Treatment Of Neuropathic Pain Research Articles

Features of diagnosis, treatment and curation of patients with neuropathic pain syndrome of traumatic genesis

BACKGROUND: The existing international and national clinical recommendations for the treatment of neuropathic pain syndrome are based mainly on the experience of providing care to patients with non-traumatic genesis of neuropathic pain. Approaches to the diagnosis, treatment and curation patients with neuropathic pain syndrome due damage of the nervous system as a result of wounds received during hostilities may differ from those in patients with somatic diseases.
 AIM: To systematize the features of medical care and improve the methodological approach of curation patients with traumatic neuropathic pain syndrome.
 MATERIALS AND METHODS: The practical experience of providing assistance to the wounded with traumatic lesions of the peripheral nervous system (including patients with phantom pain syndrome) accumulated by the staff of the Department and the Clinic of Nervous Diseases Military Medical Academy for 2022–2023 is summarized.
 RESULTS: The features of inpatient routing, diagnosis, treatment and organization of medical care for patients with traumatic neuropathic pain syndrome at the stage of a specialized medical institution are systematized. The practical aspects of the curation patients with neuropathic pain due to wounds received during hostilities, related to the appointment of medications (including narcotic analgesics), regional anesthesia and the provision of neurosurgical care are highlighted. A separate emphasis is placed on the importance of assessing the mental state and quality of sleep of the wounded with neuropathic pain syndrome, the features of drug correction identified disorders. Practical recommendations for the treatment of patients based on the results of assessing the severity neuropathic pain syndrome using a daily graphic pain diary are presented.
 CONCLUSION: The revealed differences in therapeutic and diagnostic approaches in providing medical care to the wounded with traumatic neuropathic pain syndrome, the importance of interdisciplinary interaction different specialties doctors (neurologists, surgeons, traumatologists, neurosurgeons, psychiatrists) at the early stages of treatment indicate the need to develop separate recommendations for the treatment of neuropathic pain in victims of armed conflicts.

Combined metabolomics and transcriptomics analysis of rats under neuropathic pain and pain-related depression.

Neuropathic pain often leads to negative emotions, which in turn can enhance the sensation of pain. This study aimed to investigate the molecular mechanisms mediating neuropathic pain and negative emotions. Chronic constriction injury (CCI) rats were used as model animals and behavioral tests were conducted to assess pain and negative emotions. Then, the rat anterior cingulate cortex (ACC) was analyzed using UPLC-MS/MS and subsequently integrated with our previously published transcriptome data. Metabolomics analysis revealed that 68 differentially expressed metabolites (DEMs) were identified, mainly in amino acid metabolites and fatty acyls. Combined with our previously published transcriptome data, we predicted two genes that potentially exhibited associations with these metabolites, respectively Apolipoprotein L domain containing 1 (Apold1) and WAP four-disulfide core domain 1 (Wfdc1). Taken together, our results indicated that peripheral nerve injury contributing to neuropathic pain and pain-related depression may be associated with these metabolites and genes. This research provides new insights into the molecular regulatory mechanism, which could serve as a reference for the treatment of neuropathic pain and pain-related depression.

Ropivacaine-loaded hydrogels for prolonged relief of chemotherapy-induced peripheral neuropathic pain and potentiated chemotherapy

Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

A randomized, double-blind, placebo-controlled study of histone deacetylase type 6 inhibition for the treatment of painful diabetic peripheral neuropathy.

Current treatments for painful diabetic peripheral neuropathy (DPN) are insufficiently effective for many individuals and do not treat nonpain signs and symptoms. The enzyme histone deacetylase type 6 (HDAC6) may play a role in the pathophysiology of painful DPN, and inhibition of HDAC6 has been proposed as a potential treatment. To assess the efficacy and safety of the novel HDAC6 inhibitor ricolinostat for the treatment of painful diabetic peripheral neuropathy. We conducted a 12-week randomized, double-blind, placebo-controlled phase 2 study of the efficacy of ricolinostat, a novel selective HDAC6 inhibitor, in 282 individuals with painful DPN. The primary outcome was the change in the patient-reported pain using a daily diary, and a key secondary outcome was severity of nonpain neuropathic signs using the Utah Early Neuropathy Scale (UENS) score. At the 12-week assessment, changes in average daily pain and UENS scores were not different between the ricolinostat and placebo groups. These results do not support the use of the HDAC6 inhibitor ricolinostat as a treatment for neuropathic pain in DPN for periods up to 12 weeks.

