‐interventional treatment approaches, including pharmacologic therapy, physical/occupational therapy, modalities (therapeutic, mechanical, thermal, etc.), psychology, and lifestyle modification. First line pharmacologic therapy for peripheral neuropathic pain includes gabapentinoids, tricyclic antidepressants, and serotonin‐norepinephrine reuptake inhibitors. Other classes of medications, such as topical treatments, opioids, and cannabinoids, have more limited usefulness in treatment but remain part of a treatment regimen. Physical and occupational therapy, psychological interventions, and lifestyle medicine are important adjuncts in the treatment and prevention of future peripheral neuropathic pain. The strength of the evidence supporting each intervention varies, with that for pharmacologic intervention being the strongest. A combination of these options tailored to the individual needs of the patient likely will result in the best treatment outcome for peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Microglia display similar morphological responses in the spinal cord after peripheral nerve injury (PNI). Consistent with this observation, functional studies have suggested that microglia activated by opioids or PNI engage common molecular mechanisms to induce hypersensitivity. In this article, we conducted deep RNA sequencing (RNA-seq) and morphological analysis of spinal cord microglia in male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple models of OIH and PNI. After PNI, we identify an early proliferative transcriptional event across models that precedes the upregulation of histological markers of microglial activation. However, we found no proliferative transcriptional response associated with opioid-induced microglial activation, consistent with histological data, indicating that the number of microglia remains stable during morphine treatment, whereas their morphological response differs from PNI models. Collectively, these results establish the diversity of pain-associated microglial transcriptomic responses and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other central nervous system pathologies. [ABSTRACT FROM AUTHOR]

Background Patients with chronic neuropathic pain often report symptoms of depression. The aim of this work is to determine the intensity of chronic neuropathic pain and to identify the efficacy of spinal neurostimulation in a group of patients with spinal surgery and depression. Materials and Methods: The study includes 60 patients with chronic neuropathic pain after spinal surgery, who received spinal cord neurostimulation implant between October 2017 and January 2024, at the Professor Nicolae Oblu Emergency Clinical Hospital, Iasi. Prior to the spinal implant, the patient was evaluated neurologically, psychologically, imaging, electromyography and underwent appropriate treatment for chronic neuropathic pain for about 3 months. The patient self-assessed himself by completing the VAS pain scale, as well as the Roland Morris scale. Results: Analysis of the data indicated that 37 women (61.7 %) and 23 men (38.3 %) were included, with an average age of 53.87 ± 12.033 years, the majority (35 patients, 58.3 %) being from urban areas. 39 cases (65 %), mainly women (29 patients, 78.4 %) presented depressive syndrome. In 26 cases (43.3%) chronic neuropathic pain started one year after surgery. Neurosurgical interventions prior to chronic neuropathic pain were mainly herniated disc (53 cases, 88.33%). The pain onset was generally quite violent, with 55 patients (91.7%) experiencing pain intensity between 7 and 10 on the VAS scale. The situation improved statistically significantly after implantation, with patients’ VAS pain, this time, ranging from 1 to 8. Only in patients with depressive syndrome was there a statistically significant (p = 0.041*) decrease (3.21 ±2.002 versus 4.05 ± 2.012) in the average VAS pain score after implant compared to patients without depressive syndrome. Conclusion: Neurostimulation is effective long-term as an adjuvant treatment for chronic neuropathic pain in patients with depressive syndrome.

Background: Post-mastectomy pain Syndrome (PMPS), characterized by chronic neuropathic pain stemming from intercostobrachial nerve lesions, presents a formidable clinical challenge. With the incidence of breast cancer surging, effective interventions for PMPS are urgently needed. To address this, we conducted this double-blind, placebo-controlled, randomized clinical trial to study the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) therapy over the motor cortex on pain, quality of life and thermal sensitivity in PMPS patients. Methods: We delivered 15 rTMS sessions over three weeks in a cohort of 34 PMPS patients. These patients were allocated randomly to either rTMS therapy or sham therapy groups. Pain assessments, utilizing the Visual Analogue Scale (VAS) and Short Form McGill Pain Questionnaire (SF-MPQ), alongside quality-of-life evaluations through the Functional Assessment of Cancer Therapy-Breast (FACT-B), were recorded before and after the 15 sessions. Additionally, we assessed thermal sensitivity using Quantitative Sensory Testing (QST). Results: Our findings demonstrate the superior efficacy of rTMS therapy (over sham therapy) in reducing VAS and SF-MPQ scores (p < 0.0001), improving physical (p = 0.037), emotional (p = 0.033), and functional well-being (p = 0.020) components of quality of life, as quantified by FACT-B. Our investigation also unveiled marked enhancements in thermal sensitivity within the rTMS therapy group, with statistically significant improvements in cold detection threshold (p = 0.0001), warm detection threshold (p = 0.0033), cold pain threshold (p = 0.0078), and hot pain tolerance threshold (p = 0.0078). Conclusion: The study underscores the profound positive impact of rTMS therapy on pain, quality of life, and thermal sensitivity in patients having PMPS, opening new avenues for pain management strategies. [ABSTRACT FROM AUTHOR]

Botulinum toxin (BoNT), a presynaptic inhibitor of acetylcholine (Ach) release at the neuromuscular junction (NMJ), is a successful and safe drug for the treatment of several neurological disorders. However, a wide and recent literature review has demonstrated that BoNT exerts its effects not only at the "periphery" but also within the central nervous system (CNS). Studies from animal models, in fact, have shown a retrograde transport to the CNS, thus modulating synaptic function. The increasing number of articles reporting efficacy of BoNT on chronic neuropathic pain (CNP), a complex disease of the CNS, demonstrates that the central mechanisms of BoNT are far from being completely elucidated. In this new light, BoNT might interfere with the activity of spinal, brain stem, and cortical circuitry, modulating excitability and the functional organization of CNS in healthy conditions. Botulinum toxins efficacy on CNP is the result of a wide and complex action on many and diverse mechanisms at the basis of the maladaptive plasticity, the core of the pathogenesis of CNP. This systematic review aims to discuss in detail the BoNT's mechanisms and effects on peripheral and central neuroplasticity, at the basis for the clinical efficacy in CNP syndromes. [ABSTRACT FROM AUTHOR]

