Ectopic Discharges Research Articles

Urinary kallikrein reverses neuropathic pain by inhibiting ectopic neural discharges, neural inflammation and oxidative stress.

Neuropathic pain is a refractory disease and badly impacts the lives of patients. Urinary kallikrein (UK) acted as a glycoprotein has been discovered to play a pivotal role in neuroprotection. However, the regulatory impacts and correlative pathways of UK in the progression of neuropathic pain remain dimness. The chronic constriction injury (CCI) rat model was firstly established to mimic neuropathic pain. The withdrawal threshold was measured through the Von Frey test. The levels of TNF-α, IL-1β and IL-6 were determined through ELISA. The levels of ROS, GSH, SOD and GSH-Px were examined through the commercial kits. The ectopic discharges were assessed. The protein expressions were inspected through western blot. It was demonstrated that withdrawal threshold was reduced in CCI rat model, but this change was reversed after UK treatment, indicating that UK relieved mechanical allodynia. Moreover, UK alleviated the inflammatory response through reducing TNF-α, IL-1β and IL-6 levels. It was uncovered that oxidative stress was strengthened in CCI rat model, but this impact was restrained after UK treatment. Additionally, UK suppressed ectopic discharge. At last, it was proved that UK triggered the Nrf2/ARE signaling pathway in CCI rat model. This study manifested that UK reversed neuropathic pain by inhibiting ectopic neural pathways, neural pathways and oxidation via the Nrf2/ARE pathway. This study may offer useful proofs the regulatory functions of UK in the cure of neuropathic pain.

Unraveling the pathogenic mechanism of a novel filamin a frameshift variant in periventricular nodular heterotopia.

Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder caused by the inability of neurons to move to the cortex. Patients with PVNH often experience epilepsy due to ectopic neuronal discharges. Most cases of PVNH are associated with variations in filamin A (FLNA), which encodes an actin-binding protein. However, the underlying pathological mechanisms remain unclear. Next-generation sequencing was performed to detect variants in the patient with PVNH, and the findings were confirmed using Sanger sequencing. Iterative threading assembly refinement was used to predict the structures of the variant proteins, and the search tool for the retrieval of interacting genes/proteins database was used to determine the interactions between FLNA and motility-related proteins. An induced pluripotent stem cell (iPSC) line was generated as a disease model by reprogramming human peripheral blood mononuclear cells. The FLNA expression in iPSCs was assessed using western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Immunofluorescence analysis was performed to determine the arrangement of F-actin. A novel FLNA frameshift variant (NM_001456.3: c.1466delG, p. G489Afs*9) was identified in a patient with PVNH and epilepsy. Bioinformatic analysis indicated that this variation was likely to impair FLNA function. Western blot and qRT-PCR analysis of iPSCs derived from the patient's peripheral blood mononuclear cells revealed the absence of FLNA protein and mRNA. Immunofluorescence analysis suggested an irregular arrangement and disorganization of F-actin compared to that observed in healthy donors. Our findings indicate that the frameshift variant of FLNA (NM_001456.3: c.1466delG, p. G489Afs*9) impairs the arrangement and organization of F-actin, potentially influencing cell migration and causing PVNH.

IL-10 alleviates radicular pain by inhibiting TNF-α/p65 dependent Nav1.7 up-regulation in DRG neurons of rats

