Treatment Of Neuropathic Pain Research Articles

PI3K-mediated Kif1a DNA methylation contributes to neuropathic pain: an in vivo study.

Neuropathic pain (NP) is a chronic condition caused by nerve injuries, such as nerve compression. Understanding its underlying neurobiological mechanisms is critical for developing effective treatments. Previous studies have shown that Kinesin family member 1A (Kif1a) heterozygous deficient mice display sensory deficits in response to nociceptive stimuli. PI3K has been found to mitigate these sensory deficits by enhancing Kif1a transcription, highlighting KIF1A's key role in sensory pain. However, the exact mechanism through which PI3K regulates KIF1A expression in relation to pain remains unclear. In this study, we observed a significant increase in PI3K/AKT/CREB (cyclic AMP response element-binding protein) protein levels in the dorsal root ganglia and spinal cord after chronic constriction injury in both male and female C57BL/6 mice. Notably, elevated levels of TET1, as well as Kif1a mRNA and protein, were detected in both male and female mice. Activated (phosphorylated-CREB) p-CREB recruited the DNA demethylase TET1, which interacted with the Kif1a promoter, reducing methylation and increasing Kif1a mRNA and protein expression. PI3K inhibition using wortmannin reversed the demethylation of Kif1a and decreased its expression in male mice. Furthermore, TET1 knockdown or overexpression significantly affected pain-related behaviors, as well as Kif1a methylation and transcription. Female mice given intrathecal injections of PI3K inhibitors exhibited similar molecular and behavioral outcomes as male mice. These findings offer new insights into NP mechanisms, suggesting that targeting the PI3K/KIF1A axis could be a promising therapeutic approach for NP treatment.

Treatment of neuropathic pain with repeated low-dose MDMA: a case report

A 64-year-old male patient who suffered from traumatic life experiences and neuropathic pain after oncological chemotherapy was treated with medium to high doses of lysergic acid diethylamide (LSD) and high doses and microdoses of methylenedioxymethamphetamine (MDMA). At the beginning of treatment, the patient did not experience any acute subjective effects of LSD at a dose of 200 µg. After increasing the LSD dose to 400 µg, he experienced subjective acute effects, and the first lasting therapeutic effects were observed. After changing from LSD to MDMA at both high doses (150-175 mg) and repeated low doses (12.5-25 mg), the patient exhibited marked improvements in neuropathic pain that were sustained even after stopping repeated MDMA treatment. MDMA mini/microdosing has not yet been broadly investigated. This case documents benefits of low doses of MDMA for the treatment of a pain disorder. Further research is needed on effects of MDMA on pain.

A Double-Blind Comparative Study of burstDR Versus Tonic Epidural Motor Cortex Stimulation for the Treatment of Intractable Neuropathic Pain.

Preliminary studies on epidural motor cortex stimulation (eMCS) for the treatment of drug-resistant neuropathic pain have supported the extension to novel stimulation waveforms, in particular burstDR. However, only a low level of evidence is available. The aim of this retrospective observational study was to compare the analgesic efficacy of burstDR versus tonic eMCS. Patients suffering from unilateral, drug-resistant neuropathic pain were selected for eMCS. During the trial phase, burstDR and tonic waveforms were successively applied for three consecutive months in a double-blinded fashion and in a random order. The primary outcome criterion was the percentage of pain relief (%PR) at 3 and 6 months. The secondary outcome criterion was the proportion of patients reporting a superior %PR with the burstDR waveform. Thirteen patients were included. The averaged %PR was 75.4% ± 18.6% after burstDR eMCS and 61.1% ± 28.6% after tonic eMCS (p = 0.21). Nine patients preferred the burstDR waveform for chronic eMCS (p = 0.16), and six of them were able to decrease or withdraw their analgesic drug intake. No adverse side effect was encountered in relation to burstDR eMCS. BurstDR eMCS seems at least as effective as tonic eMCS for the treatment of drug-resistant neuropathic pain and shows a similar safety profile. Although the precise mechanisms of action remain to be fully elucidated, adequate matching between the oscillatory rhythm in the motor cortex and that of the burstDR waveform may increase synaptic efficacy, thus enhancing the functional connectivity of the motor cortex with remote brain networks involved in pain modulation. In the present paper, we provide for the first time a double-blinded study comparing burstDR versus tonic eMCS for the treatment of intractable, drug-resistant neuropathic pain. Our results show that burstDR eMCS is a promising option in a population of patients especially difficult to treat, and support the ongoing move toward new stimulation waveforms able to more efficiently activate the brain networks involved in pain modulation.