Background Negative perceptions of psilocybin and challenges of participant enrollment may represent barriers to conducting a randomized controlled trial examining psilocybin for chronic neuropathic pain.Aim Prior to trial initiation, we aimed to examine patient attitudes toward the trial via a prospective preference assessment.Methods Twenty-six patients with chronic neuropathic pain participated in a prospective preference assessment comprising quantitative (survey) and qualitative (interview) components. Content analysis was used to inductively and deductively identify factors that would motivate or discourage participation in the proposed trial. Demographics, clinical characteristics, and perceptions of psilocybin were collected to explore differences in characteristics between patients who were willing and unwilling to participate.Results Survey results showed that most participants (76.9%) were willing to participate in the PEACE-PAIN trial. “Willing” participants reported higher prior psychedelic use (75%) as compared to the “maybe willing” (0%) and “not willing” participants (0%). Interviews indicated that the top two factors that motivated participation included the need for new treatment options (31.7%) and benefits to personal pain management (31.7%). The top two discouraging factors included practical difficulties of research participation (16.7%), and adverse events associated with psilocybin (16.7%).Conclusions The PEACE-PAIN trial study design is supported by patient survey responses but may benefit from modifications, namely incorporating thorough discussions of the current evidence for efficacy, safety, tolerability, and approaches to address adverse effects of psilocybin. Additionally, the interest in participation by individuals with prior psychedelic use holds important methodological implications for the inclusion/exclusion criteria of the trial.

Hongmei Yang,1,&ast; Zhongqi Liu,1,&ast; Fan Liu,1,2,&ast; Haixuan Wu,1 Xiaoyan Huang,1 Rong Huang,1 Phei Er Saw,3,4 Minghui Cao1,2 1Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2Department of Anesthesiology, Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Shanwei, 516600, People’s Republic of China; 3Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Phei Er Saw; Minghui Cao, Email caipeie@mail.sysu.edu.cn; caomh@mail.sysu.edu.cnBackground: Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia.Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA.Results: Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine (p < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group (p < 0.0001).Conclusion: Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.Keywords: lipid nanoparticle, Tet1, peripheral nerve-targeted, pain management, chronic neuropathic pain

Background: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global publichealth problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. Methods: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. Results: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. Conclusion: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity. [ABSTRACT FROM AUTHOR]

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors. Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element. [ABSTRACT FROM AUTHOR]

Background Patients with chronic neuropathic pain often report symptoms of depression. The aim of this work is to determine the intensity of chronic neuropathic pain and to identify the efficacy of spinal neurostimulation in a group of patients with spinal surgery and depression. Materials and Methods: The study includes 60 patients with chronic neuropathic pain after spinal surgery, who received spinal cord neurostimulation implant between October 2017 and January 2024, at the Professor Nicolae Oblu Emergency Clinical Hospital, Iasi. Prior to the spinal implant, the patient was evaluated neurologically, psychologically, imaging, electromyography and underwent appropriate treatment for chronic neuropathic pain for about 3 months. The patient self-assessed himself by completing the VAS pain scale, as well as the Roland Morris scale. Results: Analysis of the data indicated that 37 women (61.7 %) and 23 men (38.3 %) were included, with an average age of 53.87 ± 12.033 years, the majority (35 patients, 58.3 %) being from urban areas. 39 cases (65 %), mainly women (29 patients, 78.4 %) presented depressive syndrome. In 26 cases (43.3%) chronic neuropathic pain started one year after surgery. Neurosurgical interventions prior to chronic neuropathic pain were mainly herniated disc (53 cases, 88.33%). The pain onset was generally quite violent, with 55 patients (91.7%) experiencing pain intensity between 7 and 10 on the VAS scale. The situation improved statistically significantly after implantation, with patients' VAS pain, this time, ranging from 1 to 8. Only in patients with depressive syndrome was there a statistically significant (p = 0.041*) decrease (3.21 ±2.002 versus 4.05 ± 2.012) in the average VAS pain score after implant compared to patients without depressive syndrome. Conclusion: Neurostimulation is effective long-term as an adjuvant treatment for chronic neuropathic pain in patients with depressive syndrome. [ABSTRACT FROM AUTHOR]

Background/Objectives: The intermediate femoral cutaneous nerve (IFCN), the saphenous nerve, and the medial femoral cutaneous nerve (MFCN) innervate the skin of the anteromedial knee region. However, it is unknown whether the MFCN has a deeper innervation. This would be relevant for total knee arthroplasty (TKA) that intersects deeper anteromedial genicular tissue layers. Primary aim: to investigate deeper innervation of the anterior and posterior MFCN branches (MFCN-A and MFCN-P). Secondary aim: to investigate MFCN innervation of the skin covering the anteromedial knee area and medial parapatellar arthrotomy used for TKA. Methods: This study consists of (1) a dissection study and (2) unpublished data and post hoc analysis from a randomized controlled double-blinded volunteer trial (EudraCT number: 2020-004942-12). All volunteers received bilateral active IFCN blocks (nerve block round 1) and saphenous nerve blocks (nerve block round 2). In nerve block round 3, all volunteers were allocated to a selective MFCN-A block. Results: (1) The MFCN-A consistently innervated deeper structures in the anteromedial knee region in all dissected specimens. No deep innervation from the MFCN-P was observed. (2) Sixteen out of nineteen volunteers had an unanesthetized skin gap in the anteromedial knee area and eleven out of the nineteen volunteers had an unanesthetized gap on the skin covering the medial parapatellar arthrotomy before the active MFCN-A block. The anteromedial knee area and medial parapatellar arthrotomy was completely anesthetized after the MFCN-A block in 75% and 82% of cases, respectively. Conclusions: The MFCN-A shows consistent deep innervation in the anteromedial knee region and the area of MFCN-A innervation overlaps the skin area covering the medial parapatellar arthrotomy. Further trials are mandated to investigate whether an MFCN-A block translates into a clinical effect on postoperative pain after total knee arthroplasty or can be used for diagnosis and interventional pain management for chronic neuropathic pain due to damage to the MFCN-A during surgery. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility, safety, and potential health benefits of an 8-week home-based neurofeedback intervention. Design: Single-group preliminary study. Setting: Community-based. Participants: Nine community dwelling adults with chronic neuropathic pain, 6 women and 3 men, with an average age of 51.9 years (range, 19-78 years) and with a 7-day average minimum pain score of 4 of 10 on the visual analog pain scale. Interventions: A minimum of 5 neurofeedback sessions per week (40min/session) for 8 consecutive weeks was undertaken with a 12-week follow-up baseline electroencephalography recording period. Main Outcome Measures: Primary feasibility outcomes: accessibility, tolerability, safety (adverse events and resolution), and human and information technology (IT) resources required. Secondary outcomes: pain, sensitization, catastrophization, anxiety, depression, sleep, health-related quality of life, electroencephalographic activity, and simple participant feedback. Results: Of the 23 people screened, 11 were eligible for recruitment. One withdrew and another completed insufficient sessions for analysis, which resulted in 9 datasets analyzed. Three participants withdrew from the follow-up baselines, leaving 6 who completed the entire trial protocol. Thirteen adverse events were recorded and resolved: 1 was treatment-related, 4 were equipment-related, and 8 were administrative-related (eg, courier communication issues). The human and IT resources necessary for trial implementation were identified. There were also significant improvements in pain levels, depression, and anxiety. Six of 9 participants perceived minimal improvement or no change in symptoms after the trial, and 5 of 9 participants were satisfied with the treatment received. Conclusions: It is feasible and safe to conduct a home-based trial of a neurofeedback intervention for people with chronic neuropathic pain, when the human and IT resources are provided and relevant governance processes are followed. Improvements in secondary outcomes merit investigation with a randomized controlled trial.