BackgroundLumbar disc herniation (LDH) may induce radicular pain, the upregulation of voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) contributes to radicular pain by generating ectopic discharge of neurons, but the mechanism is unclear. Previously, we reported pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) up-regulated VGSCs in diabetic neuropathy. In this study, we explored the effect of anti-inflammatory cytokine interleukin-10 (IL-10) on radicular pain and the possible mechanisms. MethodsRat model of LDH was induced by implanting autologous nucleus pulposus (NP). Mechanical and thermal pain thresholds were assessed by von Frey filaments and hotplate test respectively. IL-10 and TNF-α level in DRG and cerebrospinal fluid (CSF) were assessed by Enzyme-linked immunosorbent assay (ELISA). IL-10 was intrathecally delivered for 12 days. The expression of IL-10R1 and sodium channel Nav1.7 was displayed by immunofluorescence staining. The protein level of TNF-α and p-p65 was measured by western blotting. ResultsNP implantation increased Nav1.7 expression in DRG neurons, decreased IL-10 level and increased TNF-α level in DRG and CSF. IL-10 significantly alleviated pain behaviors of rats with NP. IL-10R1 was co-localized with neurons but not with satellite cells in DRG. IL-10 decreased Nav1.7 and TNF-α/p-p65 expression in DRG of rats with NP. Co-administration of TNF-α with IL-10 counteracted the effect of IL-10 on pain behaviors, Nav1.7 and TNF-α/p-p65 expression of rats with NP. ConclusionsThe study revealed that IL-10 alleviated radicular pain by inhibiting TNF-α/p-p65 dependent Nav1.7 up-regulation in DRG neurons.

Resurgent neuropathic discharge: an obstacle to the therapeutic use of neuroma resection?

Ectopic discharge ("ectopia") in damaged afferent axons is a major contributor to chronic neuropathic pain. Clinical opinion discourages surgical resection of nerves proximal to the original injury site for fear of resurgence of ectopia and exacerbated pain. We tested this concept in a well-established animal neuroma model. Teased-fiber recordings were made of ectopic spontaneous discharge originating in the experimental nerve-end neuroma and associated dorsal root ganglia in rats that underwent either a single transection (with ligation) of the sciatic nerve or 2 consecutive transections separated by 7, 14, 21, or 30 days. Ectopia emerged in afferent A and C fibers after a single cut with kinetics anticipated from previous studies. When resection was performed during the early period of intense A-fiber activity, a brief period of resurgence was observed. However, resection of neuromas of more than 14 days was followed by low levels of activity with no indication of resurgence. This remained the case in trials out to 60 days after the first cut. Similarly, we saw no indication of resurgent ectopia originating in axotomized dorsal root ganglion neuronal somata and no behavioral reflection of resurgence. In summary, we failed to validate the concern that proximal resection of a problematic nerve would lead to intense resurgent ectopic discharge and pain. As the well-entrenched concept of resurgence is based more on case reports and anecdotes than on solid evidence, it may be justified to relax the stricture against resecting neuromas as a therapeutic strategy, at least within the framework of controlled clinical trials.

Electrophysiological characterization of ectopic spontaneous discharge in axotomized and intact fibers upon nerve transection: a role in spontaneous pain?

Many patients experience positive symptoms after traumatic nerve injury. Despite the increasing number of experimental studies in models of peripheral neuropathy and the knowledge acquired, most of these patients lack an effective treatment for their chronic pain. One possible explanation might be that most of the preclinical studies focused on the development of mechanical or thermal allodynia/hyperalgesia, neglecting that most of the patients with peripheral neuropathies complain mostly about spontaneous forms of pains. Here, we summarize the aberrant electrophysiological behavior of peripheral nerve fibers recorded in experimental models, the underlying pathophysiological mechanisms, and their relationship with the symptoms reported by patients. Upon nerve section, axotomized but also intact fibers develop ectopic spontaneous activity. Most interestingly, a proportion of axotomized fibers might present receptive fields in the skin far beyond the site of damage, indicative of a functional cross talk between neuromatose and intact fibers. All these features can be linked with some of the symptoms that neuropathic patients experience. Furthermore, we spotlight the consequence of primary afferents with different patterns of spontaneous discharge on the neural code and its relationship with chronic pain states. With this article, readers will be able to understand the pathophysiological mechanisms that might underlie some of the symptoms that experience neuropathic patients, with a special focus on spontaneous pain.

Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation.

