Rosacea is a prevalent skin disorder in which neurogenic inflammation plays a significant role in its pathogenesis. Gabapentin (GBP) has garnered attention as a therapeutic option; however, its precise mechanism of action in treating rosacea remains unclear. Through a comprehensive analysis of experimental and clinical data, the research team has elucidated the molecular mechanism by which GBP inhibits neurogenic inflammation, particularly through modulating the NF-κB signaling pathway to alleviate rosacea inflammation. Using a murine rosacea model induced by LL37, the efficacy of GBP was compared to Minocycline and Hydroxychloroquine combination therapy. Various techniques assessed marker expression, transcriptomic profiles, and in vitro cell experiments with BV2 cells. Clinical data from 60 rosacea patients were analyzed through a randomized trial, comparing GBP therapy to the combination treatment. Results showed GBP effectively reduced skin inflammation and facial redness in mice and patients. Metabolomic analysis indicated significant changes in metabolites post-GBP treatment, correlating with inflammatory factors. The study concludes that GBP mitigates rosacea progression by targeting neurogenic inflammation via NF-κB pathway regulation, shedding light on novel treatment mechanisms through transcriptomics and metabolomics for future clinical application in rosacea research.

A 9-year-old Toy Poodle presented with sudden hypersalivation, vomiting, and retching unresponsive to symptomatic treatment. One month later, the mandibular salivary glands were enlarged and painful. Additional signs included weight loss, intermittent stiffness and tremors, and a fly-biting behavior, which is atypical for this disease. Magnetic resonance imaging revealed bilateral enlargement of the parotid and mandibular glands. Oral phenobarbital (PB) led to marked improvement, confirming phenobarbital-responsive sialadenosis. Residual hypersalivation and retching almost completely resolved within 24 hr after gabapentin (GBP) addition, with only mild hypersalivation (about 10% of the initial level) remaining. No recurrence was observed during a 3-year follow-up, during which PB (3.6 mg/kg administered orally twice daily [PO BID]) and GBP (15 mg/kg PO BID) were continued at the same doses.

Engineering Fe-doped carbon-based nanozyme from novel source for chemiluminescence/colorimetric dual-mode microplate sensing of the anticancer drug raloxifene in different matrices.

The heterogeneity and treatment resistance of glioblastoma (GBM) can be addressed through multidrug combination therapies that target multiple biological pathways simultaneously. In this study, we explored the repurposing of antiepileptic drugs with potential antitumor effects, combined with the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) inhibitor ruxolitinib (RUX), as an alternative local therapeutic approach for GBM. The cytotoxic effects of valproic acid (VPA), oxcarbazepine (OXC), and gabapentin (GBP) were evaluated on A172 and U251 GBM cells. Both VPA and OXC significantly reduced cell viability, prompting further investigation of their effects in combination with RUX. When tested in 3-dimensional multicellular tumorspheres, the combinations at their IC50 exhibited suboptimal effectiveness compared with single-agent treatment. Using a factorial experimental design based on a minimal combination approach to analyze dose-response data, followed by subsequent Bliss synergy analysis, synergistic interactions were revealed exclusively for RUX + VPA on A172 cells. Although the interaction between RUX and OXC was additive, GBM cells displayed increased sensitivity to this combination, suggesting potential therapeutic value. Ultimately, the most effective drug ratios were assessed using live/dead cell fluorescence staining in 3-dimensional multicellular tumorspheres. The variable treatment response observed among GBM cell lines underscores the need for personalized treatment strategies tailored to the specific molecular profile of individual tumors. SIGNIFICANCE STATEMENT: Given the unmet needs in glioblastoma treatment, the study explores novel combinations of Janus kinase/signal transducer and activator of transcription-3 inhibitor ruxolitinib and antiepileptics for local codelivery, aiming to overcome resistance and heterogeneity through synergistic effects and sustained release via molecularly imprinted reservoirs.