Abstract Background The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. Methods We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. Results The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. Conclusion Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP.

Chronic neuropathic pain (CNP) remains a significant clinical challenge, with complex neurophysiological underpinnings that are not fully understood. Identifying specific neural oscillatory patterns related to pain perception and interference can enhance our understanding and management of CNP. The present study aimed to analyze resting electroencephalography data from individuals with CNP to explore potential neural signatures associated with pain intensity, pain interference, and specific characteristics of neuropathic pain. This was achieved through a secondary analysis of electroencephalography data and Brief Pain Inventory responses from 36 patients with CNP, originally collected in a previous cross-sectional study. For statistical analysis, we modeled a linear or logistic regression by dependent variable for each model. As independent variables, we used electroencephalography data with such brain oscillations: as delta, theta, alpha, and beta, as well as the oscillations low alpha, high alpha, low beta, and high beta, for the central, frontal, and parietal regions. All models were tested for confounding factors, such as age and medication. There were no significant models for pain interference in general activity, walking, work, relationships, sleep, and enjoyment of life. However, the model for pain intensity during the past 4 weeks showed decreased alpha oscillations, and increased delta and theta oscillations were associated with decreased levels of pain, especially in the central area. In terms of pain interference in mood, the model showed high oscillatory alpha signals in the frontal and central regions correlated with mood impairment due to pain. Our models confirm recent findings proposing that lower oscillatory frequencies, likely related to subcortical pain sources, may be associated with brain compensatory mechanisms and thus may be associated with decreased pain levels. On the other hand, higher frequencies, including alpha oscillations, may disrupt top-down compensatory mechanisms. [ABSTRACT FROM AUTHOR]

Background: Negative perceptions of psilocybin and challenges of participant enrollment may represent barriers to conducting a randomized controlled trial examining psilocybin for chronic neuropathic pain. Aim: Prior to trial initiation, we aimed to examine patient attitudes toward the trial via a prospective preference assessment. Methods: Twenty-six patients with chronic neuropathic pain participated in a prospective preference assessment comprising quantitative (survey) and qualitative (interview) components. Content analysis was used to inductively and deductively identify factors that would motivate or discourage participation in the proposed trial. Demographics, clinical characteristics, and perceptions of psilocybin were collected to explore differences in characteristics between patients who were willing and unwilling to participate. Results: Survey results showed that most participants (76.9%) were willing to participate in the PEACE-PAIN trial. "Willing" participants reported higher prior psychedelic use (75%) as compared to the "maybe willing" (0%) and "not willing" participants (0%). Interviews indicated that the top two factors that motivated participation included the need for new treatment options (31.7%) and benefits to personal pain management (31.7%). The top two discouraging factors included practical difficulties of research participation (16.7%), and adverse events associated with psilocybin (16.7%). Conclusions: The PEACE-PAIN trial study design is supported by patient survey responses but may benefit from modifications, namely incorporating thorough discussions of the current evidence for efficacy, safety, tolerability, and approaches to address adverse effects of psilocybin. Additionally, the interest in participation by individuals with prior psychedelic use holds important methodological implications for the inclusion/exclusion criteria of the trial. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 μA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats. [ABSTRACT FROM AUTHOR]

Aims: Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety. Preclinical and clinical work has demonstrated that electroacupuncture (EA) effectively alleviates anxiety‐like behaviors induced by chronic neuropathic pain. In this study, a potential neural circuitry underlying the therapeutic action of EA was investigated. Methods: The effects of EA stimulation on mechanical allodynia and anxiety‐like behaviors in animal models of spared nerve injury (SNI) were examined. EA plus chemogenetic manipulation of glutamatergic (Glu) neurons projecting from the rostral anterior cingulate cortex (rACCGlu) to the dorsal raphe nucleus (DRN) was used to explore the changes of mechanical allodynia and anxiety‐like behaviors in SNI mice. Results: Electroacupuncture significantly alleviated both mechanical allodynia and anxiety‐like behaviors with increased activities of glutamatergic neurons in the rACC and serotoninergic neurons in the DRN. Chemogenetic activation of the rACCGlu‐DRN projections attenuated both mechanical allodynia and anxiety‐like behaviors in mice at day 14 after SNI. Chemogenetic inhibition of the rACCGlu‐DRN pathway did not induce mechanical allodynia and anxiety‐like behaviors under physiological conditions, but inhibiting this pathway produced anxiety‐like behaviors in mice at day 7 after SNI; this effect was reversed by EA. EA plus activation of the rACCGlu‐DRN circuit did not produce a synergistic effect on mechanical allodynia and anxiety‐like behaviors. The analgesic and anxiolytic effects of EA could be blocked by inhibiting the rACCGlu‐DRN pathway. Conclusions: The role of rACCGlu‐DRN circuit may be different during the progression of chronic neuropathic pain and these changes may be related to the serotoninergic neurons in the DRN. These findings describe a novel rACCGlu‐DRN pathway through which EA exerts analgesic and anxiolytic effects in SNI mice exhibiting anxiety‐like behaviors. [ABSTRACT FROM AUTHOR]

