HCN channels in the lateral habenula regulate pain and comorbid depressive-like behaviors in mice.

AIMS: Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain. METHODS: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms. RESULTS: Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors. CONCLUSION: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.

Perspectives of people with spinal cord injury on a pain education resource.

Introduction: Spinal cord injury (SCI) often leads to neuropathic pain that negatively affects quality of life. Several qualitative research studies in individuals with SCI who experience neuropathic pain indicate the lack of adequate information about pain. We previously developed an educational resource, the SeePain, based on scientific literature and a series of qualitative interviews of people with SCI, their significant others/family members, and SCI healthcare providers. Methods: However, to quantitatively evaluate the utility of this educational resource in a larger sample, we examined the agreement and usefulness ratings of statements regarding clarity/comprehensibility, content, and format of the SeePain, derived from the thematic analysis of our previous qualitative interviews. Participants completed a survey that provided a digital version of the SeePain and then rated their agreement/usefulness with the statements using numerical rating scales. Results: There were overall high perceived agreement and usefulness ratings regarding the SeePain's clarity, content, and format. A factor analysis reduced the agreement and usefulness ratings into 4 components (content, clarity, format, and delivery medium). Group comparisons showed that individuals with higher education were more likely to endorse electronic and website formats, and the usefulness of a shorter version of the SeePain; females and younger individuals showed greater endorsement for clarity. Finally, higher pain intensity ratings were associated with greater agreement and usefulness of the content of the SeePain. Discussion: Overall, these results support the utility of the SeePain as a source of information regarding pain that may facilitate communication about pain and its management following SCI.

New Insight into Neuropathic Pain: The Relationship between α7nAChR, Ferroptosis, and Neuroinflammation.

Neuropathic pain, which refers to pain caused by a lesion or disease of the somatosensory system, represents a wide variety of peripheral or central disorders. Treating neuropathic pain is quite demanding, primarily because of its intricate underlying etiological mechanisms. The central nervous system relies on microglia to maintain balance, as they are associated with serving primary immune responses in the brain next to cell communication. Ferroptosis, driven by phospholipid peroxidation and regulated by iron, is a vital mechanism of cell death regulation. Neuroinflammation can be triggered by ferroptosis in microglia, which contributes to the release of inflammatory cytokines. Conversely, neuroinflammation can induce iron accumulation in microglia, resulting in microglial ferroptosis. Accumulating evidence suggests that neuroinflammation, characterized by glial cell activation and the release of inflammatory substances, significantly exacerbates the development of neuropathic pain. By inhibiting microglial ferroptosis, it may be possible to prevent neuroinflammation and subsequently alleviate neuropathic pain. The activation of the homopentameric α7 subtype of the neuronal nicotinic acetylcholine receptor (α7nAChR) has the potential to suppress microglial activation, transitioning M1 microglia to an M2 phenotype, facilitating the release of anti-inflammatory factors, and ultimately reducing neuropathic pain. Recent years have witnessed a growing recognition of the regulatory role of α7nAChR in ferroptosis, which could be a potential target for treating neuropathic pain. This review summarizes the mechanisms related to α7nAChR and the progress of ferroptosis in neuropathic pain according to recent research. Such an exploration will help to elucidate the relationship between α7nAChR, ferroptosis, and neuroinflammation and provide new insights into neuropathic pain management.

CBP Expression Contributes to Neuropathic Pain via CREB and MeCP2 Regulation in the Spared Nerve Injury Rat Model.

