Blockade of Piezo2 Pathway Attenuates Inflammatory and Neuropathic Pain in the Orofacial Area.

Although previous studies suggest that Piezo2 regulates chronic pain in the orofacial area, few studies have reported the direct evidence of Piezo2's involvement in inflammatory and neuropathic pain in the orofacial region. In this study, we used male Sprague Dawley rats to investigate the role of the Piezo2 pathway in the development of inflammatory and neuropathic pain. The present study used interleukin (IL)-1ß-induced pronociception as an inflammatory pain model. Subcutaneous injection of IL-1ß produced significant mechanical allodynia and thermal hyperalgesia. Subcutaneous injection of a Piezo2 inhibitor significantly blocked mechanical allodynia and thermal hyperalgesia induced by subcutaneously injected IL-1ß. Furthermore, the present study also used a neuropathic pain model caused by the misplacement of a dental implant, leading to notable mechanical allodynia as a consequence of inferior alveolar nerve injury. Western blot analysis revealed increased levels of Piezo2 in the trigeminal ganglion and the trigeminal subnucleus caudalis after inferior alveolar nerve injury. Furthermore, subcutaneous and intracisternal injections of a Piezo2 inhibitor blocked neuropathic mechanical allodynia. These results suggest that the Piezo2 pathway plays a critical role in the development of inflammatory and neuropathic pain in the orofacial area. Therefore, blocking the Piezo2 pathway could be the foundation for developing new therapeutic strategies to treat orofacial pain conditions.

Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain.

While voltage-gated sodium channels Nav1.7 and Nav1.8 both contribute to electrogenesis in dorsal root ganglion (DRG) neurons, details of their interactions have remained unexplored. Here, we studied the functional contribution of Nav1.8 in DRG neurons using a dynamic clamp to express Nav1.7L848H, a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, and demonstrate a profound functional interaction of Nav1.8 with Nav1.7 close to the threshold for AP generation. At the voltage threshold of -21.9 mV, we observed that Nav1.8 channel open-probability exceeded Nav1.7WT channel open-probability ninefold. Using a kinetic model of Nav1.8, we showed that a reduction of Nav1.8 current by even 25-50% increases rheobase and reduces firing probability in small DRG neurons expressing Nav1.7L848H. Nav1.8 subtraction also reduces the amplitudes of subthreshold membrane potential oscillations in these cells. Our results show that within DRG neurons that express peripheral sodium channel Nav1.7, the Nav1.8 channel amplifies excitability at a broad range of membrane voltages with a predominant effect close to the AP voltage threshold, while Nav1.7 plays a major role at voltages closer to resting membrane potential. Our data show that dynamic-clamp reduction of Nav1.8 conductance by 25-50% can reverse hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes pain in humans and suggests, more generally, that full inhibition of Nav1.8 may not be required for relief of pain due to DRG neuron hyperexcitability.

Follistatin drives neuropathic pain in mice through IGF1R signaling in nociceptive neurons.

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor-ß (TGF-ß) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor-1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

Transcriptomic Profiling of Primary Microglia: Effects of miR-19a-3p and miR-19b-3p on Microglia Activation.

Neuropathic pain resulting from spinal cord injury (SCI) is a significant secondary health issue affecting around 60% of individuals with SCI. After SCI, activation of microglia, the immune cells within the central nervous system, leads to neuroinflammation by producing pro-inflammatory cytokines and affects neuropathic pain. This interplay between inflammation and pain contributes to the persistent and intense pain experienced by many individuals with SCI. MicroRNAs (miRs) have been critical regulators of neuroinflammation. Previous research in our laboratory has revealed upregulation levels of circulating miR-19a and miR-19b in individuals with SCI with neuropathic pain compared to those without pain. In this study, we treated primary microglial cultures from mice with miR-19a and miR-19b for 24 h and conducted RNA sequencing analysis. Our results showed that miR-19a and miR-19b up- and downregulate different genes according to the volcano plots and the heatmaps. miR-19a and miR-19b regulate inflammation through distinct signaling pathways. The results showed that miR-19a promotes inflammation via toll-like receptor signaling, TNF signaling, and cytokine-cytokine receptor interactions, while miR-19b increases inflammatory responses through the PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix receptor interactions. The protein-protein interaction (PPI) networks used the STRING database to identify transcription factors associated with genes up- or downregulated by miR-19a and miR-19b. Key transcription factors, such as STAT1, STAT2, and KLF4 for miR-19a, and Nr4a1, Nr4a2, and Nr4a3 for miR-19b, were identified and revealed their roles in regulating neuroinflammation. This study demonstrates that miR-19a and miR-19b modulate diverse patterns of gene expression, regulate inflammation, and induce inflammatory responses in microglia.