Previous studies on the mechanisms of peripheral nerve injury (PNI) have mainly focused on the pathophysiological changes within a single injury site. However, recent studies have indicated that within the central nervous system, PNI can lead to changes in both injury sites and target organs at the cellular and molecular levels. Therefore, the basic mechanisms of PNI have not been comprehensively understood. Although electrical stimulation was found to promote axonal regeneration and functional rehabilitation after PNI, as well as to alleviate neuropathic pain, the specific mechanisms of successful PNI treatment are unclear. We summarize and discuss the basic mechanisms of PNI and of treatment via electrical stimulation. After PNI, activity in the central nervous system (spinal cord) is altered, which can limit regeneration of the damaged nerve. For example, cell apoptosis and synaptic stripping in the anterior horn of the spinal cord can reduce the speed of nerve regeneration. The pathological changes in the posterior horn of the spinal cord can modulate sensory abnormalities after PNI. This can be observed in cases of ectopic discharge of the dorsal root ganglion leading to increased pain signal transmission. The injured site of the peripheral nerve is also an important factor affecting post-PNI repair. After PNI, the proximal end of the injured site sends out axial buds to innervate both the skin and muscle at the injury site. A slow speed of axon regeneration leads to low nerve regeneration. Therefore, it can take a long time for the proximal nerve to reinnervate the skin and muscle at the injured site. From the perspective of target organs, long-term denervation can cause atrophy of the corresponding skeletal muscle, which leads to abnormal sensory perception and hyperalgesia, and finally, the loss of target organ function. The mechanisms underlying the use of electrical stimulation to treat PNI include the inhibition of synaptic stripping, addressing the excessive excitability of the dorsal root ganglion, alleviating neuropathic pain, improving neurological function, and accelerating nerve regeneration. Electrical stimulation of target organs can reduce the atrophy of denervated skeletal muscle and promote the recovery of sensory function. Findings from the included studies confirm that after PNI, a series of physiological and pathological changes occur in the spinal cord, injury site, and target organs, leading to dysfunction. Electrical stimulation may address the pathophysiological changes mentioned above, thus promoting nerve regeneration and ameliorating dysfunction.

Potential Molecular Targets for Treating Neuropathic Orofacial Pain Based on Current Findings in Animal Models.

This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.

In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model.

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents.

Icariin ameliorates partial sciatic nerve ligation induced neuropathic pain in rats: an evidence of in silico and in vivo studies.

Neuropathic pain (NP) is a chronic inflammation of the sciatic nerve, associated with complex pathophysiological events like neuronal ectopic discharge with changes in neurotransmitters, growth factors, receptors/ion channels including N-methyl-d-aspartate receptors, Transient receptor cation channels, Voltage-gated calcium channels. All these events eventually lead to inflammation and apoptosis of the sciatic nerve in NP. Icariin (ICA), a natural flavonoid is well known for its anti-inflammatory potential. Hence, the present study is designed to evaluate its anti-inflammatory potential against neuropathic pain using in silico and in vivo studies. In silico studies were conducted using targets of N-methyl-D-aspartate receptor subtype-2B (NR2B), The capsaicin receptor transient receptor cation channel subfamily-V member-1 (TRPV1), N-type voltage-gated calcium (CaV2.2) channels. In in vivo studies, after partial sciatic nerve ligation surgery to animals, received their respective treatment for 21 days, further TNF-α, IL-6, Bax (proapoptotic) and Bcl-2 (antiapoptotic) expressions were estimated. ICA decreased the expressions of TNF-α, IL-6, Bax and increased expression of Bcl-2. In silico studies revealed a good energy binding score towards NR2B, TRPV1 receptors and CaV2.2 ion Channel. ICA could be a promising agent in alleviating neuropathic pain by inhibiting NR2B, TRPV1 receptors and Cav2.2 channels, which induces anti-apoptotic potential and inhibits inflammation.

Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs.