Introduction: Metaproteomics is a rapidly advancing field that offers unique insights into the taxonomic composition and the functional activity of microbial communities, and their effects on host physiology. Classically, data-dependent acquisition (DDA) mass spectrometry (MS) has been applied for peptide identification and quantification in metaproteomics. However, DDA-MS exhibits well-known limitations in terms of depth, sensitivity, and reproducibility. Consequently, methodological improvements are required to better characterize the protein landscape of microbiomes and their interactions with the host. Methods: We present an optimized proteomic workflow that utilizes the information captured by Parallel Accumulation-Serial Fragmentation (PASEF) MS for comprehensive metaproteomic studies in complex fecal samples of mice. Results and discussion: We show that implementing PASEF using a DDA acquisition scheme (DDA-PASEF) increased peptide quantification up to 5 times and reached higher accuracy and reproducibility compared to previously published classical DDA and data-independent acquisition (DIA) methods. Furthermore, we demonstrate that the combination of DIA, PASEF, and neuronal-network-based data analysis, was superior to DDA-PASEF in all mentioned parameters. Importantly, DIA-PASEF expanded the dynamic range towards low-abundant proteins and it doubled the quantification of proteins with unknown or uncharacterized functions. Compared to previous classical DDA metaproteomic studies, DIA-PASEF resulted in the quantification of up to 4 times more taxonomic units using 16 times less injected peptides and 4 times shorter chromatography gradients. Moreover, 131 additional functional pathways distributed across more and even uniquely identified taxa were profiled as revealed by a peptide-centric taxonomic-functional analysis. We tested our workflow on a validated preclinical mouse model of neuropathic pain to assess longitudinal changes in host-gut microbiome interactions associated with pain - an unexplored topic for metaproteomics. We uncovered the significant enrichment of two bacterial classes upon pain, and, in addition, the upregulation of metabolic activities previously linked to chronic pain as well as various hitherto unknown ones. Furthermore, our data revealed pain-associated dynamics of proteome complexes implicated in the crosstalk between the host immune system and the gut microbiome. In conclusion, the DIA-PASEF metaproteomic workflow presented here provides a stepping stone towards a deeper understanding of microbial ecosystems across the breadth of biomedical and biotechnological fields. [ABSTRACT FROM AUTHOR]

Spinal arachnoid cysts (SACs) arise either intra- or extradurally and are usually solitary, while cases of multiple SACs have been scarcely reported in the literature. Herein, we report on a rare case of multiple and recurring intradural spinal arachnoid cysts (SACs) causing severe spinal cord compression and neuropathic radicular pain, in a 35-year-old female with a 10-year follow-up. Two separate attempts at surgery were performed but only provided temporary relief since the cysts recurred and new ones formed along the entirety of the spinal cord. Finally, a conservative approach with physiotherapy and a combination of analgesic medications was pursued. [ABSTRACT FROM AUTHOR]

Background: An intravenous infusion of lidocaine has been used on numerous occasions to produce analgesia in neuropathic pain. It has been shown to be beneficial for the treatment of variety of neuropathic pain states in a wide range of dosage, from 2 to 7.5 mg/kg. The aim of our study was to evaluate the efficacy of two different doses of intravenous lidocaine (3 and 4 mg/kg) in patients with chronic pain. Methods: Patients above the age of 18 years suffering from chronic pain due to postherpetic neuralgia, post-surgical scar pain, chronic low back pain having numeric analogue scale (NAS) pain score of ≥3 without satisfactory pain relief from conservative treatment were randomised to receive either 3 mg/kg or 4 mg/kg intravenous lidocaine in 250 mL normal saline infusions weekly over a period of 1 hour for 3 weeks. NAS was measured before starting each infusion, immediately after completion of infusion, 2 and 24 hours, 7th day, 14th day, 21st day, and 28th day. Results: NAS score at first hour and 24th hour was significantly reduced (P = 0.001), after each infusion [7th, 14th day] in both the groups. There was no statistical difference in pain score among both groups except for day 7 (P value 0.04). Reduction in NAS score was also present on 21st and 28th day in both groups, but it did not reach a significant value. On 28th day, NAS score values showed increasing trend. Duration of pain relief was around 1 week after each infusion in both groups. Conclusion: Intravenous lidocaine at a dose of 3 mg/kg or 4 mg/kg was effective in reducing pain in patients with chronic pain. The analgesic effect was not different among both groups. Trend of greater response was observed with 4 mg/kg dose.

IntroductionMetaproteomics is a rapidly advancing field that offers unique insights into the taxonomic composition and the functional activity of microbial communities, and their effects on host physiology. Classically, data-dependent acquisition (DDA) mass spectrometry (MS) has been applied for peptide identification and quantification in metaproteomics. However, DDA-MS exhibits well-known limitations in terms of depth, sensitivity, and reproducibility. Consequently, methodological improvements are required to better characterize the protein landscape of microbiomes and their interactions with the host.MethodsWe present an optimized proteomic workflow that utilizes the information captured by Parallel Accumulation-Serial Fragmentation (PASEF) MS for comprehensive metaproteomic studies in complex fecal samples of mice.Results and discussionWe show that implementing PASEF using a DDA acquisition scheme (DDA-PASEF) increased peptide quantification up to 5 times and reached higher accuracy and reproducibility compared to previously published classical DDA and data-independent acquisition (DIA) methods. Furthermore, we demonstrate that the combination of DIA, PASEF, and neuronal-network-based data analysis, was superior to DDA-PASEF in all mentioned parameters. Importantly, DIA-PASEF expanded the dynamic range towards low-abundant proteins and it doubled the quantification of proteins with unknown or uncharacterized functions. Compared to previous classical DDA metaproteomic studies, DIA-PASEF resulted in the quantification of up to 4 times more taxonomic units using 16 times less injected peptides and 4 times shorter chromatography gradients. Moreover, 131 additional functional pathways distributed across more and even uniquely identified taxa were profiled as revealed by a peptide-centric taxonomic-functional analysis. We tested our workflow on a validated preclinical mouse model of neuropathic pain to assess longitudinal changes in host-gut microbiome interactions associated with pain - an unexplored topic for metaproteomics. We uncovered the significant enrichment of two bacterial classes upon pain, and, in addition, the upregulation of metabolic activities previously linked to chronic pain as well as various hitherto unknown ones. Furthermore, our data revealed pain-associated dynamics of proteome complexes implicated in the crosstalk between the host immune system and the gut microbiome. In conclusion, the DIA-PASEF metaproteomic workflow presented here provides a stepping stone towards a deeper understanding of microbial ecosystems across the breadth of biomedical and biotechnological fields.