Effects of Electroacupuncture at Varied Frequencies on Analgesia and Mechanisms in Sciatic Nerve Cuffing-Induced Neuropathic Pain Mice.

Addressing the intricate challenge of chronic neuropathic pain has significant implications for the physical and psychological well-being of patients, given its enduring nature. In contrast to opioids, electroacupuncture (EA) may potentially provide a safer and more efficacious therapeutic alternative. Our objective is to investigate the distinct analgesic effects and potential mechanisms of EA at frequencies of 2 Hz, 100 Hz, and 18 kHz in order to establish more precise frequency selection criteria for clinical interventions. Analgesic efficacy was evaluated through the measurement of mice's mechanical and thermal pain thresholds. Spinal cord inflammatory cytokines and neuropeptides were quantified via Quantitative Real-time PCR (qRT-PCR), Western blot, and immunofluorescence. Additionally, RNA sequencing (RNA-Seq) was conducted on the spinal cord from mice in the 18 kHz EA group for comprehensive transcriptomic analysis. The analgesic effect of EA on neuropathic pain in mice was frequency-dependent. Stimulation at 18 kHz provided superior and prolonged relief compared to 2 Hz and 100 Hz. Our research suggests that EA at frequencies of 2 Hz, 100 Hz, and 18 kHz significantly reduce the release of inflammatory cytokines. The analgesic effects of 2 Hz and 100 Hz stimulation are due to frequency-dependent regulation of opioid release in the spinal cord. Furthermore, 18 kHz stimulation has been shown to reduce spinal neuronal excitability by modulating the serotonergic pathway and downstream receptors in the spinal cord to alleviate neuropathic pain.

Methyltransferase METTL3 regulates neuropathic pain through m6A methylation modification of SOCS1.

The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1ß, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.

Electroacupuncture Relieves Neuropathic Pain via Adenosine 3 Receptor Activation in the Spinal Cord Dorsal Horn of Mice.

Neuropathic pain (NPP) is a devastating and unbearable painful condition. As prevailing treatment strategies have failed to mitigate its complications, there remains a demand for effective therapies. Electroacupuncture (EA) has proved a potent remedial strategy in NPP management in humans and mammals. However, past studies have investigated the underlying mechanism of the analgesic effects of EA on NPP, focusing primarily on adenosine receptors in peripheral tissues. Herein, we elucidate the role of the adenosine (Adora-3) signaling pathway in mediating pain relief through EA in the central nervous system, which is obscure in the literature and needs exploration. Specific pathogen-free (SPF) male adult mice (C57BL/6 J) were utilized to investigate the effect of EA on adenosine metabolism (CD73, ADA) and its receptor activation (Adora-3), as potential mechanisms to mitigate NPP in the central nervous system. NPP was induced via spared nerve injury (SNI). EA treatment was administered seven times post-SNI surgery, and lumber (L4-L6) spinal cord was collected to determine the molecular expression of mRNA and protein levels. In the spinal cord of mice, following EA application, the expression results revealed that EA upregulated (p < 0.05) Adora-3 and CD73 by inhibiting ADA expression. In addition, EA triggered the release of adenosine (ADO), which modulated the nociceptive responses and enhanced neuronal activation. Meanwhile, the interplay between ADO levels and EA-induced antinociception, using an Adora-3 agonist and antagonist, showed that the Adora-3 agonist IB-MECA significantly increased (p < 0.05) nociceptive thresholds and expression levels. In contrast, the antagonist MRS1523 exacerbated neuropathic pain. Furthermore, an upregulated effect of EA on Adora-3 expression was inferred when the Adora-3 antagonist was administered, and the EA treatment increased the fluorescent intensity of Adora-3 in the spinal cord. Taken together, EA effectively modulates NPP by regulating the Adora-3 signaling pathway under induced pain conditions. These findings enhance our understanding of NPP management and offer potential avenues for innovative therapeutic interventions.