We aimed to synthesise carbon quantum dots (CQDs) from the active molecule gabapentin (GBP) and to evaluate their effects on pentylenetetrazol (PTZ)-induced seizures in rats. Gabapentin CQDs (GBPCQDs) were synthesised using a rapid, one-pot microwave-assisted method and characterised by particle size, polydispersity index, zeta potential and fluorescence properties. Adult male Wistar rats received GBP or GBPCQDs (15, 30, 60 or 120 mg/kg, intraperitoneally) 30 min before PTZ administration (50 mg/kg). Seizure onset times and severity were assessed, and locomotor activity was evaluated at the most effective doses. While GBP did not significantly affect seizure onset, GBPCQDs at 15 mg/kg significantly prolonged the onset time of PTZ-induced seizures. Both GBP and GBPCQDs significantly reduced seizure severity at all tested doses, however, GBPCQDs at 60 and 120 mg/kg were more effective than the corresponding doses of GBP. Neither treatment produced significant changes in locomotor activity. Fluorescence imaging demonstrated the presence of GBPCQDs in the prefrontal cortex, striatum and hippocampus, with the highest fluorescence intensity observed in the prefrontal cortex. These findings indicate that GBPCQDs may provide therapeutic advantages over conventional GBP and represent a promising fluorescent nanocarrier for brain-targeted drug delivery in epilepsy.

Neuropathic pain (NP), a chronic and debilitating condition resulting from nerve injury, remains a significant clinical challenge due to limited effective therapies. Ethyl gallate (EG), a natural ester of gallic acid, possesses potent antioxidant and antiinflammatory properties; however, its role in NP management has not been previously explored. This study investigated the neuroprotective potential of EG in a chronic constriction injury (CCI)-induced NP model in rats. EG was administered intraperitoneally at doses of 10, 15, and 20 mg/kg/day for 14 days. Behavioral assessments, including thermal hyperalgesia, mechanical allodynia, and motor nerve conduction velocity (MNCV), were performed. Biochemical evaluations, such as oxidative stress markers (SOD, GSH, catalase, MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were conducted. Histopathological analysis of the sciatic nerve was performed to assess structural integrity. Additionally, molecular docking was employed to evaluate the binding interactions of EG with key redox and inflammatory regulators, Nrf2 and NF-κB, in comparison with the standard drug gabapentin (GBP). EG significantly alleviated CCI-induced pain behaviors, demonstrated by increased paw withdrawal latency, enhanced mechanical threshold, and improved MNCV. EG treatment restored antioxidant enzyme activities and reduced MDA levels, indicating decreased oxidative stress. Additionally, EG markedly lowered pro-inflammatory cytokine levels. Histological findings revealed preserved nerve fiber integrity and reduced structural damage in EG-treated groups. Molecular docking revealed stronger binding affinity of EG (-6.8 kcal/mol with Nrf2; -5.1 kcal/mol with NF-κB) compared to GBP (-5.9 kcal/mol and -4.3 kcal/mol, respectively), supporting its potential mechanistic role in modulating oxidative stress and inflammatory pathways. These results suggest that EG mitigates NP symptoms by modulating oxidative stress and inflammation. Its ability to enhance endogenous antioxidant defenses and suppress pro-inflammatory responses underlies its neuroprotective action. EG demonstrates promising therapeutic potential in the management of NP through its antioxidant, anti-inflammatory, and neuroprotective properties. Further molecular studies are warranted to elucidate its underlying mechanisms.

IntroductionNeuropathic pain distinguishes itself from nociceptive pain not only in its etiology and clinical presentation but also in its limited responsiveness to non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics. Gabapentin and pregabalin, collectively referred to as gabapentinoids, are anticonvulsant agents that have demonstrated efficacy in managing neuropathic pain. Evidence supports their use in comparison to placebo or antidepressants, such as tricyclic antidepressants, for the treatment of neuropathic pain. However, despite extensive investigation, there remains a paucity of conclusive data and often contradictory findings regarding the relative superiority of one drug over the other, particularly in resource-constrained settings and including the practicality of the money spent.AimThe aim of the study is to evaluate and compare the efficacy, safety parameters and cost-effectiveness of gabapentin (GB) and pregabalin (PG) in neuropathic pain.MethodsA randomized double-blind comparative study was conducted to evaluate the effectiveness of GB and PG in the treatment of neuropathic pain, involving 60 patients attending the Neurology outpatient department (OPD) at Sri Ramachandra Institute of Higher Education and Research, Chennai. The participants were equally divided into two groups: Group A received GB and Group B received PG. Both groups were followed up regularly at four, eight, and 12 weeks. From day 0, doses were titrated according to the response and side effects, costs were noted down at each visit and pain was assessed using the Visual Analog Scale (VAS) and the McGill Pain Questionnaire.ResultsBoth GB and PG demonstrate significant effectiveness in improving the symptoms of the patients after three months of treatment (2.5±0.9 for PG vs. 4.5±1.3 for GB, p<0.001) according to VAS, with a similar result when analysed with the McGill Pain Questionnaire. PG also has the advantages in terms of statistical results and evidence along with fewer reported adverse effects and better patient compliance.Cost evaluation indicated that the cumulative expense for PG over three months was INR 1,286 compared to INR 3,420 for GB, even with dose adjustments. Moreover, PG demonstrated a 75% reduction in cost per VAS point and a 72% decrease in cost per McGill point, highlighting its greater cost-effectiveness along with improved clinical results.ConclusionThis randomized prospective study provides a comparison of the efficacy and safety of GB and PG in neuropathic pain, while throwing light into health economic part by including cost analysis. Such comparisons, including expense analysis, are limited in the literature. Our study plays a role in substantiating PG as a better analgesic in many respects for neuropathic pain while also proposing a possibility for evaluating combination therapies and to provide an optimize healthcare resource allocation.