Depression has a high rate of comorbidity with neuropathic pain. This study aims to investigate the effect of Mygalin, an acylpolyamine synthesized from a natural molecule in the hemolymph of the Acanthoscurria gomesiana spider, injected into the prelimbic (PrL) region of the medial prefrontal cortex on chronic neuropathic pain and depression comorbidity in rats. To investigate that comorbidity, neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. The biotinylated biodextran amine (BDA) bidirectional neural tract tracer was microinjected into the PrL cortex to study brain connections. Rodents were further subjected to von Frey (mechanical allodynia), acetone (cold allodynia), and forced swim (depressive‐like behavior) tests. BDA neural tract tracer‐labeled perikarya were found in the dorsal columns of the periaqueductal gray matter (dPAG) and the dorsal raphe nucleus (DRN). Neuronal activity of DRN neurons decreased in CCI rats. However, PrL cortex treatment with Mygalin increased the number of spikes on DRN neurons. Mygalin treatment in the PrL cortex decreased both mechanical and cold allodynia and immobility behavior in CCI rats. PrL cortex treatment with N‐methyl‐D‐aspartate (NMDA) receptor receptors attenuated the analgesic and antidepressive effects caused by Mygalin. The PrL cortex is connected with the dPAG and DRN, and Mygalin administration into the PrL increased the activity of DRN neurons. Mygalin in the PrL cortex produced antinociceptive and antidepressive‐like effects, and the NMDA agonist reversed these effects. Highlights: Intra‐PrL cortex Mygalin (MY) decreases the mechanical and cold allodynia related to neuropathic pain (NP);MY in the prelimbic (PrL) cortex decreases NP‐related depressivon‐like behavior;PrL cortex NMDA attenuates MY‐induced analgesiaThe PrL cortex sends neural connections to the dPAG and dorsal raphe nucleus (DRN);MY in the PrL cortex increased neuronal activity in the DRN of chronic constriction injury rats. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a common type of chronic pain, primarily caused by peripheral nerve injury. Different T-cell subtypes play various roles in neuropathic pain caused by peripheral nerve damage. Peripheral nerve damage can lead to co-infiltration of neurons and other inflammatory cells, thereby altering the cellular microenvironment and affecting cellular metabolism. By elaborating on the above, we first relate chronic pain to T-cell energy metabolism. Then we summarize the molecules that have affected T-cell energy metabolism in the past five years and divide them into two categories. The first category could play a role in neuropathic pain, and we explain their roles in T-cell function and chronic pain, respectively. The second category has not yet been involved in neuropathic pain, and we focus on how they affect T-cell function by influencing T-cell metabolism. By discussing the above content, this review provides a reference for studying the direct relationship between chronic pain and T-cell metabolism and searching for potential therapeutic targets for the treatment of chronic pain on the level of T-cell energy metabolism. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) is the devastating neurological damage to the spinal cord that becomes more complicated in the secondary phase. The secondary injury comes with inevitable long-lasting complications, such as chronic neuropathic pain (CNP) and spasticity which interfere with day to day activities of SCI patients. Mechanisms underlying CNP post-SCI are complex and remain refractory to current medical treatment. Due to the damage, extensive inhibitory, excitatory tone dysregulation causes maladaptive synaptic transmissions, further altering the nociceptive and nonnociceptive pathways. Excitotoxicity mediated GABAergic cell loss, downregulation of glutamate acid decarboxylase enzyme, upregulation of gamma-aminobutyric acid (GABA) transporters, overactivation of glutamate receptors are some of the key evidence for hypoactive inhibitory tone contributing to CNP and spasticity post-SCI. Restoring the inhibitory GABAergic tone and preventing damage-induced excitotoxicity by employing various strategies provide neuroprotective and analgesic effects. The present article will discuss CNP and spasticity post-SCI, understanding their pathophysiological mechanisms, especially GABA-glutamate-related mechanisms, therapeutic interventions targeting them, and progress regarding how regulating the excitatory-inhibitory tone may lead to more targeted treatments for these distressing complications. Taking background knowledge of GABAergic analgesia and recent advancements, we aim to highlight how far we have reached in promoting inhibitory GABAergic tone for SCI-CNP and spasticity.

Thirty-six chronic neuropathic pain patients (8 men and 28 women) of Mexican nationality with a mean age of 44±13.98 were recruited for EEG signal recording in eyes open and eyes closed resting state condition. Each condition was recorded for 5 min, with a total recording session time of 10 min. An ID number was given to each patient after signing up for the study, with which they answered the painDETECT questionnaire as a screening process for neuropathic pain alongside their clinical history. The day of the recording, the patients answered the Brief Pain Inventory, as an evaluation questionnaire for the interference of the pain with their daily life. Twenty-two EEG channels positioned in accordance with the 10/20 international system were registered with Smarting mBrain device. EEG signals were sampled at 250 Hz with a bandwidth between 0.1 and 100 Hz. The article provides two types of data: (1) raw EEG data in resting state and (2) the report of patients for two validated pain questionnaires. The data described in this article can be used for classifier algorithms considering stratifying chronic neuropathic pain patients with EEG data alongside their pain scores. In sum, this data is of extreme relevance for the pain field, where researchers have been seeking to integrate the pain experience with objective physiological data, such as the EEG.

To investigate the role of DNA methylation in modulating chronic neuropathic pain (NPP), identify possible target genes of DNA methylation involved in this process, and preliminarily confirm the medicinal value of the DNA methyltransferases (DNMTs) inhibitor 5-azacytidine (5-AZA) in NPP by targeting gene methylation. Two rat NPP models, chronic constriction injury (CCI) and spinal nerve ligation (SNL), were used. The DNA methylation profiles in the lumbar spinal cord were assayed using an Arraystar Rat RefSeq Promoter Array. The underlying genes with differential methylation were then identified and submitted to Gene Ontology and pathway analysis. Methyl-DNA immunoprecipitation quantitative PCR (MeDIP-qPCR) and quantitative reverse transcription-PCR (RT-qPCR) were used to confirm gene methylation and expression. The protective function of 5-AZA in NPP and gene expression were evaluated via behavioral assays and RT-qPCR, respectively. Analysis of the DNA methylation patterns in the lumbar spinal cord indicated that 1205 differentially methylated fragments in CCI rats were located within DNA promoter regions, including 638 hypermethylated fragments and 567 hypomethylated fragments. The methylation levels of Grm4, Htr4, Adrb2, Kcnf1, Gad2, and Pparg, which are associated with long-term potentiation (LTP) and glutamatergic synapse pathways, were increased with a corresponding decrease in their mRNA expression, in the spinal cords of CCI rats. Moreover, we found that the intraperitoneal injection of 5-AZA (4 mg/kg) attenuated CCI- or SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, the mRNA expression of hypermethylated genes such as Grm4, Htr4, Adrb2, Kcnf1, and Gad2 was reversed after 5-AZA treatment. CCI induced widespread methylation changes in the DNA promoter regions in the lumbar spinal cord. Intraperitoneal 5-AZA alleviated hyperalgesia in CCI and SNL rats, an effect accompanied by the reversed expression of hypermethylated genes. Thus, DNA methylation inhibition represents a promising epigenetic strategy for protection against chronic NPP following nerve injury. Our study lays a theoretical foundation for 5-AZA to become a clinical targeted drug. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a common chronic condition, which remains poorly understood. Many patients receiving treatment continue to experience severe pain, due to limited diagnostic/treatment management programmes. The development of objective clinical diagnostic/treatment strategies requires identification of robust biomarkers of neuropathic pain. To this end, we looked to identify biomarkers of chronic neuropathic pain by assessing gene expression profiles in an animal model of neuropathic pain, and differential gene expression in patients to determine the potential translatability. We demonstrated cross-species validation of several genes including those identified through bioinformatic analysis by assessing their expression in blood samples from neuropathic pain patients, according to conservative assessments of significance measured using Bonferroni-corrected p-values. These include CASP5 (p = 0.00226), CASP8 (p = 0.00587), CASP9 (p = 2.09 × 10−9), FPR2 (p = 0.00278), SH3BGRL3 (p = 0.00633), and TMEM88 (p = 0.00038). A ROC analysis revealed several combinations of genes to show high levels of discriminatory power in the comparison of neuropathic pain patients and control participants, of which the combination SH3BGRL3, TMEM88, and CASP9 achieved the highest level (AUROC = 0.923). The CASP9 gene was found to be common in five combinations of three genes revealing the highest levels of discriminatory power. In contrast, the gene combination PLAC8, ROMO1, and A3GALT2 showed the highest levels of discriminatory power in the comparison of neuropathic pain and nociceptive pain (AUROC = 0.919), when patients were grouped by S-LANSS scores. Molecules that demonstrate an active role in neuropathic pain have the potential to be developed into a biological measure for objective diagnostic tests, or as novel drug targets for improved pain management. [ABSTRACT FROM AUTHOR]