MTOR Promotes Astrocyte Activation and Participates in Neuropathic Pain through an Upregulation of RIP3

Neuropathic pain (NP), a chronic pain condition, is the result of abnormalities in both central and peripheral pain conduction pathways. Here, we investigated the underlying mechanisms associated with this effect. We found that following chronic constriction injury (CCI) surgery, there was an increase of mTOR in astrocytes and an activation of astrocytes within the spinal cord. Pharmacological inhibition of mTOR reversed CCI-induced hyperalgesia and neuroinflammation. Moreover, knockdown of astrocytic mTOR rescued the downregulation of spinal glutamate metabolism-related protein expression, underscoring the pivotal role of mTOR in modulating this pathway. Intriguingly, we observed that overexpression of mTOR, achieved via intrathecal administration of TSC2-shRNA, led to an upregulation of RIP3. Notably, pharmacological inhibition of RIP3, while ineffective in modulating mTOR activation, effectively eliminated the mTOR-induced astrocyte activation. Mechanistically, we found that mTOR controlled the expression of RIP3 in astrocytes through ITCH-mediated ubiquitination and an autophagy-dependent degradation. Taken together, our results reveal an unanticipated link between mTOR and RIP3 in promoting astrocyte activation, providing new avenues of investigation directed toward the management and treatment of NP.

Design, Synthesis, and Biological Evaluations of 5-aryl-pyrazole-3-carboxamide Derivatives as Selective CB2 Receptor Agonists for the Treatment of Colitis

Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound 33, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC50, CB2 = 16.2 nM, EC50, CB1 > 105 nM). Furthermore, 33 treatment significantly attenuate colon inflammation in a dextran sodium sulfate (DSS)-induced mouse model of colitis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating colitis.

OVERVIEW OF PAIN IN UKRAINIAN WAR INJURED

Our objective is to study the relationship between armed conflict injuries and pain and the treatments that have been applied to Ukrainian injured soldiers in our hospital. We performed an observational study of a sample of 91 injured soldiers. The metrics we selected for the study included time from injury, length of stay, diagnosis, treatment, type and intensity of pain and questionnaires about pain and quality of life for the group of amputees. The statistical study was carried out using SPSS v.30. 85 % of the 91 patients suffered from pain in at least one part of their body. 53 patients experienced neuropathic pain, 15 patients had somatic pain and 29 patients had a combination of both. The average pain intensity was 6 points in the Visual Analogue Scale (VAS) and 5 points in the DN-4 scale. The most common treatments for neuropathic pain were neuromodulators, nerve blocks, capsaicin patches and TMR (targeted muscle reinnervation). The study of injuries caused in current armed conflicts can help us anticipate complications and understand and treat pain early to improve the independence of patients, especially of amputee patients.

Evidence-Based Umbrella Review of Non-Invasive Neuromodulation in Chronic Neuropathic Pain.

Non-invasive neuromodulation techniques (NIN), such as transcranial Direct Current Stimulation (tDCS) and repetitive Transcranial Magnetic Stimulation (rTMS), have been extensively researched for their potential to alleviate pain by reversing neuroplastic changes associated with neuropathic pain (NP), a prevalent and complex condition. However, treating NP remains challenging due to the numerous variables involved, such as different techniques, dosages and aetiologies. It is necessary to provide insights for clinicians and public healthcare managers to support clinical decision-making. This umbrella review aims to consolidate existing evidence on the effectiveness of various NIN in managing chronic NP. A systematic search was conducted in the PubMed/MEDLINE database, including meta-analyses of controlled trials comparing NIN techniques with sham interventions for NP treatment. The quality of included studies was assessed using the AMSTAR-2 tool and the GRADE system, with effect sizes adjusted to the standard mean difference (SMD). The review included 22 meta-analyses comprising 8151 participants from 214 controlled trials. The most investigated NIN techniques were tDCS and rTMS, with primary targets being the motor cortex and dorsolateral prefrontal cortex. The findings suggest that excitatory protocols, particularly high-frequency rTMS and anodal tDCS, are effective in reducing pain intensity in individuals with NP. However, the overall quality of evidence was rated low, primarily due to heterogeneity among studies and small sample sizes. NIN techniques show promise in managing NP, with potential benefits in pain reduction. However, further high-quality research is needed to establish optimal protocols and long-term effects. This paper consolidates the evidence regarding non-invasive neuromodulation for the treatment of neuropathic pain, including differentiating the most effective techniques based on the aetiology of pain, and provides clinicians with easy access to this critical information. It also highlights key aspects that require further research in the field of non-invasive neuromodulation and neuropathic pain.