A series of azo-linked pyrazolophthalazine-5,10-diones (APPDs) were synthesized via multicomponent reaction of phthalic anhydride, synthetized azo-aldehyde, malononitrile, and hydrazine hydrate using the gabapentin (GBP) functionalized silica coated Fe3O4 magnetic nano composites (MT@SP@GBP MNCs) as a catalyst. All derivatives were characterized by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. MT@SP@GBP MNCs was characterized by FT-IR, FE-SEM, TEM, TGA, XRD, EDX and VSM.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-19325-8.

Effects of naltrexone on gabapentin reward and buprenorphine combinations in male mice.

The presence of pharmaceuticals in water poses emerging environmental risks to aquatic ecosystems and potentially human health. This study investigates the occurrence and ecological threat of antiepileptic drugs and lipid-lowering agents in surface water, specifically in the Cauca River, one of the most important rivers in Colombia. Quantification was conducted using liquid chromatography coupled with mass spectrometry. Additionally, conventional physicochemical parameters were evaluated. The hazard associated with the compounds was assessed using the persistence, bioaccumulation, and toxicity (PBT) index. The ecological threat was determined via the Hazard Quotient (HQ) and Toxic Units (TU). A literature review was also performed to evaluate existing treatment systems for their removal. Among a total of 11 pharmaceutical compounds analyzed, 5 were detected. The findings revealed the presence of antiepileptic drugs such as carbamazepine (CBZ), 10,11-dihydro-10,11-dihydroxycarbamazepine (CBZ-Diol), and gabapentin (GBP). Detected lipid-lowering agents included fenofibric acid (FFA) and gemfibrozil (GFZ). Concentrations of up to 92ng.L-1 were found for GFZ and CBZ-Diol. Physicochemical alterations were observed near wastewater discharge points. The PBT index indicated medium hazard for CBZ, CBZ-Diol, FFA, and GFZ, whereas the HQ revealed medium ecological risk for CBZ, with TUs corroborating these findings. Findings underscore the need for pharmaceutical monitoring and management in water sources. Removing these compounds remains challenging due to their variable removal patterns, necessitating the development of effective mitigation strategies.

The effectiveness of gabapentin (GBP) and pregabalin (PGB) in mitigating acute postoperative pain following lumbar surgery remains understudied. This study assessed the effectiveness of GBP and PGB in mitigating acute postoperative pain following lumbar spine surgery, measured through patient-reported outcome measures such as visual analog scale (VAS) pain scores and the 24-hour morphine requirement. Online databases including PubMed/MEDLINE, Scopus, and Cochrane were searched for randomized clinical trials conducted among adults undergoing lumbar spine surgery who were treated with GBP, PGB, or placebo and reported VAS scores 24 hours postoperatively. Seven studies were identified involving 724 eligible patients. The mean age of the cohort was 53.97 years. No significant differences in VAS pain scores were noted 24 hours postoperatively for patients treated with GBP, PGB, or placebo. Of the 7 included studies, 3 directly compared the pain sparing effect of PGB and GBP. Again, no significant difference in 24-hour VAS scores was noted. However, patients treated with GBP had a significantly lower 24-hour morphine consumption (3.80 mg, 95% confidence interval: 2.00 mg-5.60 mg) than patients treated with placebo (11.03 mg, 95% confidence interval: 8.98 mg-13.08 mg). There was no significant difference in 24-hour morphine requirement between patients treated with PGB versus placebo or PGB versus GBP. Definitive conclusions regarding the efficacy of GBP and PGB in managing acute postoperative pain remain limited. Well-designed randomized controlled trials with standardized protocols are needed to clarify their role in perioperative pain management following lumbar spine surgery.