Peripheral Neuropathic Pain.

OBJECTIVE: This article synthesizes current knowledge on neuropathic pain, with a brief review of mechanisms, diagnostic approaches, and treatment strategies to help neurologists provide effective and individualized care for patients with this complex condition. LATEST DEVELOPMENTS: The most promising developments in peripheral neuropathic pain are related to the molecular biology of the peripheral nervous system. Systematic molecular and genetic analyses of peripheral nerve terminals and dorsal root ganglia have advanced our understanding of the genetics of function and disease of peripheral nerves, as well as their physiology and clinical manifestations. ESSENTIAL POINTS: Peripheral neuropathic pain, similar to central neuropathic pain, is primarily influenced by the biology and pathophysiology of the underlying structures, peripheral sensory nerves, and their central pathways. The clinical course is widely variable in sensory symptoms and intensities, natural history, and response to treatments.

Central Neuropathic Pain.

OBJECTIVE: This article provides an approach to the assessment, diagnosis, and treatment of central neuropathic pain. LATEST DEVELOPMENTS: Recent studies of the pathophysiology of central neuropathic pain, including evidence of changes in the expression of voltage-gated sodium channels and N-methyl-d-aspartate (NMDA) receptors, may provide the basis for new therapies. Other areas of current research include the role of cannabinoid-receptor activity and microglial cell activation in various animal models of central neuropathic pain. New observations regarding changes in primary afferent neuronal activity in central neuropathic pain and the preliminary observation that peripheral nerve blocks may relieve pain due to central neuropathic etiologies provide new insights into both the mechanism and treatment of central neuropathic pain. ESSENTIAL POINTS: In the patient populations treated by neurologists, central neuropathic pain develops most frequently following spinal cord injury, multiple sclerosis, or stroke. A multimodal, individualized approach to the management of central neuropathic pain is necessary to optimize pain relief and may require multiple treatment trials to achieve the best outcome.

Neuromodulation for Neuropathic Pain Syndromes.

OBJECTIVE: This article reviews the principles, applications, and emerging trends of neuromodulation as a therapeutic approach for managing painful neuropathic diseases. By parsing evidence for possible mechanisms of action and clinical trial outcomes for various diseases, this article focuses on five common therapy modalities: cutaneous, peripheral nerve, spinal cord, and brain stimulation, and intrathecal drug delivery. LATEST DEVELOPMENTS: Recent advances in both invasive and noninvasive neuromodulation for pain have introduced personalized and closed-loop techniques, integrating real-time feedback mechanisms and combining therapies to improve physical and psychosocial function. Novel stimulation waveforms may influence distinct neural tissues to rectify pathologic pain signaling. ESSENTIAL POINTS: With appropriate patient selection, peripheral nerve stimulation or epidural stimulation of the spinal cord can provide enduring relief for a variety of chronic pain syndromes. Newer technology using high frequencies, unique waveforms, or closed-loop stimulation may have selective advantages, but our current understanding of therapy mechanisms is very poor. For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life. While many therapies are supported by data from large clinical trials, there is a risk of bias as most clinical studies were funded by device manufacturers or insurance companies, which increases the importance of real-world data analysis. Emerging methods like invasive or noninvasive brain stimulation may help us dissect basic mechanisms of pain processing and hold promise for personalized therapies for refractory pain syndromes. Finally, intrathecal delivery of drugs directly to segments of the spinal cord can also modify pain signaling to provide therapy for severe pain syndromes.

Opioids and Cannabinoids in Neurology Practice.