An observational comparative study to evaluate the efficacy and safety of pregabalin and gabapentin in neuropathic pain- at a Teritiary Care Centre

Background: Millions of people around the world suffer from Neuropathic pain (Nep), a prevalent and debilitating condition. Treatment for NeP typically includes anticonvulsants, antidepressants, opioids, topical medications, and local anesthetics. Although Pregabalin and Gabapentin are commonly used for this purpose, there is a lack of conclusive evidence supporting their efficacy. NeP significantly diminishes patients' quality of life. This study aims to evaluate the safety and effectiveness of Gabapentin and Pregabalin in treating patients with NeP. Methods: Among a total of 100 patients 50 patients (Group A) were given Gabapentin and 50 Patients (Group B) were given Pregabalin. The efficacy of drug was measured on the basis of decrease in NeP based on Douleur Neuropathique 4 questions (DN4) pain scale measured at baseline, after one month and after two months. Adverse drug reaction (ADR) reported by the patient or observed by the clinician during the study was reported using ADR reporting form. Result: The mean reduction of the neuropathic pain score in Group A from baseline to 2 months was 2.15, while in Group B it was 3.49. Hence, pregabalin showed comparable pain reduction to gabapentin at the end of the 2-months study. Conclusion: Pregabalin 100 mg once daily brought better improvement of symptoms and signs than Gabapentin 300 mg administered once daily. The study found that Pregabalin is a better drug for the treatment of neuropathic pain than Gabapentin. Gabapentin had fewer adverse effects than Pregabalin.

Duhuo Jisheng Mixture attenuates neuropathic pain by inhibiting S1PR1/P2Y1R pathway after Chronic Constriction Injury in mice.

The pathogenesis of neuropathic pain is complex and lacks effective clinical treatment strategies. Medical plants and herbal extracts from traditional Chinese medicine with multi-target comprehensive effects have attracted great attention from scientists. To investigate the pharmacological active components and mechanism underlying the anti-neuralgia effect of classic analgesic formulas Duhuo Jisheng Mixture (DJM). Chronic Constriction Injury (CCI) surgery was used to assess the efficiency of DJM in treating neuropathic pain. Forty-two C57BL/6 mice were evenly divided into seven groups: sham-operated, sham treatment with DJM (20 ml/kg), CCI treatment with DJM (0, 10, 20, or 40 ml/kg) and CCI treatment with Morphine (3 mg/kg). DJM irrigation stomach was implemented from post-operative day (POD) 0 to POD 21. Paw withdrawal threshold and Thermal latency were conducted on POD 0, 1, 3, 5, 7, 14 and 21. On POD 14, eEPSP in spinal dorsal horn neurons was recorded by patch-clamp. mRNA transcription in spinal cord was also monitored to screen molecular targets and signaling pathways on POD 14. To further validate the influence of DJM on the S1PR1 signaling pathway, 1 mg/kg W146 was infused into mice intrathecally and delivered to the cerebral spinal fluid through one 30 G needle with a whole 20 μl intervertebral between the L5 and L6. Furthermore, the active ingredients of DJM were identified through LC/MS equipment and predicted through Molecular Docking. We demonstrated that DJM treatment reversed CCI-induced pain sensitivity and the excitability of neurons, decreased up-regulation of astrocyte S1PR1, inhibited astrocyte activation, and further inhibited the expression of Purinergic P2Y1R and its downstream molecule p-JNK in mouse spinal cord, as well as the release of inflammatory factors. Interestingly, due to the regulatory role of astrocytes on neurons, the effects of DJM on astrocytes ultimately manifest in pain-effector neurons, resulting in decreased p-ERK, p-CREB, and pain-marking protein c-fos in neurons. S1PR1 Antagonist W146 possessed an equivalent analgesic effect as DJM and inhibited S1PR1 and c-fos expression. According to LC/MS analysis results, a total of 33 active ingredients were screened, of which 20 active ingredients had good binding activity with S1PR1 and were considered to be the main active ingredients for analgesia. This study is the first to clarify the effect and molecular mechanism of DJM for anti-neuralgia in particular, which confirms the clinical value of DJM in relieving neuropathic pain. Furthermore, this study innovatively identifies the potential pharmacological components of DJM through LC/MS and Bioinformatics technology, which forms a framework for people's understanding of DJM treatment for neuropathic pain and provides a sufficient theoretical basis of DJM for clinical application.