Purpose: Neuropathic pain is a complication after groin hernia surgery. Triple neurectomy of the iliohypogastric nerve, ilioinguinal nerve and genitofemoral nerve is an efficient treatment modality, with several surgical approaches. The minimally invasive endoscopic method to neurectomy was specifically investigated in this meta-analysis. Our aim is to determine the efficacy of this method in the treatment of chronic neuropathic pain posthernia repair surgery. Methods: A systematic review was conducted using four databases to search for the keywords (“endoscopic retroperitoneal neurectomy” and “laparoscopic retroperitoneal neurectomy”). The NCBI National Library of Medicine, Cochrane Library, MEDLINE Complete and BioMed Central were last searched on 26 May 2022. Randomised control trials and retrospective or prospective papers involving endoscopic retroperitoneal neurectomy operations after inguinal hernia repair were included. All other surgeries, procedures and study designs were excluded. The internal quality of included studies was assessed using the Newcastle–Ottawa Scale. The percentage of patients who had reduction in pain (“positive treatment outcome”) was used to assess the procedure’s effectiveness in each analysis. Results: Five comparable endoscopic retroperitoneal neurectomy studies with a total of 142 patients were analysed. Both the Wald test (Q (6) = 1.79, =.775) and the probability ratio test (Q (6) = 4.24, =.374) provide similar findings (0.000, 0.0% [0.0%; 78%]). The meta-analysis’ key finding is that the intervention was up to 78% effective (95% confidence interval, 71%; 84%). Conclusion: Endoscopic retroperitoneal neurectomy can be an effective treatment option for postoperative neuropathic pain relief following surgical hernia repair. Although there is limited reported experience with this technique, it may provide a clinical benefit to the patient. We recommend further prospective data and long-term follow-up studies be conducted to confirm and expand on these outcomes. [ABSTRACT FROM AUTHOR]

Background Spinal-cord stimulation (SCS) for relief of chronic neuropathic pain is well established. Objective The inherent limitations with conventional percutaneous lead SCS are lead migration, positional variations in stimulation, as well as possible nonreplication of benefits after permanent SCS implantation, which were experienced during a positive trial period. To circumvent these limitations, we analyzed five consecutive cases of chronic intractable neuropathic pain who underwent direct SCS paddle lead placement during the trial period for pain relief. In addition, during the process of placing a permanent paddle lead, the impediment created by prior epidural scarring in such chronic patients can be obviated mechanically thereby increasing the efficacy of the procedure. Material and Methods The demographic details, diagnosis, preoperative visual analogue scale score (VAS), and follow-up VAS were recorded. Surgical procedure consisted of a standard dorsal laminotomy followed by placement of permanent paddle leads. Results All patients reported significant improvement in their VAS scores. Mean duration of follow-up was 23.6 months (9–35 months). Mean preoperative VAS was 9.4 and 1.4 at the last follow-up. No major complications were found. Conclusion With careful patient selection and appropriate surgical strategy, it was possible to implant permanent paddle leads during SCS trial itself in our five patients thereby replicating and sustaining the trial period pain relief. We argue that this can be a new cost-effective and reliable technique for the placement of SCS leads achieving excellent and sustained pain relief. [ABSTRACT FROM AUTHOR]

Background: Spinal cord stimulation (SCS) involves the utilization of an implantable neurostimulation device, stereotypically used in the treatment of patients with chronic neuropathic pain. While these devices have been shown to have significant clinical benefits, there have also been documented potential complications, including the risk of infection, fractured electrodes, electrode migration, and lack of symptom improvement. In addition, there has been minimal documentation on gastrointestinal (GI) side effects after SCS implantation. Case Description: A 42-year-old patient with chronic axial and radicular neuropathic pain in her back and left leg status post multiple lumbar surgeries underwent implantation of an open paddle lead in the T8-T9 region. After the procedure, the patient endorsed a 50% decrease in pain at the 6-week follow-up with no further concerns. However, at the 18 months follow-up, the patient endorsed severe constipation when the SCS was turned on, leading to subsequent evaluation by gastroenterology, motility studies, and a thorough bowel regimen. Symptoms persisted, and the patient ultimately opted for the removal of the SCS implant at 21 months after the initial surgery. Conclusion: While the exact mechanism behind the GI side effects endorsed in this patient is unknown, current literature postulates a variety of theories, including a SCS-induced parasympathetic blockade of the GI tract. Further, investigation is needed to determine the exact effects of SCS on the GI tract. [ABSTRACT FROM AUTHOR]

Background: An intravenous infusion of lidocaine has been used on numerous occasions to produce analgesia in neuropathic pain. It has been shown to be beneficial for the treatment of variety of neuropathic pain states in a wide range of dosage, from 2 to 7.5 mg/kg. The aim of our study was to evaluate the efficacy of two different doses of intravenous lidocaine (3 and 4 mg/kg) in patients with chronic pain. Methods: Patients above the age of 18 years suffering from chronic pain due to postherpetic neuralgia, post-surgical scar pain, chronic low back pain having numeric analogue scale (NAS) pain score of ≥3 without satisfactory pain relief from conservative treatment were randomised to receive either 3 mg/kg or 4 mg/kg intravenous lidocaine in 250mL normal saline infusions weekly over a period of 1 hour for 3 weeks. NAS was measured before starting each infusion, immediately after completion of infusion, 2 and 24 hours, 7th day, 14th day, 21st day, and 28th day. Results: NAS score at first hour and 24th hour was significantly reduced (P=0.001), after each infusion [7th, 14th day] in both the groups. There was no statistical difference in pain score among both groups except for day 7 (P value 0.04). Reduction in NAS score was also present on 21st and 28th day in both groups, but it did not reach a significant value. On 28th day, NAS score values showed increasing trend. Duration of pain relief was around 1 week after each infusion in both groups. Conclusion: Intravenous lidocaine at a dose of 3 mg/kg or 4 mg/ kg was effective in reducing pain in patients with chronic pain. The analgesic effect was not different among both groups. Trend of greater response was observed with 4 mg/kg dose. [ABSTRACT FROM AUTHOR]