Background and Objectives: This study aimed to investigate the relationship between neuropathic pain and CREB-binding protein (CBP) and methyl-CpG-binding protein 2 (MeCP2) expression levels in a rat model with spared nerve injury (SNI). Materials and Methods: Rat (male Sprague-Dawley white rats) models with surgical SNI (n = 6) were prepared, and naive rats (n = 5) were used as controls. The expression levels of CBP and MeCP2 in the spinal cord and dorsal root ganglion (DRG) were compared through immunohistochemistry at 7 and 14 days after surgery. The relationship between neuropathic pain and CBP/MeCP2 was also analyzed through intrathecal siRNA administration. Results: SNI induced a significant increase in the number of CBPs in L4 compared with contralateral DRG as well as with naive rats. The number of MeCP2 cells in the dorsal horn on the ipsilateral side decreased significantly compared with the contralateral dorsal horn and the control group. SNI induced a significant decrease in the number of MeCP2 neurons in the L4 ipsilateral DRG compared with the contralateral DRG and naive rats. The intrathecal injection of CBP siRNA significantly inhibited mechanical allodynia induced by SNI compared with non-targeting siRNA treatment. MeCP2 siRNA injection showed no significant effect on mechanical allodynia. Conclusions: The results suggest that CBP and MeCP2 may play an important role in the generation of neuropathic pain following peripheral nerve injury.

Dysfunction of Small-Conductance Ca2+-Activated Potassium (SK) Channels Drives Amygdala Hyperexcitability and Neuropathic Pain Behaviors: Involvement of Epigenetic Mechanisms.

Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we addressed the role of small-conductance Ca2+-activated potassium (SK) channels in pain-related amygdala plasticity. The facilitatory effects of the intra-CeA application of an SK channel blocker (apamin) on the pain behaviors of control rats were lost in a neuropathic pain model, whereas an SK channel activator (NS309) inhibited pain behaviors in neuropathic rats but not in sham controls, suggesting the loss of the inhibitory behavioral effects of amygdala SK channels. Brain slice electrophysiology found hyperexcitability of CeA neurons in the neuropathic pain condition due to the loss of SK channel-mediated medium afterhyperpolarization (mAHP), which was accompanied by decreased SK2 channel protein and mRNA expression, consistent with a pretranscriptional mechanisms. The underlying mechanisms involved the epigenetic silencing of the SK2 gene due to the increased DNA methylation of the CpG island of the SK2 promoter region and the change in methylated CpG sites in the CeA in neuropathic pain. This study identified the epigenetic dysregulation of SK channels in the amygdala (CeA) as a novel mechanism of neuropathic pain-related plasticity and behavior that could be targeted to control abnormally enhanced amygdala activity and chronic neuropathic pain.

Motor disorders related to oxaliplatin-induced peripheral neuropathy: long-term severity and impact on quality of life.

PURPOSE: Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. METHODS: Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5 years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). RESULTS: Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. CONCLUSION: The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. TRIAL REGISTRATION: NCT02970526 (2016-11-22). https://classic. CLINICALTRIALS: gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

[Features of course of pain syndrome in patients with schwannomatosis]. / Osobennosti techeniya bolevogo sindroma u patsientov s shvannomatozami.

OBJECTIVE: To identify the characteristics of pain syndrome in patients with schwannomas depending on genetic predisposition. MATERIAL AND METHODS: The study included 46 patients with peripheral, spinal and intracranial schwannomas, corresponding to the schwannomatosis phenotype according to the 2022 clinical criteria. All patients underwent sequencing of the LZRT1, Nf2 and SMARCB1 and a copy number study in the NF2. RESULTS: The most severe widespread pain was observed in patients with pathogenic LZRT1 variants, while patients with mosaic variants may not even have local tumor-related pain. Patients with SMARCB1variants may have no pain or have localized pain that responds well to surgical treatment. CONCLUSION: Further studies of the molecular features of schwannomatosis and driver mutations in the pathogenesis of pain are necessary to improve the effectiveness of pain therapy in this group of patients. Schwannomatosis is a disease from the group of neurofibromatosis, manifested by the development of multiple schwannomas. Neuropathic pain is one of the main symptoms characteristic of peripheral schwannomas, however, the severity and prevalence of the pain syndrome does not always correlate with the location of the tumors. According to modern concepts, the key factors influencing the characteristics of the pain syndrome are the target gene and the type of pathogenic variant. The most severe widespread pain is observed in patients with pathogenic variants in the LZRT1 gene, while patients with mosaic variants may not even have local pain associated with tumors. Patients with variants in SMARCB1 may have no pain or localized pain that responds well to surgical treatment.