Evaluating Treatment Preferences and the Efficacy of Capsaicin 179 mg Patch vs. Pregabalin in a Randomized Trial for Postsurgical Neuropathic Pain in Breast Cancer: CAPTRANE.

Background/Objectives: CAPTRANE evaluated the efficacy and tolerability of high-concentration capsaicin patch (HCCP) vs. oral pregabalin for the treatment of postsurgical neuropathic pain (PSNP) following breast cancer surgery. The study was designed with the aim of demonstrating noninferiority of one HCCP against daily pregabalin. Methods: This was a multicenter, randomized, parallel-arm, open-label study conducted across nine centers in France. The primary endpoint was a change from baseline in the Numeric Pain Rating Scale (NPRS) score after 2 months. Results: Recruitment challenges resulted in the randomization of 140 patients (versus 644 planned); the per-protocol population comprised 107 patients (HCCP: n = 65; pregabalin: n = 42). Baseline characteristics were similar between the two groups. In the per-protocol analysis, the mean (standard deviation) change versus baseline in NPRS score was -1.926 (2.554) with HCCP and -1.634 (2.498) with pregabalin. The prespecified analysis showed that HCCP was not inferior to pregabalin: the lower bound of the 90% confidence interval for the between-arm difference was -0.889 and the upper bound was +0.260 (i.e., below the predefined clinical threshold of +0.4). Patient-reported outcomes showed no statistically significant differences between treatments. The painful area size decreased significantly more with HCCP. Tolerability profiles differed, with HCCP mostly causing application-site reactions. While >50% of patients switched from pregabalin to HCCP, none switched from HCCP to pregabalin. Conclusions: This comparative study in PSNP post breast cancer surgery, evaluating a single treatment of HCCP, shows a noninferior reduction in pain intensity, a superior reduction in painful area size, and a patient preference for HCCP compared with pregabalin. Despite limitations, it contributes valuable initial data for PSNP management in breast cancer care.

Neuropathic postamputation residual limb pain after combat trauma: an evidence-based review of diagnosis and injection therapy

Background. The devastating nature of the russian-Ukrainian war has led to a dramatic increase in the incidence of limb amputations. The purpose was to analyze the available medical literature concerning neuropathic postamputation residual limb pain and injection therapy. Materials and methods. A comprehensive literature search of electronic databases MEDLINE/PubMed, Embase, and Scopus was conducted to identify primary studies. The evidence-based review was reported in accordance with the critical evaluation of published articles, PRISMA, and OCEBM. A total of 64 publications were included in the final quantitative analyses. Results. The estimated prevalence of residual limb pain after combat traumatic amputations is higher (61 %) than due to general diseases or civilian injuries (22–27 %). Recent Ukrainian data (63.6 %) correspond to this pooled combat-related residual limb pain prevalence. Pro-inflammatory mediators and symptomatic neuromas are determined to make significant contribution to the peripheral mechanisms of postamputation neuropathic pain. Given the distinct nature of combat trauma, further research of military populations is needed. Ultrasound-guided alcohol injections and radiofrequency ablation of neuromas have comparable efficacy profiles in the treatment for neuropathic residual limb pain. Conclusions. A standardized approach to the terminology and diagnosis of postamputation pain is essential for producing high-quality research. The injection therapy of symptomatic terminal neuromas is promising; however, given the insufficient number of high-quality studies including homogeneous groups of patients after amputations, further analysis of the pharmacological agent effectiveness is required.