Pain is a multifactorial debilitating condition associated with some psychiatric comorbidities such as generalized anxiety and depression. Concerning pharmacological treatment, which is often inefficient or associated with intense side effects, the physical and social context may be fundamental for patient's health improvement. In this sense, we sought to assess the impact of an enriched environment (EE) on neuropathic pain (NP) and depression comorbid. For this purpose, mice exposed to EE or non-enriched conditions for three weeks were submitted to either a chronic constriction injury (CCI) of the ischiadicus nervus or a sham procedure. After three weeks of EE or non-enriched exposition, allodynia (recorded by von Frey and acetone tests), hyperalgesia (recorded by hot plate test), despair behavioral response (recorded by tail suspension test), and apathy (recorded by sucrose spray test) were evaluated. Mice submitted to CCI procedure showed increased rates of hyperalgesia and allodynia, as well as depression-like behaviors compared to the sham procedure-submitted mice. Exposure to EE significantly increased pain thresholds and significantly diminished depression-related behaviors. These findings suggest that the sensory, physical, and social context can be an extra tool for controlling not only sensory-discriminative pain but also emotional pain-related psychiatric comorbidities, such as depression., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest concerning the work presented herein., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objective: Neuropathic pain, a debilitating condition stemming from nervous system injuries, has profound impacts on quality of life. The medial prefrontal cortex (mPFC) plays a crucial role in the modulation of pain perception and emotional response. This study explores the involvement of Slingshot Homolog 1 (SSH1) protein in neuropathic pain and related emotional and cognitive dysfunctions in a mouse model of spared nerve injury (SNI)., Methods: SNI was induced in C57BL/6J mice. SSH1's role was investigated via its overexpression and knockdown using lentiviral vectors in the mPFC. Behavioral assays (thermal and mechanical allodynia, open field test, elevated plus maze, tail suspension test, Y-maze, and novel object recognition were conducted to assess pain sensitivity, anxiety, depression, and cognitive function. Tissue samples underwent Hematoxylin and Eosin staining, Western blotting, immunofluorescence, co-immunoprecipitation, and enzyme-linked immunosorbent assay for inflammatory markers., Results: SNI mice displayed significant reductions in neuronal density and dendritic integrity in the mPFC, alongside heightened pain perception and emotional disturbances, as compared to sham controls. Overexpression of SSH1 ameliorated these alterations, improving mechanical and thermal thresholds, reducing anxiety and depressive behaviors, and enhancing cognitive performance. Conversely, SSH1 knockdown exacerbated these phenotypes. Molecular investigations revealed that SSH1 modulates pain processing and neuronal health in the mPFC partially through the dephosphorylation of Cofilin and LIM domain kinase 1 (LIMK1), as evidenced by changes in their phosphorylation states and interaction patterns., Conclusion: SSH1 plays a pivotal role in the modulation of neuropathic pain and associated neuropsychological disturbances in the mPFC of mice. Manipulating SSH1 expression can potentially reverse the neurophysiological and behavioral abnormalities induced by SNI, highlighting a promising therapeutic target for treating neuropathic pain and its complex comorbidities., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Trigeminal neuralgia (TN) is a prevalent chronic neuropathic pain syndrome characterized by severe pain, often accompanied by cognitive dysfunction and cerebral degeneration. However, its mechanisms remain poorly understood. Hyperphosphorylation of tau protein (p-tau) is often seen in neurodegenerative disorders such as Alzheimer's disease (AD). LRP1 expression on brain neurons and microglial cells is believed to facilitate the propagation of p-tau. We established a TN rat model via infraorbital nerve chronic constrictive injury (ION-CCI). Once the model was established, we investigated the association between p-tau and cognitive impairment in TN rats by evaluating behavioral and degenerative markers. During the initial phase, we noted an increase in p-tau level in the prefrontal cortex and hippocampal tissues of TN rats. The accompanied impaired learning and memory abilities suggested cognitive dysfunction. Blocking p-tau synthesis by orally administering a protein phosphatase and by injecting adenoviral vectors targeting LRP1 into the lateral ventricle of rats ameliorated cognitive impairment. This suggests that cognitive decline in TN rats is linked to elevated p-tau levels. Our findings show that LRP1-mediated p-tau propagation may drive cognitive impairment associated with neuropathic pain in TN rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: We present our experience in using Gamma knife surgery (GKS) on the posterior part of the central lateral nucleus (CLp) for refractory neuropathic pain, examining its long-term efficacy and safety in patients with one of the longest pretreatment pain duration in the literature. Furthermore, we examined certain factors that might influence the outcome of this technique., Methods: We conducted a prospective study involving 9 patients who underwent GKS between 2020 and 2023. We employed Icon model GKS and Vantage stereotactic frame. The planning process encompassed a dual localization system. The assessments involved the use of both the visual analog and Barrow Neurological Institute (BNI) scales (6 months, 12 months, and then annually). Data analysis was developed using SPSS 25., Results: Our series consisted of 6 women and 3 men with an average age of 52.3 ± 17.4 years. A maximum dose of 130 Gy was administered. The mid-term postoperative period (1 year) showed that 8 patients (88.9%) experienced significant pain relief (visual analog scale P = 0.011; BNI IIIa). The median follow-up time was 24.8 ± 8.2. At the last assessment, all patients maintained their improvement (visual analog scale P = 0.018; BNI IIIa). We found no association between patient age (P = 0.329), duration of pretreatment pain (P = 0.469), multiple previous surgical treatments (P = 0.750) or the pain's etiology (P = 0.25), and poorer outcomes post CLp thalamotomy. None of the cases has experienced a recurrence so far. Both morbidity and mortality were 0%., Conclusions: Our findings suggest that bilateral ablation of the CLp using GKS is both effective and safe for treating drug-resistant neuropathic pain. This simple, accurate, and noninvasive surgical technique effectively achieves pain control across various localized areas and sustains a lasting clinical response, even in patients with multiple previous surgical interventions or prolonged pain duration., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder often following trauma, associated with severe pain and autonomic disturbances in the affected limbs. Managing CRPS is challenging due to the lack of FDA-approved medications, often requiring off-label treatments. Traditional options like nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids show limited efficacy, while adjunctive treatments such as gabapentin, antidepressants, and bisphosphonates are increasingly favored. Surgical interventions, including nerve blocks and spinal cord stimulation, may help in refractory cases but have varying success rates. Recent discussions highlight intraoperative ketamine, which targets N-methyl-D-aspartate (NMDA) pathways linked to CRPS. This case study illustrates the complexity of CRPS management, particularly how psychosocial factors and secondary trauma can exacerbate or alleviate symptoms. The case centers on a treatment-resistant flare-up of CRPS, managed through revision neurolysis of the sciatic, tibial, and perineal nerves, along with the release of the right tibial nerve and intraoperative ketamine. Trauma's impact is evident, as the patient initially went into remission after nerve decompression, only for symptoms to return severely following a subsequent trauma. This emphasizes the need for a multipronged treatment approach. Intraoperative ketamine provides rapid pain relief during and after surgery, benefiting patients with severe chronic pain while reducing post-surgery opioid needs and minimizing dependency risks. Patients typically achieve improved functional recovery and better rehabilitation engagement. Research suggests ketamine may offer long-lasting pain relief and psychological benefits, positively impacting mood and anxiety., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, La Spina et al.)