Enhancing post-operative analgesia following spinal cord stimulation implant: a comprehensive evaluation of the effectiveness of erector spinae plane block utilizing liposomal bupivacaine.

Erector spinae plane block (ESPB) is an inter-fascial plane block that provides multi-dermatomal analgesia for treatment of acute pain and chronic neuropathic pain in the trunk. This retrospective case series describes a novel method of treating acute postoperative pain after spinal cord stimulation implant with erector spinae plane block using liposomal bupivacaine. Bilateral erector spinae plane block was administered at L1-L2 intervertebral level in 18 cases prior to performing spinal cord stimulationimplant at one interspace above. This study reveals that the block provides effective analgesia as evidenced by low pain scores and less opioid consumption after surgery.

Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase with Tetrazole Core.

The attractive biological actions of the eicosatrienoic acids (EETs) and endocannabinoids (eCBs) are terminated by means of enzymatic hydrolysis via soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) enzymes. Simultaneous inhibition of both enzymes is considered a novel approach in the treatment of inflammatory and neuropathic pain. In this study, a novel series of tetrazole derivatives as dual sEH/FAAH inhibitors were designed, synthesized, and biologically evaluated. Compounds 6c, 7d, and 8a, the most potent inhibitors against FAAH and sEH enzymes with acceptable IC50 values, significantly decreased carrageenan- induced paw edema 5h after carrageenan injection compared to the control group compound. In addition, compound 7d exhibited a significant reduction in pain scores compared to the control group. Docking studies showed that the presented dual inhibitors could bind to the essential residues in the catalytic sites of both enzymes. In silico prediction of several pharmacokinetic properties suggests that these dual inhibitors could potentially be orally active agents. These structures will be a valuable scaffold to develop soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.

Treatment and assessment of neuropathic pain: Insights into clinical trial development

Treatment and assessment of neuropathic pain: Insights into clinical trial development

Patient and clinician beliefs about potential barriers to treatment of neuropathic pain for adolescents with sickle cell disease.

Pain is the hallmark symptom causing morbidity for people with sickle cell disease (SCD) and may present as nociceptive, neuropathic, or mixed type pain. Neuropathic pain (NP) is underrecognized and undertreated in patients with SCD and is associated with decreased patient-reported quality of life. Surveys were completed by clinicians caring for adolescents with SCD in the outpatient setting. SCD patients ages 1418 at increased risk of NP completed a patient-facing survey at a scheduled clinic visit. Ninety-four percent of responding clinicians agreed that NP significantly contributes to reported pain in SCD. Clinicians believed that NP medications are effective for reducing chronic pain (62%) and decreasing opioid utilization (44%). Clinician-identified barriers to prescribing NP medications included concerns about medication adherence (82%), lack of pediatric guidelines for NP medications (70%), and perceived patient concern about side effects (65%). More than 1/3 (35%) of clinicians reported that they were not comfortable managing NP medications. Clinician-identified barriers to referral to a pain management specialist included scheduling concerns (88%) and perceived patient/family lack of interest (77%). Most patients expressed willingness to take a medication for NP (78%), see a pain management specialist (84%), or learn more about nonpharmacologic interventions (72%), although most (51%) also reported some concerns about taking a medication for NP, citing insufficient knowledge (34%), and potential for side effects (32%). A minority of respondents (15%) worried about referral to a pain management specialist. Clinician and patient perspectives provide insights that may guide education efforts or other interventions to improve treatment of SCD-related NP.

Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats.