Marine-derived bioactive compounds for neuropathic pain: pharmacology and therapeutic potential.

Neuropathic pain, a challenging condition often associated with diabetes, trauma, or chemotherapy, impairs patients' quality of life. Current treatments often provide inconsistent relief and notable adverse effects, highlighting the urgent need for safer and more effective alternatives. This review investigates marine-derived bioactive compounds as potential novel therapies for neuropathic pain management. Marine organisms, including fungi, algae, cone snails, sponges, soft corals, tunicates, and fish, produce a diverse range of secondary metabolites with significant pharmacological properties. These include peptides (e.g., conopeptides, piscidin 1), non-peptides (e.g., guanidinium toxins, astaxanthin, docosahexaenoic acid, fucoidan, apigenin, fumagillin, aaptamine, flexibilide, excavatolide B, capnellenes, austrasulfones, lemnalol), and crude extracts (e.g., Spirulina platensis, Dunaliella salina, Cliothosa aurivilli). These compounds exhibit diverse mechanisms of action, such as modulating ion channels (e.g., transient receptor potential channels, voltage-gated sodium, calcium, and potassium channels, and G protein-coupled inwardly rectifying potassium channels), interacting with cell-surface receptors (e.g., nicotinic acetylcholine, NMDA, kainate, GABAB​, and neurotensin receptors), inhibiting norepinephrine transporters, reducing oxidative stress, and attenuating neuroinflammation. These effects collectively contribute to alleviating nerve degeneration and symptoms of neuropathic pain, including hyperalgesia, allodynia, and associated psychomotor disturbances. Marine-derived bioactive compounds represent promising alternatives to conventional neuropathic pain treatments, to advance their development and assess their integration into neuropathic pain management strategies.

Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury

BackgroundNeuropathic pain resulting from spinal cord injury (SCI) is associated with persistent hyperactivity of primary nociceptors. Anandamide (AEA) has been reported to modulate neuronal excitability and synaptic transmission through activation of cannabinoid type-1 receptors (CB1Rs) and transient receptor potential vanilloid 1 (TRPV1). However, the role of AEA and these receptors in the hyperactivity of nociceptors after SCI remains unclear.ResultsIn this study, we investigated the effects of AEA and its receptors on the hyperexcitability of mouse dorsal root ganglion (DRG) neurons after SCI. Using a whole-cell patch-clamp technique, we found that the timing of SCI-induced hyperexcitability in nociceptors paralleled an increase in the endocannabinoid AEA content. The expression of TRPV1 and CB1R was also upregulated at different time points after SCI. High-dose extracellular administration of AEA increased the excitability of naive DRG neurons, leading to the transition from a rapidly accommodating (RA) hypoexcitable state to a highly excitable non-accommodating (NA) state. These AEA-induced transitions were facilitated by increased TRPV1 transcription. Pharmacological and Ca2+ imaging experiments revealed that AEA induced hyperexcitability in nociceptors after SCI via the AEA-TRPV1-Ca2+ pathway, whereas activation of CB1Rs reduced SCI-induced hyperexcitability and maintained cytosolic Ca2+ concentration ([Ca2+]cyto) at low levels in the early stages of SCI. As the AEA and TRPV1 levels increased after SCI, adaptive neuroprotection transitioned to a maladaptive hyperactive state, leading to sustained pain.ConclusionsTaken together, this study provides new insights into how endocannabinoids regulate nociceptor activity after SCI, offering potential targets for the treatment of neuropathic pain.

Pregabalin vs. gabapentin in the treatment of neuropathic pain: a comprehensive systematic review and meta-analysis of effectiveness and safety.