DN4 questionnaire as a useful tool for evaluating the pharmacotherapeutic response to opioid pharmacotherapy in malignant neuropathy.

Objective: Tapentadol is a drug of choice for neuropathic cancer pain. DN4 questionnaire quickly determines neuropathic pain component. The aim of this study is to determine the correlation between neuropathic malignant pain component by applying tapentadol antidolorose pharmacotherapy in combination with palliative radiotherapy of osseous neuropathic metastatic changes in breast cancer patients before and after palliative radiotherapy. Methods: The first patients group comprised 30 patients with primary breast cancer and proved painful bone secondary deposits with neuropathy for which tapentadol was prescribed, and they underwent palliative radiotherapy. The second group comprised 30 patients with primary breast cancer and proved painful bone metastases with neuropathy treated only with palliative antidolorose radiotherapy. Key findings : After two-months-follow up, tapentadol group patients had lower DN4 score values (Z=2,021; p=0.043). Significantly lower number of tapentadol group patients was without neuropathic pain after a three-month-follow up (χ ²=5,711; p=0.017). Significantly greater number of tapentadol group patients had best ECOG score 0 ( χ² =7,486; p=0.023). There was statistically significant positive correlation between tapentadol dose and DN4 score in patients after a month (ρ=0,471; p=0.009) and three months after the radiotherapy completion (ρ=0,610; p<0.001). Tapentadol is an opioid analgesic efficient for neuropathy relief in these patients and DN4 questionnaire is an efficient pharmacotherapy tool.

Minocycline Abrogates Individual Differences in Nerve Injury-Evoked Affective Disturbances in Male Rats and Prevents Associated Supraspinal Neuroinflammation.

Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.

Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.

BACKGROUND: Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. METHODS: We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. RESULTS: Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1ß and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. CONCLUSIONS: Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.

Spinal nerve ligation: An experimental model to study neuropathic pain in rats and mice.

Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.

6-Methoxyflavone antagonizes chronic constriction injury and diabetes associated neuropathic nociception expression.

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.

ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain.

Peripheral nerve injury-induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.

[The intensity of neuropathic pain and the severity of insomnia in diabetic polyneuropathy]. / Intensivnost' neiropaticheskoi boli i tyazhest' insomnii pri diabeticheskoi polineiropatii.

OBJECTIVE: To determine the prevalence of insomnia and the effectiveness of its treatment in patients with a painful form of diabetic polyneuropathy (DPN). MATERIAL AND METHODS: Fifty patients with the painful form of DPN were randomly divided into 2 groups: the standard therapy group (ST) and the extended therapy group (ET). In the ST group, a single lesson on sleep hygiene was conducted, in the ET group there were 3-4 face-to-face individual sessions for the treatment of insomnia for two weeks. Both groups were interviewed at the time of hospitalization, after 3 and 6 months. The severity of polyneuropathy and the nature of neuropathic pain were assessed using the Neuropathic Neuropathy Impairment Score in the Lower Limbs (NIS-LL) and the Neuropathy Total Symptom Score - 9 (NTSS-9); the intensity of pain was assessed using a Visual Analog Scale (VAS). Sleep disorders were analyzed using the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI). RESULTS: Sleep disorders of varying severity were observed in 82% of patients in the initial survey. In both groups, improvement in sleep quality was noted during treatment, but significantly better results were in the ET group, the ISI score after 6 months was 7.15±2.08 for the ST group and 3.07±2.49 for the ET group (p<0.0001). In the ST group, there was no significant decrease in the intensity of pain and the severity of polyneuropathy in dynamics. In the ET group, a significant decrease in NTSS-9 and VAS scores was found during the initial survey and after 6 months (p<0.0001). The intensity of pain also significantly decreased in the ET group compared with the ST group (p<0.0001) at the end of follow-up, which indicates the importance of sleep normalization in the treatment of neuropathic pain. CONCLUSION: Most patients with the painful form of DPN have insomnia. Treatment of insomnia has shown its effectiveness as part of a multimodal approach to the managing of neuropathic pain in DPN and improving the quality of life of patients.