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant for the treatment of partial seizures and neuropathic pain. Whereas a majority of the side effects are associated with the nervous system, emerging evidence suggests there is a high risk of heart diseases in patients taking GBP. In the present study, we first used a preclinical model of rats to investigate, firstly, the acute cardiovascular responses to GBP (bolus i.v. injection, 50 mg/kg) and secondly the effects of chronic GBP treatment (i.p. 100 mg/kg/day × 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane anesthesia, rat blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics were measured using Millar pressure transducers. The LV myocardium and brain cortex were analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction. In the first experiment, we found that i.v. GBP significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (* p < 0.05 and ** p < 0.01 vs. baseline; n = 4). In the second experiment, we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium, we identified 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Notably, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function.

Virtual reality in the treatment of anxiety and chronic neuropathic pain. Preliminary study

Background: Pain and anxiety caused by prolonged treatment of neuropathic pain can result in discomfort for patients. Virtual Reality (VR) is a technology that is capable of entertaining and distracting the user. Among its many applications, we find the improvement of pain management and the reduction of anxiety in patients undergoing medical treatment. Objective: We aim to publish the protocol of a clinical trial for the reduction of pain and anxiety after a couple of VR sessions in patients with neuropathic pain that is difficult to treat. Methods: An observational, analytical, and prospective study was conducted. Virtual Reality (VR) was employed as a technique aimed at reducing pain and anxiety, twice a week for 30 days, as a complement to pharmacological treatment. Pain was assessed using the ‘Pain Detect’ questionnaire and the Visual Analog Scale (VAS), while anxiety was evaluated through the Goldberg Scale. Results: The preliminary results indicate that immersive virtual reality therapy is a promising alternative treatment for challenging-to-treat neuropathic pain. Without side effects, an appealing feature of VR therapy. Conclusion: Virtual reality can be a useful tool for patients who present with neuropathic pain that is resistant to conventional treatments that generate pain and anxiety.

Potential therapeutic application of probiotics in the treatment of neuropathic pain: A mechanistic aspects of brain-gut axis

The “gut-brain axis” or “brain-gut axis” communication mechanism has a bidirectional approach because it depends on showing top-down or bottom-up channels to function. It is one of the few systems in the body that combines neuronal routes with humoral pathways, which include cytokines, hormones, and neuropeptides as chemical messages. It was also discovered to be diverse because it contains spinal, vagus, sympathetic, and intestinal nerves. The role of microbes as signaling agents in the gut-brain axis has been proven by the most recent research, which is primarily based on animal models. Probiotics are living bacteria that improve one’s health when ingested in large enough doses. Gut microbes are suspected to play a role in a variety of psychiatric disorders, making them a potential therapeutic target. The stomach and the brain are linked via a two-way communication pathway called the microbiota-gut-brain axis. Current interventional research on probiotics and the gut-brain axis has been evaluated for its findings in the treatment of depression, anxiety, and schizophrenia. Neuropathic pain is brought on by a lesion or injury to the nerve system, which is further demonstrated by a malfunction of the somatosensory system. Such a developed form of pain affects both peripheral and central nervous system neurons. According to research, probiotics can enhance the gut’s dynamic environment and are good for both the gut and the brain. Therefore, the focus of this review is on how probiotics, the microbiota-gut-brain axis, and the gut-brain axis relate to neuropathic pain.

Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp.

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia.

Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood-brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms.

Microsurgical posterior fossa re-exploration for recurrent trigeminal neuralgia after previous microvascular decompression: common grounds—scarring, deformation, and the “piston effect”