Gabapentin (GBP), at high plasma concentrations, negatively impacts cardiovascular function, causing bradycardia, hypotension, and impaired left ventricular (LV) function in rats. This study examines the combined effects of GBP with Verapamil (Ver) or Metoprolol (Met) on cardiovascular function in anesthetized male rats and its impact on Ca2+ current and calmodulin (CaM) protein expression in cultured H9c2 cells. Twenty-two male Sprague Dawley rats were assigned to four groups: Saline+Ver, GBP+Ver, Saline+Met, and GBP+Met. Under isoflurane anesthesia, rats underwent ECG monitoring and LV hemodynamic and blood pressure (BP) assessment. GBP (50mg/kg) was administered intravenously, followed by Ver (0.05-0.4mg/kg) or Met (0.5mg/kg). In the first experiment, Ver induced a dose-dependent reduction in BP, heart rate (HR), and maximal dP/dt, while increasing minimal dP/dt, in both saline control and GBP-treated groups with the latter group showing greater effects. In the second experiment, GBP significantly reduced BP, HR, and maximal dP/dt while increasing minimal dP/dt compared to baseline. These effects were further exacerbated by Met, leading to greater reductions in BP, HR, and maximal dP/dt, and increases in minimal dP/dt compared to Met alone. In addition, in vitro experiments demonstrated that GBP reduced Ca2+ current and downregulated CaM protein. These findings suggest that, at high plasma concentrations, GBP enhances the negative chronotropic, negative inotropic, and hypotensive effects of both Ver and Met, further highlighting the need for additional preclinical and clinical studies to characterize the potential drug interactions between GBP and calcium channel blockers or beta-1 blockers, particularly in patients with cardiovascular disease.

Gabapentin fails to provide analgesia while duloxetine remains effective in an attention deficit hyperactivity disorder rat model with neuropathic pain.

Study DesignA double-blind randomized placebo-controlled trial.PurposeTo evaluate the efficacy and safety of gabapentin (GBA) and pregabalin (PGB) versus placebo in managing neurogenic intermittent claudication (NIC), functional outcomes, and quality of life in patients with lumbar spinal stenosis (LSS).Overview of LiteratureGBA and PGB are frequently prescribed for NIC associated with LSS. However, evidence supporting their efficacy, either in comparison with placebo or in direct comparison between the two gabapentinoids in LSS, remains limited.MethodsLSS patients with predominant NIC symptoms for ≥3 months were randomized (1:1:1) to receive GBA (1,800 mg/day), PGB (300 mg/day), or placebo in addition to standard conservative management, including physical therapy and naproxen. GBA and PGB were both titrated to the effective dose over 14 days. The primary outcome was NIC pain measured by Visual Analog Scale (VAS). Secondary outcomes included the Swiss Spinal Stenosis Score (SSS), self-paced shuttle walk test (SPSWT; time to NIC symptoms and walking distance), Euro-QoL Group’s 5-Dimension, 5-Level (EQ-5D-5L), and adverse effects. All outcomes were assessed monthly over 4 months.ResultsNinety patients (mean age, 63.14 years; symptoms duration, 19.38 months) were included. All groups demonstrated significant improvements in VAS, SSS, SPSWT, and EQ-5D-5L at 4 months. At 1 and 2 months, PGB showed greater EQ-5D-5L improvement compared to GBA (mean differences: 0.07 [p=0.045] and 0.08 [p=0.001], respectively). No significant differences in other outcomes were observed between groups at any time point. Adverse effects, including dizziness and sedation, were more common in the GBA and PGB groups compared to placebo (p<0.001).ConclusionsGBA and PGB did not demonstrate superior efficacy over placebo in reducing NIC and improving functional outcomes in LSS. Moreover, their use was associated with a higher incidence of adverse effects. These findings suggest limited utility for gabapentinoids as adjunctive treatments for LSS.