Simple SummaryChemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition that severely reduces the quality of life of a considerable proportion of cancer patients. There is no cure for CIPN to date. Here, we explore the potential of flavonoids as pharmacological agents in combating CIPN. Flavonoids alleviate CIPN by reducing oxidative stress, inflammation, and neuronal damage, among other mechanisms. Future research should evaluate the efficacy and side effects of flavonoids in human models of CIPN.Purpose: This study aimed to assess the potential of flavonoids in combating CIPN. Methods: PubMed and Google Scholar were used, and studies that investigated flavonoids in models of CIPN and models of neuropathic pain similar to CIPN were included. Only studies investigating peripheral mechanisms of CIPN were used. Results: Flavonoids inhibit several essential mechanisms of CIPN, such as proinflammatory cytokine release, astrocyte and microglial activation, oxidative stress, neuronal damage and apoptosis, mitochondrial damage, ectopic discharge, and ion channel activation. They decreased the severity of certain CIPN symptoms, such as thermal hyperalgesia and mechanical, tactile, and cold allodynia. Conclusions: Flavonoids hold immense promise in treating CIPN; thus, future research should investigate their effects in humans. Specifically, precise pharmacological mechanisms and side effects need to be elucidated in human models before clinical benefits can be achieved.

Basic guide to chronic pain assessment: from neurophysiology to bedside.

Chronic musculoskeletal pain is a highly prevalent condition that is commonly encountered in both general and specialist practice. Nonetheless, it still represents a significant challenge to the practitioners because of the lack of substantial evidence-based guidance. This review aimed to summarize the main pathophysiological mechanisms of chronic pain offering a mechanism-oriented approach to diagnosis and management. We believe that a basic knowledge of the physical signs and symptoms of these mechanisms could empower the clinician to choose appropriate medication and identify high-risk pain patients. Central sensitization and neuropathic features may arise in previously nociceptive and inflammatory pain syndromes. Central sensitization is a functional remodeling of the spinal cord, where light touch afferents are recruited by nociceptive second-order neurons. Neuropathic features include both negative signs, such as reduced perception of vibration and touch, and positive symptoms, such as paroxysmal electric shock pain, due to ectopic discharge. These phenomena are the neurobiological basis of the commonly defined refractory chronic pain. Early detection and specific treatment of these mechanisms are required in order to restrain the reinforcement of pronociceptive remodeling of the nervous system.

Abstract 16545: Sinus Rhythm Dynamics and Ventricular Ectopy in an Experimental Model of Aging

Aging is coupled with alterations of heart rate and heart rate variability (HRV), together with increased incidence of arrhythmias and sudden cardiac death. But whether changes of sinus rhythm properties of the aged heart correlate with enhanced occurrence of ventricular ectopic discharge remains unclear. Thus, we studied the effects of aging on heart rate, HRV, and occurrence of premature ventricular complexes (PVCs) in aging C57Bl/6 mice. Electrocardiograms (ECG) were obtained in male and female conscious mice at ~4, ~12, ~18, and ~24 months of age (n=37-66). Heart rate was preserved at ~4, ~12, and ~18 months (729±30, 730±22, and 725±20 bpm) and reached a minimum at ~24 months (708±37 bpm). Standard deviation of RR intervals, an indicator of HRV, was maximal at ~4 months (3.5±1.7 ms) and was reduced at ~12, ~18, and ~24 months (2.6±1.5, 2.5±1.3, and 2.6±1.3 ms). By frequency domain analysis, high-frequency components of RR interval variations, indicative of parasympathetic influence, were preserved with aging. In contrast, low frequency components, comprising the influence of sympathetic and parasympathetic axis, were maximal in young animals and progressively decrease at ~12, ~18, and ~24 months. PVCs were observed in only 3% of mice at ~4 months, a fraction that increased to 11%, 10%, and 22% at ~12, ~18, and ~24 months, respectively. For each age interval, heart rate and HRV parameters for animals with PVCs were distributed within the range observed in mice not experiencing ventricular ectopy. Moreover, for animals with PVCs, parameters of HRV before the occurrence of ectopic beats were comparable to those observed during undisturbed sinus rhythm, although a tendency for lower heart rate was seen. To address the role of the autonomic nervous system on incidence of ectopic events, ECGs were collected before and after block of the sympathetic and parasympathetic axis in mice at ~4 months (n=30) and ~24 months (n=26). This intervention reduced heart rate in both groups of animals and attenuated HRV exclusively in young. Moreover, combine autonomic block decreased incidence of PVCs by 50% and 57% in young and old animals, respectively. Collectively, these results suggest that occurrence of ventricular ectopy does not correlate with heart rhythm dynamics.