Neuropathic pain is a prevalent and burdensome condition, and both pregabalin and gabapentin are widely used for its treatment. However, there is a lack of clarity regarding their comparative efficacy and safety. This meta-analysis aims to evaluate and compare the effectiveness and safety of pregabalin vs. gabapentin in managing neuropathic pain. This study followed PRISMA guidelines and employed the PICOS search strategy. Comparative studies (clinical trials and cohort studies) were included, with patients with neuropathic pain treated either with pregabalin or gabapentin. Primary outcomes assessed were efficacy and safety. Data were extracted from PubMed, Embase, Scopus, and the Cochrane Collaboration Library databases. The risk of bias was evaluated using the Cochrane Review Manager tool. Statistical analysis was performed using Review Manager 5.4.1 software, calculating effect sizes and conducting sensitivity analysis based on medication dosage. A total of 14 studies with 3,346 patients were analyzed. Pregabalin showed superior results compared to gabapentin in the Visual Analog Scale (VAS) at various time intervals up to 12-14 weeks (SMD -0.47, 95% CI -0.74 to -0.19). The pregabalin group also had significant improvements in SF-12/SF-36/EQ-5D scores (SMD 0.39, 95% CI 0.11-0.68) and experienced more days with no/mild pain (MD 9.00, 95% CI 8.93-9.07) and fewer days with severe pain (MD -3.00, 95% CI -4.96 to -1.04). Pregabalin resulted in lower opioid consumption (OR 0.50, 95% CI 0.33-0.76). Gabapentin had a higher incidence of nausea and vomiting. Sensitivity analysis supported the efficacy of pregabalin. In conclusion, pregabalin demonstrated superior and faster efficacy in alleviating neuropathic pain than gabapentin did. Additionally, it improved patient-reported outcomes, resulted in lower opioid consumption, and led to fewer adverse events. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=565208, PROSPERO (CRD42024565208).

A novel approach to completely alleviate peripheral neuropathic pain in human patients: insights from preclinical data.

Neuropathic pain is a pervasive health concern worldwide, posing significant challenges to both clinicians and neuroscientists. While acute pain serves as a warning signal for potential tissue damage, neuropathic pain represents a chronic pathological condition resulting from injury or disease affecting sensory pathways of the nervous system. Neuropathic pain is characterized by long-lasting ipsilateral hyperalgesia (increased sensitivity to pain), allodynia (pain sensation in response to stimuli that are not normally painful), and spontaneous unprovoked pain. Current treatments for neuropathic pain are generally inadequate, and prevention remains elusive. In this review, we provide an overview of current treatments, their limitations, and a discussion on the potential of capsaicin and its analog, resiniferatoxin (RTX), for complete alleviation of nerve injury-induced neuropathic pain. In an animal model of neuropathic pain where the fifth lumbar (L5) spinal nerve is unilaterally ligated and cut, resulting in ipsilateral hyperalgesia, allodynia, and spontaneous pain akin to human neuropathic pain. The application of capsaicin or RTX to the adjacent uninjured L3 and L4 nerves completely alleviated and prevented mechanical and thermal hyperalgesia following the L5 nerve injury. The effects of this treatment were specific to unmyelinated fibers (responsible for pain sensation), while thick myelinated nerve fibers (responsible for touch and mechanoreceptor sensations) remained intact. Here, we propose to translate these promising preclinical results into effective therapeutic interventions in humans by direct application of capsaicin or RTX to adjacent uninjured nerves in patients who suffer from neuropathic pain due to peripheral nerve injury, following surgical interventions, diabetic neuropathy, trauma, vertebral disc herniation, nerve entrapment, ischemia, postherpetic lesion, and spinal cord injury.

Use of ascorbic acid (vitamin C) and alpha tocopherol (vitamin E) as adjuvants in the treatment of neuropathic pain

Use of ascorbic acid (vitamin C) and alpha tocopherol (vitamin E) as adjuvants in the treatment of neuropathic pain

Intranasal Administration of the Combination of Dextro-Ketamine and Dexmedetomidine for Treatment of Diabetic Neuropathic Pain in Rats.

