Afferent Stimulation Research Articles

Kinesiotape on quadriceps and gluteus in counter movement jump and sprint in soccer players

BackgroundKinesiotape (KT) is a technique commonly used in sports practice. It may be beneficial in enhancing muscle function by additional cutaneous afferent stimulation. The objective of this study was to analyse the effect of KT on countermovement jump (CMJ) and 20-m sprints (sp) immediately and 24 h after its application on the quadriceps and gluteus maximus. Methods37 male soccer players (19.7 ± 0.9 years old) were randomly assigned to one of 3 groups: experimental group: KT activation (KTact), placebo group: sham tape (KTst), and control group (CG). Participants performed a 30-min preliminary warm-up, after which they conducted CMJ and 20-m sp tests. These tests were repeated later (with KT application or not) and after 24 h. ResultsIntergroup results found no significant differences either post-test (CMJ, p = 0.115; sp, p = 0.307) or after 24 h (p = 0.053). Intragroup results showed no significant results for CMJ, although 20-m sp seemed to display significant differences in the (KTst) (p = 0.002, post-hoc: 0.015 in pre_sp vs post_sp) and the (KTact) (0.021, in post-hoc: 0.007 in pre_sp vs post_sp), with a moderate effect in pre_sp vs post_sp (0.66) in the (KTact) after KT was applied. ConclusionKT application on the gluteus maximus and quadriceps in young soccer players increases the sprint execution time immediately and 24 h after application, even that the sprint execution time had not been grater that one tenth of the second (0.08 s). It also has no effect on CMJ.

Divergence of neuroimmune circuits activated by afferent and efferent vagal nerve stimulation in the regulation of inflammation.

It has previously been shown that afferent and efferent vagal nerve stimulation potently inhibits lipopolysaccharide (LPS)-induced inflammation Our data show inhibition of inflammation by efferent but not afferent vagal nerve stimulation requires T-cell derived acetylcholine We show that afferent and efferent neuroimmune circuits require β2 -adrenergic receptor signalling ABSTRACT: Chronic inflammation due to inappropriate immune cell activation can have significant effects on a variety of organ systems, reducing lifespan and quality of life. As such, highly targeted control of immune cell activation is a major therapeutic goal. Vagus nerve stimulation (VNS) has emerged as a therapeutic modality that exploits neuroimmune communication to reduce immune cell activation and consequently inflammation. Although vagal efferent fibres were originally identified as the primary driver of anti-inflammatory actions, the vagus nerve in most species of animals predominantly comprises afferent fibres. Stimulation of vagal afferent fibres can also reduce inflammation; it is, however, uncertain how these two neuroimmune circuits diverge. Here we show that afferent VNS induces a mechanism distinct from efferent VNS, ameliorating lipopolysaccharide (LPS)-induced inflammation independently of T-cell derived acetylcholine (ACh) which is required by efferent VNS. Using a β2 -adrenergic receptor antagonist (β2 -AR), we find that immune regulation induced by intact, afferent, or efferent VNS occurs in a β2- AR-dependent manner. Together, our findings indicate that intact VNS activates at least two distinct neuroimmune circuits each with unique mechanisms of action. Selective targeting of either the vagal efferent or afferent fibres may provide more personalized, robust and effective control over inappropriate immune responses.

Afferent vagal stimulation via gastric electrical stimulation alters sympathetic-vagal balance in domestic pigs - a pilot trial.

The disturbance of the sympathetic-vagal balance with increasing sympathetic activity and consecutive increase in cytokine release is a major threat in numerous hyperinflammatory syndromes. Therapeutic interventions that modulate the activity in the sympathetic-vagal system are suggested as an effective treatment in these incidences. The purpose of this pilot study was to investigate the effect of electrical stimulation of the gastric wall on sympathetic-vagal balance. German domestic pigs (n=5) were prepared with a modified gastric tube (mGT) for repetitive gastric electrical stimulation (GES). Electrocardiogram was recorded continuously and heart rate variability (HRV) as measure of sympathetic-vagal activity was calculated for three-minute epochs at baseline condition before GES and during GES condition. In comparison to baseline, activity of the autonomic nervous system (ANS) shifted significantly toward increased dominance of vagal activity during GES with a decrease of normalized low frequency (nLF from 58.00 to 25.52) as marker of sympathetic dominance and parallel increase of normalized high frequency (nHF from 41.48 to 74.16) as marker of vagal dominance. During GES, compared to baseline, no difference in heart rate was found. These results indicate that electrical stimulation of the gastric wall may result in shifting the sympathetic-vagal balance toward a parasympathetic predominance.

Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors

Recent evidence suggests that kappa opioid receptors (KOR) in limbic brain regions such as the amygdala contribute to pain conditions, but underlying mechanisms remain to be determined. The amygdala is an important player in averse-affective aspects of pain and pain modulation. The central nucleus (CeA) serves output functions through projection neurons that include corticotropin releasing factor (CRF) expressing neurons. The CeA is also rich in KOR. Here we tested the novel hypothesis that KOR activation in the CeA generates pain-like behaviors through a mechanism that involves inhibition of synaptic inhibition (disinhibition) of CRF neurons. Intra-CeA administration of a KOR agonist (U-69,593) increased vocalizations of naïve rats to noxious stimuli, and induced anxiety-like behaviors in the open field test (OFT) and avoidance in the conditioned place preference test, without affecting mechanosensory thresholds. Optogenetic silencing of CeA-CRF neurons blocked the facilitatory effects of systemically applied U-69,593 in naïve rats. Patch-clamp recordings of CRF neurons in rat brain slices found that U-69,593 decreased feedforward inhibitory transmission evoked by optogenetic stimulation of parabrachial afferents, but had no effect on monosynaptic excitatory transmission. U-69,593 decreased frequency, but not amplitude, of inhibitory synaptic currents, suggesting a presynaptic action. Multiphoton imaging of CeA-CRF neurons in rat brain slices showed that U-69,593 increased calcium signals evoked by electrical stimulation of presumed parabrachial input. This study shows for the first time that KOR activation increases activity of amygdala CRF neurons through synaptic disinhibition, resulting in averse-affective pain-like behaviors. Blocking KOR receptors may therefore represent a novel therapeutic strategy.

Evidence of two modes of spiking evoked in human firing motoneurones by Ia afferent electrical stimulation.

Neurone firing behaviour is a result of complex interaction between synaptic inputs and cellular intrinsic properties. Intriguing firing behaviour, delayed spiking, was shown in some neurones, in particular, in cat neocortical neurones and rat pyramidal hippocampal neurones. In contrast, the similar spiking mode was not reported for animal spinal motoneurones. In the present study, an attempt was made to look for possible evidence of delayed spiking in human motoneurones firing within the low-frequency, sub-primary range, characteristic for voluntary muscle contractions and postural tasks. Forty-seven firing motor units (MUs) were analyzed in ten experiments on three muscles (the flexor carpi ulnaris, the tibialis anterior, and the abductor pollicis brevis) in four healthy humans. Single MUs were activated by gentle voluntary muscle contractions. MU peri-stimulus time histograms, durations of inter-spike intervals, and motoneurone excitability changes within a target interspike interval were analyzed. It was found that during testing the firing motoneurone excitability by small, transient excitatory Ia afferent volley, depending firstly on volley timing within a target interspike interval and excitatory volley strength, the same motoneurone displayed either the direct short-latency response (the H-reflex) or the delayed response (with prolonged and variable latency). Thus, the findings, for the first time, provide evidence for a possibility of two modes of spiking in firing motoneurones. Methods of the estimation of delayed responses and their possible functional significance are discussed. It is emphasized that, for understanding of this issue, the integration of data from studies on experimental animals and humans is desirable.

Toll-Like Receptor 7 (TLR7) Mediated Transcriptomic Changes on Human Mast Cells.