Chronic pain is a distressful condition that impacts strongly on people's health, and, to date, no cure has been found. However, several strategies against pain have been proposed. Promising data regarding the usage of nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with gabapentin in pain management laid the foundations for more complex approaches. A recently published study proposed a multimodal approach based on ketoprofen lysine salt (KLS) combined with gabapentin (GABA) in the context of chronic pain. Experiments on in vitro models showed supra-additive effects in modulating key pathways involved in neuropathic pain and gastric mucosal damage. Thus, the co-crystallization of ketoprofen, lysine, and gabapentin led to a new ternary drug-drug co-crystal (KLS-GABA co-crystal) to better take advantage of such effects. The new compound showed positive features in in vitro and in vivo pain models, particularly at the gastrointestinal level. To better understand the gastric impact of the co-crystal we chose to analyze proteomic fluctuations that occur in an in vitro model of gastric epithelium upon ethanol injury, aiming to observe the gastric effects of KLS-GABA co-crystal's administration in comparison with KLS or GABA alone or co-administered as in the multimodal approach. Thus, we performed a 2-dimensional gel electrophoresis (2DE) to compare proteomes from lysates of NCI-N87 cells, chosen as model of gastric epithelium. Among all the localized spots (n = 117), the differentially abundant ones have been filtered and excised (n = 24) to perform mass spectrometry. A total of 414 non-redundant proteins have been found in the excised spots analyzed. A Gene Ontology-based enrichment analysis identified the proteins involved in biological processes, cellular components, and pathways. We then compared the 2DE findings with the western blot analysis confirming the differential proteomic fluctuations in the model. The methodology described here provides a broader picture of the effects of KLS, GABA, and KLS-GABA co-crystal administration in the ethanol-gastric injury model, identifying processes not revealed by other studies by showing proteomic changes and related mechanisms in detail, particularly via modulation of the oxidative stress-related GSTP1 which suggests the higher gastric tolerability of KLS-GABA co-crystal in the analyzed model highlighting its clinical reliability.

Neuropathic pain affects approximately 10% of the adult population and is commonly treated with gabapentin (GBP), a repurposed anticonvulsant drug. Despite its widespread use, GBP’s effectiveness varies significantly among patients, highlighting the need to better understand its functional and molecular impacts on human nociceptors. Here we characterized the electrophysiological and transcriptomic effects of GBP on primary neurons derived from the dorsal root ganglia (DRGs) of ethically consented human donors. Using patch-clamp electrophysiology, we demonstrated that GBP treatment reduced neuronal excitability, with more pronounced effects in multi-firing vs. single-firing neurons. Notably, significant donor-specific variability was observed in electrophysiological responsiveness to GBP treatment in vitro. RNA sequencing of DRG tissue from the donor that was more responsive to GBP revealed differences in transcriptome-wide expression of genes associated with ion transport, synaptic transmission, inflammation, and immune response. Cross-transcriptomic analyses further showed that GBP treatment counteracted these alterations, rescuing aberrant gene expression at the pathway level and for several key genes. This study provides a comprehensive electrophysiological and transcriptomic profile of the effects of GBP on human DRG neurons. These findings enhance our understanding of GBP’s mechanistic actions on peripheral sensory neurons and could help optimize its use for managing neuropathic pain.

Epilepsy is a chronic neurological disease that affects the brain and causes a recurrent seizure. This condition affects a lot of people worldwide making it a global neurological disorder. The first line for managing epilepsy, is the use of Anti-epileptic drugs. Herein, a reliable and ecological chromatographic method was developed, verified and validated for the simultaneous determination of three approved drugs that can be co-administered in many treatment protocols for epilepsy management; Piracetam (PIR), Gabapentin (GBP) and Levetiracetam (LEV). The developed method was founded on high performance liquid chromatography (HPLC–UV). Separation was accomplished using a 5.0 μm particle size, 250 × 4.6 mm Inertsil ODS-3 C18 column with the UV detection set at 210.0 nm. An isocratic elution system was employed, consisting of a mixture of methanol and water in a ratio of 15:85 (v/v) at ambient temperature. The developed method demonstrated linearity throughout a range of concentration of 30.0–1000.0 µg/mL for GBP and 10.0–100.0 µg/mL for LEV and PIR. The suggested method was optimized and validated following the guidelines stated by the ICH and was utilized for the determination of the aforementioned drugs in their respective pharmaceutical formulation. Moreover, the supremacy of the developed method was further extended for monitoring the in-vitro release profile of the stated drugs and content uniformity of their marketed pharmaceutical formulations. Finally, the ecological impact of the suggested method was monitored, evaluated and compared to the official HPLC ones utilizing newly introduced greenness, blueness and whiteness assessment methods tools.