Diabetes mellitus (DM) has become a public health problem, which is associated with high morbidity and mortality, due to the chronic complications, such as diabetic neuropathy. Current recommendations for the treatment of neuropathic pain achieve a reduction of 30% in only 30% of cases. Therefore, it is necessary to identify new therapeutic approaches to improve the quality of life of diabetic patients. This work evaluated the antinociceptive effect of intranasal administration of the combination of dextro-ketamine (keta), a non-competitive glutamatergic receptor antagonist, and dexmedetomidine (DEX), a selective alpha2-adrenergic agonist, in rats with neuropathic pain induced by streptozotocin-DM. The thermal hyperalgesia and mechanical allodynia observed in DM model are reduced with the intranasal administration of the combination of keta and DEX (200 + 0.10 μg/kg) after 3 days of treatment. The antinociceptive action could be due to reduction of Ca2+ influx with lower glutamate release and reduced excitability through the activation of alpha2-adrenergic receptors by DEX and reduction of NMDA receptor activation by glutamate with lower excitability due to the antagonism produced by keta. DM induced increased expression of glial fibrillary acid protein (GFAP) and tumor necrosis factor-alpha (TNF-alpha) detected by immunohistochemistry, indicating greater astrocyte activity and intense inflammatory response. Intranasal administration for 10 days of the combination of low doses of keta and DEX promoted an intense decrease in the expression of both GFAP and TNF-alpha, indicating lower activation of astrocytes in the spinal cord and reduced production and release of TNF-alpha, favoring the reduction of inflammation. Intranasal administration of low doses of keta with DEX could be a new therapeutic approach to reduce neuropathic pain and consequently improve the quality of life of diabetic patients.

A Review on Recent Trends in Neuropathic Pain Treatment

A Review on Recent Trends in Neuropathic Pain Treatment

Reducing IgG accumulation via neonatal Fc receptor (FcRn) blockade relieves neuropathic pain.

Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and IgG deposition induced by CCI. FcRn are prominently expressed on myeloid and endothelial cells and extend the half-life of IgG via pinocytosis and recycling into the extracellular milieu. We show here that administration of the FcRn blocker efgartigimod either 7- or 28-days post-CCI relieved allodynia among both male and female mice, compared to the Fc fragment control. Efgartigimod, administered systemically (intraperitoneal) or to the lumbar region (intrathecal), attenuated mechanical allodynia for at least one month w. CCI-induced allodynia was similarly reduced in FcRn-deficient (FcRn-) mice compared to wild-type mice. Biologic inhibition or genetic deletion of FcRn also reduced CCI-induced accumulation of IgG on macrophages and neurons in lumbar DRG, as well as microglia in the lumbar dorsal spinal cord. Expression of the Fc receptor γ subunit (FcRγ) was reduced in efgartigimod-treated or FcRn- mice post-CCI compared to controls. The FcRγ subunit is a key component of Fc gamma receptors (FcγRs), which are activated by IgG immune complexes. In macrophage cultures stimulated by IgG immune complexes, FcRn blockade also dampened FcγR-dependent production of proinflammatory cytokines. Collectively, our study demonstrates that FcRn blockade or deletion alleviates mechanical allodynia and reduces IgG accumulation after CCI, attenuating pronociceptive IgG-FcγR signaling around the lumbar region. Strategies to block FcRn and reduce IgG recycling warrant further investigation as potential treatments for IgG-mediated neuropathic pain.

Quantification of crisugabalin (HSK16149) in biological matrix by LC-MS/MS method: An application to rat pharmacokinetic and tissue distribution studies

Crisugabalin (HSK16149), a novel VGCC α2δ ligand, has been approved for the treatment of adult diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN). In this study, an LC-MS/MS method was developed for the determination of crisugabalin in rat plasma and tissues homogenate. Samples were extracted by protein precipitation and separated on a Hypersil GOLD aQ column with methanol and 2 mM ammonium acetate in water containing 0.1 % formic acid as mobile phase. Crisugabalin and its internal standard HSK7891 were ionized by electrospray ionization source and detected by multiple reaction monitoring with transitions of m/z 210.9 → 134.4 and m/z 246.0 → 129.3. Over the range of 0.0100–10.0 μg/mL, the selectivity, linearity, precision and accuracy, matrix effect, stability, recovery and dilution integrity of crisugabalin were validated in rat plasma. Validation was also performed in rat liver homogenate at concentrations ranging from 0.0200-20.0 μg/g. The method was then successfully applied to determine the pharmacokinetics and tissue distribution of crisugabalin. In rats, orally administered crisugabalin was completely and rapidly absorbed with a peak time of about 0.57 h, and was mainly distributed to kidney, bladder and liver tissues. crisugabalin exhibited linear pharmacokinetics over the oral dose range of 3–30 mg/kg.