ObjectiveMicrovascular decompression (MVD) is a well-accepted treatment modality for trigeminal neuralgia (TN) with high initial success rates. The causes for recurrence of TN after previously successful MVD have not been fully clarified, and its treatment is still a matter of debate. Here, we present the surgical findings and the clinical outcome of patients with recurrent TN after MVD who underwent posterior fossa re-exploration.MethodsMicrosurgical posterior fossa re-exploration was performed in 26 patients with recurrent TN (mean age 59.1 years) who underwent MVD over a period of 10 years. The trigeminal nerve was exposed, and possible factors for recurrent TN were identified. Arachnoid scars and Teflon granulomas were dissected meticulously without manipulating the trigeminal nerve. Outcome of posterior fossa re-exploration was graded according to the Barrow Neurological Institute (BNI) pain intensity score. Follow-up was analyzed postoperatively at 3, 12, and 24 months and at the latest available time point for long-term outcome.ResultsThe mean duration of recurrent TN after the first MVD was 20 months. Pain relief was achieved in all patients with recurrent TN on the first postoperative day. Intraoperative findings were as follows: arachnoid scar tissue in 22/26 (84.6%) patients, arterial compression in 1/26 (3.8%), venous contact in 8/26 (30.8%), Teflon granuloma in 14/26 (53.8%), compression by an electrode in Meckel’s cave used for treatment of neuropathic pain in 1/26 (3.8%), evidence of pulsations transmitted to the trigeminal nerve through the Teflon inserted previously/scar tissue (“piston effect”) in 15/26 (57.7%), and combination of findings in 18/26 (69.2%). At long-term follow-up (mean 79.5 months; range, 29–184 months), 21/26 (80.8%) patients had favorable outcome (BNI I-IIIa). New hypaesthesia secondary to microsurgical posterior fossa re-exploration occurred in 5/26 (19.2%) patients.ConclusionsPosterior fossa re-exploration avoiding manipulation to the trigeminal nerve, such as pinching or combing, may be a useful treatment option for recurrent TN after previously successful MVD providing pain relief in the majority of patients with a low rate of new hypaesthesia.

Pharmacological and computational evaluation of an isoxazolone derivative for mitigating cisplatin-induced neuropathic pain

Cisplatin-induced neuropathic pain poses a significant clinical challenge. This study induced neuropathy via cisplatin treatment, measuring pain levels through mechanical threshold and thermal escape latency. Isoxazolone derivatives were administered at doses of 20, 40, and 60 mg/kg to evaluate their effects on allodynia and pregabalin, a known therapeutic agent, was used for comparison. Place preference tests were conducted to gauge responses, while molecular docking and dynamic simulations assessed the binding affinity for relevant receptors. Results showed that cisplatin-induced neuropathy by day four, with reduced mechanical threshold and sustained thermal escape latency for eight days. Isoxazolone derivatives at 20 mg/kg and 40 mg/kg effectively reversed allodynia, while 60 mg/kg showed limited impact. Pregabalin exhibited similar effects, though less significance after day 10. Place preference tests demonstrated positive responses to both isoxazolone derivatives and pregabalin in allodynic rats. Molecular docking analysis highlighted strong binding to receptors, particularly cyclooxygenase-2 (Cox-2), Tumor Necrosis Factor (TNF)-α. Binding free energies indicated potent inhibitory activity of isoxazolone derivatives against Cox-2 and TNF-α. This study underscores the potential of isoxazolone derivatives as therapeutic agents for cisplatin-induced mechanical allodynia, with innovative implication for neuropathic pain treatment. Further research and validation are necessary to confirm their therapeutic efficacy and safety for human clinical use.

Evaluation of trans- and cis-4-[18F]Fluorogabapentin for Brain PET Imaging.

Gabapentin, a selective ligand for the α2δ subunit of voltage-dependent calcium channels, is an anticonvulsant medication used in the treatment of neuropathic pain, epilepsy, and other neurological conditions. We recently described two radiofluorinated derivatives of gabapentin (trans-4-[18F]fluorogabapentin, [18F]tGBP4F, and cis-4-[18F]fluorogabapentin, [18F]cGBP4F) and showed that these compounds accumulate in the injured nerves in a rodent model of neuropathic pain. Given the use of gabapentin in brain diseases, here we investigate whether these radiofluorinated derivatives of gabapentin can be used for imaging α2δ receptors in the brain. Specifically, we developed automated radiosynthesis methods for [18F]tGBP4F and [18F]cGBP4F and conducted dynamic PET imaging in adult rhesus macaques with and without preadministration of pharmacological doses of gabapentin. Both radiotracers showed very high metabolic stability, negligible plasma protein binding, and slow accumulation in the brain. [18F]tGBP4F, the isomer with higher binding affinity, showed low brain uptake and could not be displaced, whereas [18F]cGBP4F showed moderate brain uptake and could be partially displaced. Kinetic modeling of brain regional time-activity curves using a metabolite-corrected arterial input function shows that a one-tissue compartment model accurately fits the data. Graphical analysis using Logan or multilinear analysis 1 produced similar results as compartmental modeling, indicating robust quantification. This study advances our understanding of how gabapentinoids work and provides an important advancement toward imaging α2δ receptors in the brain.