MR-guided focused ultrasound (FUS) represents a promising alternative for patients with chronic neuropathic who have failed medical management and other treatment options. Early single-center experience with chronic neuropathic pain and trigeminal neuralgia has demonstrated favorable long-term outcomes. Excellent safety profile with low risk of motor and sensory complications and so far anecdotal permanent neurologic deficits make FUS a powerful tool to treat patients who are otherwise hopeless. Neuromodulation may be the most influential factor driving outcomes and studies devised to detect neuroplasticity will be critical to guide such therapies., Competing Interests: Disclosure D. Gandhi reports grants from Microvention, the Focused Ultrasound Foundation, United States, the NIH, United States, and University of Calgary, Canada/Nano Therapeutics. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic neuropathic pain often leads to cognitive impairment, but the exact mechanism remains unclear. Gamma-aminobutyric acid A receptors (GABAARs) are the major inhibitory receptors in the brain, of which the α5-containing GABAARs (GABAARs-α5) are implicated in a range of neuropsychiatric disorders with cognitive deficits. However, whether GABAARs-α5 are involved in chronic neuropathic pain-related cognitive impairment remains unknown. In this study, the rats with chronic neuropathic pain induced by right sciatic nerve ligation injury (SNI) exhibited cognitive impairment with declined spontaneous alternation in Y-maze test and discrimination index in novel object recognition test. The GABAARs-α5 expressing on parvalbumin and somatostatin interneurons increased remarkably in hippocampus, resulting in decreased mean frequency of spontaneous inhibitory postsynaptic currents in hippocampal pyramidal neurons. Significantly, antagonizing the GABAARs-α5 by L655708 rescued weakened inhibitory synaptic transmission and cognitive impairment induced by chronic neuropathic pain. Taken together, these data suggest that the GABAARs-α5 play a crucial role in chronic neuropathic pain-induced cognitive impairment by weakening inhibitory synaptic transmission, which may provide insights into the pharmacologic treatment of chronic neuropathic pain-related cognitive impairment. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) is the devastating neurological damage to the spinal cord that becomes more complicated in the secondary phase. The secondary injury comes with inevitable long-lasting complications, such as chronic neuropathic pain (CNP) and spasticity which interfere with day to day activities of SCI patients. Mechanisms underlying CNP post-SCI are complex and remain refractory to current medical treatment. Due to the damage, extensive inhibitory, excitatory tone dysregulation causes maladaptive synaptic transmissions, further altering the nociceptive and nonnociceptive pathways. Excitotoxicity mediated GABAergic cell loss, downregulation of glutamate acid decarboxylase enzyme, upregulation of gamma-aminobutyric acid (GABA) transporters, overactivation of glutamate receptors are some of the key evidence for hypoactive inhibitory tone contributing to CNP and spasticity post-SCI. Restoring the inhibitory GABAergic tone and preventing damageinduced excitotoxicity by employing various strategies provide neuroprotective and analgesic effects. The present article will discuss CNP and spasticity post-SCI, understanding their pathophysiological mechanisms, especially GABA-glutamate-related mechanisms, therapeutic interventions targeting them, and progress regarding how regulating the excitatory-inhibitory tone may lead to more targeted treatments for these distressing complications. Taking background knowledge of GABAergic analgesia and recent advancements, we aim to highlight how far we have reached in promoting inhibitory GABAergic tone for SCI-CNP and spasticity. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain is commonly accompanied by cognitive impairment. However, the underlying mechanism in the occurrence of cognitive deficits under constant nociceptive irritation remains elusive. Herein, we established a chronic neuropathic pain model by chronic constriction injury (CCI) of the unilateral sciatic nerve in rats. Behavioral tests indicated that CCI rats with long-term nociceptive threshold decline developed significant dysfunction of working memory and recognitive memory starting at 14 days and lasting for at least 21 days. Afterward, circRNA expression profiles in the hippocampus of CCI and sham rats were analyzed via high-throughput sequencing to explore the potential key factors associated with cognitive impairment induced by ongoing nociception, which showed 76 differentially expressed circRNAs, 39 upregulated and 37 downregulated, in the CCI group. These differentially expressed circRNA host genes were validated to be primarily associated with inflammation and apoptotic signaling pathways according to GO/KEGG analysis and the circRNA-miRNA-mRNA network, which was also confirmed through the analysis of neuroinflammation and neuronal apoptosis. Consequently, we assumed that enhanced neuroinflammation and neuronal apoptosis might act as potential regulators of cognitive impairment induced by chronic neuropathic pain. The identification of the regulatory mechanism would provide promising clinical biomarkers or therapeutic targets in the diagnostic prediction and intervention treatment of memory deficits under neuropathic pain conditions. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain refractory to medical management can be debilitating and can seriously affect one's quality of life. The interest of ablative surgery for the treatment or palliation of chronic neuropathic pain, cancer-related or chemotherapy-induced, has grown. Numerous regions along the nociceptive pathways have been prominent targets including the various nuclei of the thalamus. Traditional targets include the medial pulvinar, central median, and posterior complex thalamic nuclei. However, there has been little research regarding the role of the central lateral nucleus. In this paper, we aim to summarize the anatomy, pathophysiology, and patient experiences of the central lateral thalamotomy.

Abstract Background Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4′-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain. Methods A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1β), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry. Results DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1β p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential. Conclusion Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.