Are environmental levels of gabapentin (GBP) a cause for concern? Chronic reproductive effects of GBP in zebrafish.

Purpose: This investigation aimed to evaluate the potential cytogenotoxic effects of gabapentin (GBP) on neuroblastoma cells (SH-SY5Y cell line) given its broad range of applications. Furthermore, the interaction between GBP and DNA polymerase beta (DNApolβ) was evaluated using in silico methods. Material and Methods: The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was used to investigate the cytotoxicity of GBP at concentrations of 1 µM, 10 µM, 100 µM and 1000 µM. The IC₅₀ value of GBP was calculated, as were the genotoxic effects of GBP at concentrations of 0.14 µM, 0.28 µM, 0.56 µM and 1.12 µM, using the Comet assay. Additionally, AutoDock 4.0 was used to predict the interaction between GBP and the DNApolβ molecule in silico. Results: GBP significantly decreased the viability of SH-SY5Y cells by 70.2 ± 3.084% and 86.8 ± 3.324% at concentrations of 1 µM and 10 µM, respectively. Concentrations of GBP (0.14 µM, 0.28 µM, 0.56 µM and 1.12 µM) were found to be statistically significant for the damaged cell index (DCI) in SH-SY5Y cells at 298.219 ± 104.66, 593.436 ± 120.16, 1216.378 ± 215.96 and 1589.733 ± 472.65, respectively. The genetic damage index (GDI) for these concentrations was found to be statistically significant at 4.150 ± 1.92, 6.568 ± 1.27, 8.216 ± 0.60 and 9.181 ± 1.16, respectively. The Gibbs free binding energy of GBP with DNApolβ was calculated as -7.35 kcal/mol. Conclusion: The results of this study indicate that GBP, used in the treatment of epilepsy and neuropathic pain, increases both cytotoxicity and genotoxicity in SH-SY5Y neuroblastoma cells. Furthermore, in silico predictions have revealed a significant interaction between GBP and DNApolβ.

Voltage-gated calcium channels (VGCCs) are critical for calcium ion influx during action potentials, playing a key role in neurotransmitter release, synaptic transmission, and pain perception. We hypothesized that gabapentin (GBP) and pregabalin (PGB) interact with VGCCs, particularly the auxiliary α2δ subunit, in C. elegans. Our goal was to investigate VGCCs' role in nociception and assess C. elegans as a screening model for antinociceptive compounds. We exposed C. elegans to varying GBP and PGB concentrations, followed by thermal avoidance assays (32-35°C) and proteomic analyses. Both drugs significantly impeded nocifensive responses at 100 µM, with diminished efficacy at higher concentrations. Mutant strains unc-2 and unc-36 exhibited impaired heat avoidance, confirming VGCCs' involvement in nociceptive signaling. Proteomic analysis revealed distinct drug-specific pathway modulations. Our study demonstrated that both pregabalin and gabapentin are associated with calcium activity either directly or indirectly. Although both drugs influence VGCC, pregabalin exhibited greater efficiency compared to gabapentin in mammals. Our data also clearly indicates that calcium-related pathways were more prominently upregulated or downregulated in the pregabalin treatment group compared to gabapentin. GBP 100 µM modulate mostly muscle or actinomycin related pathways. Conversely, at 500 µM, GBP activates pathways linked to translation and ribosomal biogenesis, potentially enhancing pro-neuropeptide synthesis, which may counteract its antinociceptive effects. PGB exhibits similar concentration-dependent effects, with the 100 µM treatment suppressing glutamatergic signaling and the 500 µM treatment failing to suppress neurotransmitter release. This might be due to the influence of SUMOylation, which enhances the release of pro-nociceptive neurotransmitters, or receptor saturation as we see ligand gated ion channels are highly expressed in this cohort. Our findings support the use of C. elegans as a model for screening novel analgesics and provide insight into the multiple molecular pathways underlying gabapentinoid-mediated pain modulation.