Pacemaking Activity in the Peripheral Nervous System: Physiology and Roles of Hyperpolarization Activated and Cyclic Nucleotide-Gated Channels in Neuropathic Pain.

The most famous pacemaking activity found in the human body is in the cardiac system. However, pacemaking is also widely present in the nervous system. The ion channels responsible for the pacemaking activity are called hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. HCN channels are activated during hyperpolarization and create an inward current named Ih containing mixed sodium and potassium ions. The molecular mechanism of these unique features remains mysterious. In the peripheral nervous system (PNS), pacemaking is unique because it is only present in pathologic states when nerve damage occurs and leads to neuropathic pain. For this reason, pacemaking in neuropathic pain is also known as ectopic discharge. In our literature review, the HCN channel physiology is one of the research interests. We will present studies exploring the molecular mechanisms involved in HCN gating and ion permeability. The second research question is, what makes the pacemaking activity unique in the PNS? Thus, our paper will include studies that discuss the role of HCN channels in neuropathic pain. Given the fundamental role of HCN channels in regulating neuronal cells' discharge activity, the modulation of their function for therapeutic purposes could be useful in various pathological conditions. Here we review the present knowledge of the efficacy of HCN blocker treating neuropathic pain in humans.

Intralesional triamcinolone acetonide in notalgia paresthetica: Treatment outcomes in five patients.

Numerous treatment modalities have been tried with diverse results for pruritus due to notalgia paresthetica (NP). Corticosteroids suppress ectopic neural discharges from injured nerve fibers and also have short-lived suppressive effect on transmission in normal C-fibers. Herein, we evaluated the efficacy of intralesional triamcinolone acetonide in the treatment of NP. The medical reports of five patients who had been diagnosed with NP and treated with intralesional triamcinolone acetonide injections were retrospectively evaluated. Triamcinolone acetonide solution was injected intradermally (10 mg/mL; 0.1 mL/cm2 ) every 3 weeks for a maximum of four treatments. The severity of itch was scored by the patients on a combined numerical and visual analogue scale. After treatment, reduction in itch severity scores varied between 33% and 100%.

Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury.

The neurochemical mechanisms underlying neuropathic pain (NP) are related to peripheral and central sensitization caused by the release of inflammatory mediators in the peripheral damaged tissue and ectopic discharges from the injured nerve, leading to a hyperexcitable state of spinal dorsal horn neurons. The aim of this work was to clarify the role played by cyclooxygenase (COX) in the lesioned peripheral nerve in the development and maintenance of NP by evaluating at which moment the non-steroidal anti-inflammatory drug indomethacin, a non-selective COX inhibitor, attenuated mechanical allodynia after placing one loose ligature around the nervus ischiadicus, an adaptation of Bennett and Xie's model in rodents. NP was induced in male Wistar rats by subjecting them to chronic constriction injury (CCI) of the nervus ischiadicus, placing one loose ligature around the peripheral nerve, and a sham surgery (without CCI) was used as control. Indomethacin (2 mg/kg) or vehicle was intraperitoneally and acutely administered in each group of rats and at different time windows (1, 2, 4, 7, 14, 21, and 28 days) after the CCI or sham surgical procedures, followed by von Frey's test for 30 min. The data showed that indomethacin decreased the mechanical allodynia threshold of rats on the first, second, and fourth days after CCI (P<0.05). These findings suggested that inflammatory mechanisms are involved in the induction of NP and that COX-1 and COX-2 are involved in the induction but not in the maintenance of NP.