The role of spinal neurons targeted by corticospinal neurons in central poststroke neuropathic pain.

BACKGROUND: Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood. METHODS: By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology. RESULTS: We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP. CONCLUSION: The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.

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

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

MiR-503-5p alleviates peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 to inhibit astrocyte activation.

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.

Treatment of chronic mini-thoracotomy wound pain and lung herniation with intercostal cryoablation and surgical mesh repair: a case report.

BACKGROUND: The incidence of minimally invasive heart surgery via mini-thoracotomy (MT; right anterior thoracotomy) is on the rise, accompanied by an increase in post-MT intercostal nerve neuralgia and the risk of lung herniation through the incision site. While various methods have been proposed to address these issues, none have been commonly effective. In this case report, we attempted to simultaneously address these problems by performing intercostal cryoablation (IC) and mesh repair. CASE PRESENTATION: A 43-year-old male was referred to our hospital for chronic post-thoracotomy neuralgia following heart surgery via MT, involving patch closure of an atrial septal defect and tricuspid annuloplasty. He presented with intercostal nerve neuralgia and lung herniation accompanied by severe pain. Despite medication and lidocaine injections, there was no relief. Consequently, he underwent surgical treatment with IC for chronic MT wound pain and simultaneously underwent mesh repair for a lung hernia. He was discharged from hospital free of complications. Subsequently, he no longer required further pain medication and experienced a favorable recovery. CONCLUSION: Our findings suggest that concurrent IC and mesh repair can effectively relieve chronic post-MT intercostal nerve neuralgia and severe lung herniation pain in patients who underwent MT surgery, leading to a decrease in opioid medication usage.

Current trends in the medical treatment of neuropathic low back pain: a Swedish registry-based study of 1.7 million people.

BACKGROUND: Low back pain, a common problem worldwide, causes more global disability than any other condition and is associated with high costs to society. This observational registry-based study describes the current trends in the medical treatment of neuropathic low back pain in the Swedish region of Västra Götaland, which has a population of 1.7 million. The study aims to; (1) identify the prevalence of neuropathic low back pain within the study population; (2) to explore the patterns of medical treatment utilization, including the prevalence and distribution of opioids (OG) and analgesics specified for neuropathic low back pain (NG) and (3) to evaluate the long-term trends and changes in medical treatment practice for neuropathic low back pain over the study period. METHODS: This study includes a descriptive analysis of aggregated data extracted from the Swedish primary care registry VEGA and the pharmaceutical prescription registry Digitalis between the years 2017 and 2021. The data were stratified by year, age, gender, pharmaceutical code (ATC), and sub-diagnoses and presented as the prevalence of unique patients retrieving prescribed medication within six months before or after a registered diagnosis of neuropathic low back pain. The pharmaceutical codes were furthermore grouped into two groups depending on their mechanism of action; opioid group (OG) and neuropathic group (NG). RESULTS: In all four diagnosis groups, more patients used opioid analgesics than neuropathic analgesics. The greatest difference between the opioid group and neuropathic group was in the lumbar spinal stenosis diagnosis group (67.1% vs. 40.6%), followed by the lumbar root canal stenosis diagnosis (65.9% vs. 44.2%), the nerve root and plexus compressions in intervertebral disc disorders diagnosis (57.5% vs. 40.8%), and lumbago with sciatica diagnosis (38.4% vs. 22.7%). CONCLUSIONS: The trends suggest a general increase in the prescription rate and therefore patients' use of neuropathic analgesics for neuropathic pain associated with the studied diagnoses. However, opioid treatment remains the most common. The results indicate that the treatment for neuropathic low back pain needs to be improved.