Focused Ultrasound Central Lateral Thalamotomy for the Treatment of Refractory Neuropathic Pain: Phase I Trial.

Magnetic resonance-guided focused ultrasound (MRgFUS) central lateral thalamotomy (CLT) has not yet been validated for treating refractory neuropathic pain (NP). Our aim was to assess the safety and potential efficacy of MRgFUS CLT for refractory NP. In this prospective, nonrandomized, single-arm, investigator-initiated phase I trial, patients with NP for more than 6 months related to phantom limb pain, spinal cord injury, or radiculopathy/radicular injury and who had undergone at least one previous failed intervention were eligible. The main outcomes were safety profile and pain as assessed using the brief pain inventory, the pain disability index, and the numeric rating scale. Medication use and the functional connectivity of the default mode network (DMN) were also assessed. Ten patients were enrolled, with nine achieving successful ablation. There were no serious adverse events and 12 mild/moderate severity events. The mean age was 50.9 years (SD: 12.7), and the mean symptom duration was 12.3 years (SD: 9.7). Among eight patients with a 1-year follow-up, the brief pain inventory decreased from 7.6 (SD: 1.1) to 3.8 (SD: 2.8), with a mean percent decrease of 46.3 (SD: 40.6) (paired t -test, P = .017). The mean pain disability index decreased from 43.0 (SD: 7.5) to 25.8 (SD: 16.8), with a mean percent decrease of 39.3 (SD: 41.6) ( P = .034). Numeric rating scale scores decreased from a mean of 7.2 (SD: 1.8) to 4.0 (SD: 2.8), with a mean percent decrease of 42.8 (SD: 37.8) ( P = .024). Patients with predominantly intermittent pain or with allodynia responded better than patients with continuous pain or without allodynia, respectively. Some patients decreased medication use. Resting-state functional connectivity changes were noted, from disruption of the DMN at baseline to reactivation of connectivity between DMN nodes at 3 months. MRgFUS CLT is feasible and safe for refractory NP and has potential utility in reducing symptoms as measured by validated pain scales.

Commentary: Focused Ultrasound Central Lateral Thalamotomy for the Treatment of Refractory Neuropathic Pain: Phase I Trial.

Commentary: Focused Ultrasound Central Lateral Thalamotomy for the Treatment of Refractory Neuropathic Pain: Phase I Trial.

Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model

Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of β-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment.

Gabapentinoids for the treatment of stroke.

Gabapentinoid drugs (pregabalin and gabapentin) have been successfully used in the treatment of neuropathic pain and in focal seizure prevention. Recent research has demonstrated their potent activities in modulating neurotransmitter release in neuronal tissue, oxidative stress, and inflammation, which matches the mechanism of action via voltage-gated calcium channels. In this review, we briefly elaborate on the medicinal history and ligand-binding sites of gabapentinoids. We systematically summarize the preclinical and clinical research on gabapentinoids in stroke, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, seizures after stroke, cortical spreading depolarization after stroke, pain after stroke, and nerve regeneration after stroke. This review also discusses the potential targets of gabapentinoids in stroke; however, the existing results are still uncertain regarding the effect of gabapentinoids on stroke and related diseases. Further preclinical and clinical trials are needed to test the therapeutic potential of gabapentinoids in stroke. Therefore, gabapentinoids have both opportunities and challenges in the treatment of stroke.