OBJECTIVE: Opioid and cannabinoid therapies for chronic pain conditions including neuropathic pain are controversial. Understanding patient and prescribing factors contributing to risks and implementing risk mitigation strategies optimizes outcomes. LATEST DEVELOPMENTS: The ongoing transformation from a biomedical model of pain care toward a biopsychosocial model has been accompanied by a shift away from opioid therapy for pain, in particular for chronic pain. Opioid overdose deaths and opioid use disorder have greatly increased in the last several decades, initially because of increases in opioid prescribing and more recently associated with illicit drug use, in particular fentanyl derivatives. Opioid risk mitigation strategies may reduce risks related to opioid prescribing and tapering or discontinuation. Opioid therapy guidelines from the Centers for Disease Control and Prevention have become the consensus best practice for opioid therapy. Regulatory agencies and licensing medical boards have implemented restrictions and other mandates regarding opioid therapy. Meanwhile, interest in and use of cannabinoids for chronic pain has grown in the United States. ESSENTIAL POINTS: Opioid therapy is generally not recommended for the chronic treatment of neuropathic pain conditions. Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions (such as postherpetic neuralgia), and only as part of a multimodal treatment regimen. Opioid risk mitigation strategies include careful patient selection and evaluation, patient education and informed consent, querying the state prescription drug monitoring programs, urine drug testing, and issuance of naloxone as potential rescue medication. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required. There is evidence for the efficacy of cannabinoids for neuropathic pain, with meaningful response rates in select patient populations.

CTRP9 attenuates peripheral nerve injury-induced mechanical allodynia and thermal hyperalgesia through regulating spinal microglial polarization and neuroinflammation mediated by AdipoR1 in male mice.

Peripheral nerve injury triggers rapid microglial activation, promoting M1 polarization within the spinal cord, which exacerbates the progression of neuropathic pain. C1q/TNF-related protein 9 (CTRP9), an adiponectin homolog, is known to suppress macrophage activation and exhibit anti-inflammatory properties through the activation of adiponectin receptor 1 (AdipoR1) in various disease contexts. Nevertheless, the involvement of CTRP9 in microglial polarization in the context of neuropathic pain is still unclear. Our study aimed to how CTRP9 influences spinal microglial polarization, neuroinflammation, and pain hypersensitivity, as well as the underlying mechanism, using a neuropathic pain model in male mice with spared nerve injury (SNI) of sciatic nerve. Our findings revealed SNI elevated the spinal CTRP9 and AdipoR1 levels in microglia. Furthermore, intrathecal administration of recombinant CTRP9 (rCTRP9) substantially weakened mechanical hypersensitivity and heat-related pain response triggered by SNI. On the other hand, rCTRP9 mediated a phenotypic switch in microglia, from the pro-inflammatory M1 state to the anti-inflammatory M2 state, by influencing the spinal AMPK/NF-κB mechanism in SNI mice. Additionally, treatment with AdipoR1 siRNA or an AMPK-specific antagonist both reversed the effects of CTRP9 on the phenotypic switching of spinal microglia and pain hypersensitivity. Collectively, these results indicate that CTRP9 ameliorates mechanical hypersensitivity and heat-related pain response, shifted the balance of microglia towards the anti-inflammatory M2 state, and suppresses neuroinflammatory responses by modulating the AMPK/NF-κB pathway, mediated by AdipoR1 activation, in mice with SNI.

Exploring the potential therapeutic benefits of 7-methoxy coumarin for neuropathy pain: an in vivo, in vitro, and in silico approach.

BACK GROUND: 7-Methoxycoumarin (7-MC) is well recognized for its anti-inflammatory and anti-nociceptive actions. Its capacity to lessen neuropathic pain hasn't been documented yet. Hence the impact of 7-MC on vincristine-induced peripheral neuropathic pain in rodents was investigated. The investigation also looked at the impact of 7-MC in reducing neuropathic pain via voltage-gated calcium channels and phospholipase enzyme inhibition using pertinent in vitro and in silico methods. METHODS AND RESULTS: Vincristine (0.1 mg/kg, i.p., daily) was administered continuously for 7 days to induce peripheral neuropathic pain in mice, with cold allodynia and thermal hyperalgesia and evaluated on the 8th day using the acetone bubble test and hot water tail immersion test. In order to derive the mechanistic approach for ameliorating neuropathic pain, the role of 7-MC in the inhibition of the phospholipase enzyme, gene expression studies on voltage-gated calcium channels using mouse BV2 microglial cells and in silico studies for its calcium channel binding affinity were also performed. The test compounds reduced vincristine-induced cold allodynia and thermal hyperalgesia in mice in a dose-dependent experiments. In vitro studies on phospholipase inhibition by 7-MC showed an IC50 of 27.08 µg/ml and down-regulated the gene expression of calcium channels in the BV2 microglial cell line. In silico docking scores for 7-MCwere higher than the standard drug gabapentin. CONCLUSION: The compound 7-MC has shown promise in alleviating vincristine-induced peripheral neuropathicin mice. Studies conducted in parallel, both in silico and in vitro have demonstrated that 7-MC effectively reduces neuropathic pain. This pain reduction is achieved through two mechanisms: inhibiting the phospholipase enzyme and blocking voltage-gated calcium channels.