Mechanisms of dynamical complexity changes in patterns of sensory neurons under antinociceptive effect emergence

The aim is to elucidate mechanisms of changes in dynamical complexity of impulse activity patterns of sensory neurons during the emergence of the antinociceptive response on the painful stimulus. To solve the problem we used the method of bifurcation analysis that enabled us to determine relations between parameters of the nociceptive neuron model and a type of the solution before and during the emergence of the antinociceptive effect. We have shown that the mechanism of the suppression of ectopic bursting discharges is the base for the changes in the dynamical complexity of patterns in the nociceptive neurons. Under the conditions of the potassium blocking, the molecular mechanism of suppression of these discharges can be connected entirely with the modification of the activation gating system of slow NaV1.8 sodium channels by the specific action of comenic acid that is a drug substance of a new non-opioid analgesic anoceptin. The obtained results explain one of the possible molecular mechanisms of the analgesic suppression of the neuropathic pain.

Atrial fibrillation and its arrhythmogenesis associated with insulin resistance

BackgroundInsulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes develops. The pathophysiology and underlying mechanism are largely unclear.MethodsWe investigated the corresponding mechanism in two IR models of rats fed 15-week high-fat (HFa) and high-fructose/cholesterol (HFr) diets. AF was evaluated and induced by burst atrial pacing. Isolated atrial myocytes were used for whole-cell patch clamp and calcium assessment. Ex vivo whole heart was used for optical mapping. Western blot and immunofluorescence were used for quantitative protein evaluation.ResultsBoth HFa and HFr rat atria were vulnerable to AF evaluated by burst atrial pacing. Isolated atrial myocytes from HFa and HFr rats revealed significantly increased sarcoplasmic reticulum calcium content and diastolic calcium sparks. Whole-heart mapping showed prolonged calcium transient duration, conduction velocity reduction, and repetitive ectopic focal discharge in HFa and HFr atria. Protein analysis revealed increased TGF-β1 and collagen expression; increased superoxide production; abnormal upregulation of calcium-homeostasis-related proteins, including oxidized CaMKIIδ, phosphorylated-phospholamban, phosphorylated-RyR-2, and sodium-calcium exchanger; and increased Rac1 activity in both HFa and HFr atria. We observed that inhibition of CaMKII suppressed AF in both HF and HFr diet-fed rats. In vitro palmitate-induced IR neonatal cardiomyocytes and atrial fibroblasts expressed significantly more TGF-β1 than did controls, suggesting paracrine and autocrine effects on both myocytes and fibroblasts.ConclusionsIR engenders both atrial structural remodeling and abnormal intracellular calcium homeostasis, contributing to increased AF susceptibility. The inhibition of CaMKII may be a potential therapeutic target for AF in insulin resistance.

The Effects of folic acid and topiramate on peripheral nerve regeneration

ABSTRACTPeripheral nerve injury creates unusual sensitivity and pathological spontaneous activity in neurons that are described as ectopic discharge. Voltage dependent Na channels are responsible for ectopic discharge. Topiramate (TOP) inhibits voltage-gated sodium channels by blocking both the amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor and folic acid (FA) activity in neurotransmitter synthesis reactions. FA and TOP are anti-apoptotic agents by both phosphorylated-Akt (p-Akt) signaling activation and anti-inflammatory effects at the injury site. We investigated the effects of FA and TOP in peripheral nerve injury. We used rats with a sciatic nerve injury (SNI) treated with FA or TOP once daily for 6 weeks. Histological and electrophysiological tests were used to evaluate the morphology, and motor and sensory functions. Numbers of axons, myelin sheath thickness and axon area were measured using stereological techniques; functionality also was evaluated. Although FA exhibited a positive effect on regeneration by increasing the number of axons, we found no difference in axonal outgrowth or myelin sheath formation between the TOP and FA groups.