Beneficial Effects of Ginger Root Extract on Pain Behaviors, Inflammation, and Mitochondrial Function in the Colon and Different Brain Regions of Male and Female Neuropathic Rats: A Gut-Brain Axis Study.

BACKGROUND: Neuroinflammation and mitochondrial dysfunction have been implicated in the progression of neuropathic pain (NP) but can be mitigated by supplementation with gingerol-enriched ginger (GEG). However, the exact benefits of GEG for each sex in treating neuroinflammation and mitochondrial homeostasis in different brain regions and the colon remain to be determined. OBJECTIVE: Evaluate the effects of GEG on emotional/affective pain and spontaneous pain behaviors, neuroinflammation, as well as mitochondria homeostasis in the amygdala, frontal cortex, hippocampus, and colon of male and female rats in the spinal nerve ligation (SNL) NP model. METHODS: One hundred rats (fifty males and fifty females) were randomly assigned to five groups: sham + vehicle, SNL + vehicle, and SNL with three different GEG doses (200, 400, and 600 mg/kg BW) for 5 weeks. A rat grimace scale and vocalizations were used to assess spontaneous and emotional/affective pain behaviors, respectively. mRNA gene and protein expression levels for tight junction protein, neuroinflammation, mitochondria homeostasis, and oxidative stress were measured in the amygdala, frontal cortex, hippocampus, and colon using qRT-PCR and Western blot (colon). RESULTS: GEG supplementation mitigated spontaneous pain in both male and female rats with NP while decreasing emotional/affective responses only in male NP rats. GEG supplementation increased intestinal integrity (claudin 3) and suppressed neuroinflammation [glial activation (GFAP, CD11b, IBA1) and inflammation (TNFα, NFκB, IL1ß)] in the selected brain regions and colon of male and female NP rats. GEG supplementation improved mitochondrial homeostasis [increased biogenesis (TFAM, PGC1α), increased fission (FIS, DRP1), decreased fusion (MFN2, MFN1) and mitophagy (PINK1), and increased Complex III] in the selected brain regions and colon in both sexes. Some GEG dose-response effects in gene expression were observed in NP rats of both sexes. CONCLUSIONS: GEG supplementation decreased emotional/affective pain behaviors of males and females via improving gut integrity, suppressing neuroinflammation, and improving mitochondrial homeostasis in the amygdala, frontal cortex, hippocampus, and colon in both male and female SNL rats in an NP model, implicating the gut-brain axis in NP. Sex differences observed in the vocalizations assay may suggest different mechanisms of evoked NP responses in females.

Negative allosteric modulator of Group â mGluRs: Recent advances and therapeutic perspective for neuropathic pain.

Neuropathic pain (NP) is a widespread public health problem that existing therapeutic treatments cannot manage adequately; therefore, novel treatment strategies are urgently required. G-protein-coupled receptors are important for intracellular signal transduction, and widely participate in physiological and pathological processes, including pain perception. Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are predominantly implicated in central sensitization, which can lead to hyperalgesia and allodynia. Many orthosteric site antagonists targeting Group I mGluRs have been found to alleviate NP, but their poor efficacy, low selectivity, and numerous side effects limit their development in NP treatment. Here we reviewed the advantages of Group I mGluRs negative allosteric modulators (NAMs) over orthosteric site antagonists based on allosteric modulation mechanism, and the challenges and opportunities of Group I mGluRs NAMs in NP treatment. This article aims to elucidate the advantages and future development potential of Group I mGluRs NAMs in the treatment of NP.

Exploring the Therapeutic Potential of N-Methyl-D-Aspartate Receptor Antagonists in Neuropathic Pain Management.

Neuropathic pain (NeP) is a complex and debilitating condition that impacts millions of people globally. Although various treatment options exist, their effectiveness is often limited, and they can be accompanied by significant side effects. In recent years, there has been increasing interest in targeting the N-methyl-D-aspartate receptor (NMDAR) as a potential therapeutic approach to alleviate different types of neuropathic pain. This narrative review aims to provide a comprehensive examination of NMDAR antagonists, specifically ketamine, memantine, methadone, amantadine, carbamazepine, valproic acid, phenytoin, dextromethorphan, riluzole, and levorphanol, in the management of NeP. By analyzing and summarizing current preclinical and clinical studies, this review seeks to evaluate the efficacy of these pharmacologic agents in providing adequate relief for NeP.

Surgical Outcomes of Spiral Vein Wrapping Flaps for Painful Neuromas: A Case Series Analysis.

BACKGROUND Neuropathic pain symptoms caused by neuromas impose physical burdens and affect patients mentally and socioeconomically. Surgical intervention offers more promising outcomes than do conservative approaches. An accessible and cost-effective surgical treatments is neuroma excision, coupled with nerve wrapping flaps. However, few reports have detailed the outcomes of this approach. In this study, we report 4 patients who underwent neuroma excision and nerve wrapping with vein autographs. CASE REPORT We present 4 patients who experienced persistent neuropathic pain and did not respond to conservative treatment for more than 6 months. Three patients had upper limb neuromas in continuity and 1 patient had a stump femoral neuroma. Surgical intervention involved neuroma excision, nerve grafting, and the application of nerve wrapping flaps at the site of anastomosis. Evaluation of our patients included neuroma pain scores and the Weber 2-point discrimination test. Follow-up assessments demonstrated significant clinical improvement, with all patients showing up to 60% reduction in pain and an average improvement of 5 mm in 2-point discrimination. No recurrence or need for further surgery was observed. CONCLUSIONS Surgical intervention was superior to conservative treatment in patients with painful neuromas. Nerve wrapping flaps, one of the surgical procedures for neuroma management, represents an effective surgical option for neuromas in continuity and stump neuromas. This is related to the more physiological nerve regeneration process when nerve ends are closed. The use of autograft veins as one of the materials for closing nerve ends is advantageous owing to its affordability and versatility in accommodating nerves of varying sizes.

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor.

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABAB) receptor-coupled CaV2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABAB receptor-coupled CaV2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatin-induced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

AB033. Factors related to neuropathic pain in spinal metastasis tumor patients experiencing cancer pain at Dr. Cipto Mangunkusumo Hospital.

BACKGROUND: Spinal metastatic tumors are a common complication in advanced cancer patients, frequently leading to debilitating pain that significantly impairs quality of life. Cancer-related pain can encompass various etiologies, including nociceptive and neuropathic components. Neuropathic pain, arising from nerve damage or dysfunction, presents unique challenges in terms of diagnosis and management. Despite its high prevalence in cancer patients, neuropathic pain often remains underrecognized and undertreated. This study aimed to determine the factors related to neuropathic pain in patients with spinal metastatic tumors who experience cancer pain. METHODS: This study used a retrospective cross-sectional to analyze cancer pain in patients with spinal metastatic tumors. It was conducted at Dr. Cipto Mangunkusumo Hospital using secondary data from January 2023 to January 2024. Prevalence data were calculated using the prevalence formula and expressed as percentages. Normality was assessed using the Kolmogorov-Smirnov test. Chi-square was employed for data management in groups with categorical scales, with Fisher's test used if the requirements for the chi-square test were not met. RESULTS: The study involved 82 patients with spinal metastatic tumors experiencing cancer pain, 51.2% were women. The patients' mean age was 51.5±12.5 years of these patients, 12.2% had lung tumors. The study findings indicate that a significant proportion (73.2%) of patients exhibited tumors with metastases in multiple locations, 61% in thoracal region with the majority (91.5%) experiencing moderate to severe pain intensity. Regarding pain characterization, 9.6% of patients reported neuropathic pain, 47.6% experienced mixed pain, and 42.2% had nociceptive pain. Data analysis found a significant proportion between pain onset (P=0.05), location of lesion (P=0.03), and pain intensity (P=0.01). CONCLUSIONS: This study shows patients with spinal metastatic tumors suffering pure neuropathic pain (9.6%) and mixed type pain (47.6%). Pain onset, location of lesion, and pain intensity were significantly different between types of pain. The high incidence of neuropathic pain and mixed pain serves as a crucial reference for treating patients with cancer pain.

MR-guided Focused Ultrasound Thalamotomy for Chronic Pain.

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.