Suppression of neuropathic pain by selective silencing of dorsal root ganglion ectopia using nonblocking concentrations of lidocaine.

Neuropathic pain is frequently driven by ectopic impulse discharge (ectopia) generated in injured peripheral afferent neurons. Observations in the spinal nerve ligation (SNL) model in rats suggest that cell bodies in the dorsal root ganglion (DRG) contribute 3 times more to the ectopic barrage than the site of nerve injury (neuroma). The DRG is therefore a prime interventional target for pain control. Since DRG ectopia is selectively suppressed with lidocaine at concentrations too low to block axonal impulse propagation, we asked whether targeted delivery of dilute lidocaine to the L5 DRG can relieve L5 SNL-induced tactile allodynia without blocking normal sensation or motor function. Results showed that intraforaminal injection of 10-µL bolus doses of 0.2% lidocaine suppressed allodynia transiently, while sustained infusion over 2 weeks using osmotic minipumps suppressed it for the duration of the infusion. Bolus injections of morphine or fentanyl were ineffective. Lidocaine applied to the cut spinal nerve end or the L4 DRG did not affect allodynia, suggesting that discharge originating in the neuroma and in neighboring "uninjured" afferents makes at best a minor contribution. Spike electrogenesis in the DRG is apparently the primary driver of tactile allodynia in the SNL model of neuropathic pain, and it can be controlled selectively by superfusing the relevant DRG(s) with nonblocking concentrations of lidocaine. This approach has potential clinical application in conditions such as postherpetic neuralgia and phantom limb pain in which one or only a few identifiable ganglia are implicated as pain drivers.

Epidural levobupivacaine versus a combination of levobupivacaine and dexamethasone in patients receiving epidural analgesia.

Background and Aims:The use of dexamethasone as an adjuvant to local anesthetic rarely has been described. Some studies have demonstrated the analgesic effect of local spinal and systemic corticosteroids in combination with bupivacaine. It works by decreasing inflammation and blocking transmission of nociceptive C-fibers and by stopping the ectopic discharge of the nerve. The aim of this randomized controlled trial was to compare the efficacy of epidural levobupivacaine alone versus a combination of levobupivacaine with dexamethasone for labor analgesia.Material and Methods:This prospective double-blind trial included the 60 primigravidas during vaginal delivery with a cervical dilatation ≥4 cm and 50% effacement randomly assigned to one of two groups – Group A (n=30): epidural levobupivacaine 0.125% in normal saline in a total volume of 15 mL and Group B (n=30): epidural levobupivacaine 0.125% in normal saline combined with dexamethasone 4 mg in a total volume of 15 mL. At first request of analgesia, 10 mL of 0.125% levobupivacaine was administrated through epidural catheter. Further analgesia was provided with 8 mL of 0.125% levobupivacaine hourly. Primary outcome measure was the duration of epidural analgesia. Secondary outcome measures include pain score by Visual Analog Scale score before the block and 15 min following it, the total amount of levobupivacaine used, Apgar score and umbilical vein blood gas analysis, maternal satisfaction, and side effects recorded.Results and Conclusion:The duration of epidural analgesia was significantly longer (P < 0.05) upon adding dexamethasone to levobupivacaine. Total epidural levobupivacaine consumption was significantly lower (P = 0.05) in Group B. There were no statistical differences between the two groups regarding hemodynamics, pain score, neonatal outcome, and complications. Epidural dexamethasone plus levobupivacaine prolongs the duration of epidural analgesia during management of labor pain with hemodynamic stability and limited maternal and neonatal adverse effects.