BackgroundMast cells are skin immune sentinels located in the upper dermis, where wheal formation and sensory nerve stimulation take place. Skin inflammation is occasionally accompanied by mast cell-driven responses with wheals, angioedema, or both. Immunoglobulin E (IgE) antibodies are regarded as typical stimuli to drive mast cell activation. However, various causative factors, including microbial infections, can drive IgE-independent mast cell response. When infected, the innate immunity orchestrates an immune response by activating receptor signaling via Toll-like receptors (TLRs).ObjectiveIn this study, we determined the effect of TLR7 stimulation on mast cells to investigate the possible mechanism of IgE-independent inflammatory response.MethodsHuman mast cell (HMC) line, HMC-1 cells were treated with TLR7 agonist and the morphologic alteration was observed in transmission electron microscopy. Further, TLR7 agonist treated HMC-1 cells were conducted to RNA sequencing to compare transcriptomic features.ResultsHMC-1 cells treated with TLR7 agonist reveals increase of intracellular vesicles, lipid droplets, and ribosomes. Also, genes involved in pro-inflammatory responses such as angiogenesis are highly expressed, and Il12rb2 was the most highly upregulated gene.ConclusionOur data suggest that TLR7 signaling on mast cells might be a potential therapeutic target for mast cell-driven, IgE-independent skin inflammation.

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice.

Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.

Modulation of Muscle Pain Is Not Somatotopically Restricted: An Experimental Model Using Concurrent Hypertonic-Normal Saline Infusions in Humans.

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)—ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)—50 μl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.

Nicotinic receptor activation induces NMDA receptor independent long-term potentiation of glutamatergic signalling in hippocampal oriens interneurons.

Key points Long‐term potentiation of glutamatergic transmission to hippocampal interneurons in stratum oriens does not require NMDA receptors and the induction mechanisms are incompletely understood.Extracellular stimulation, conventionally used to monitor synaptic strength and induce long‐term potentiation (LTP), does not exclusively recruit glutamatergic axons.We used optogenetic stimulation of either glutamatergic or cholinergic afferents to probe the relative roles of different signalling mechanisms in LTP induction.Selective stimulation of cholinergic axons was sufficient to induce LTP, which was prevented by chelating postsynaptic Ca2+ or blocking nicotinic receptors.The present study adds nicotinic receptors to the list of sources of Ca2+ that induce NMDA receptor independent LTP in hippocampal oriens interneurons. Many interneurons located in stratum oriens of the rodent hippocampus exhibit a form of long‐term potentiation (LTP) of glutamatergic transmission that does not depend on NMDA receptors for its induction but, instead, requires Ca2+‐permeable AMPA receptors and group I metabotropic glutamate receptors. A role for cholinergic signalling has also been reported. However, electrical stimulation of presynaptic axons, conventionally used to evoke synaptic responses, does not allow the relative roles of glutamatergic and cholinergic synapses in the induction of LTP to be distinguished. Here, we show that repetitive optogenetic stimulation confined to cholinergic axons is sufficient to trigger a lasting potentiation of glutamatergic signalling. This phenomenon shows partial occlusion with LTP induced by electrical stimulation, and is sensitive to postsynaptic Ca2+ chelation and blockers of nicotinic receptors. ACh release from cholinergic axons is thus sufficient to trigger heterosynaptic potentiation of glutamatergic signalling to oriens interneurons in the hippocampus.

Spinal motor mapping by epidural stimulation of lumbosacral posterior roots in humans.

SummaryEpidural electrical stimulation of the spinal cord is an emergent strategy for the neurological recovery of lower-extremity motor function. Motoneuron pools are thought to be recruited by stimulation of posterior roots. Here, we linked electromyographic data of epidurally evoked lower-extremity responses of 34 individuals with upper motoneuron disorders to a population model of the spinal cord constructed using anatomical parameters of thousands of individuals. We identified a relationship between segmental stimulation sites and activated spinal cord segments, which made spinal motor mapping from epidural space possible despite the complex anatomical interface imposed by the posterior roots. Our statistical approach provided evidence for low-threshold sites of posterior roots and effects of monopolar and bipolar stimulation previously predicted by computer modeling and allowed us to test the impact of different upper motoneuron disorders on the evoked responses. Finally, we revealed a statistical association between intraoperative and postoperative mapping of the spinal cord.

Effects of Electrical Stimulation of NAc Afferents on VP Neurons' Tonic Firing.

Afferents from the nucleus accumbens (NAc) are a major source of input into the ventral pallidum (VP). Research reveals that these afferents are GABAergic, however, stimulation of these afferents induces both excitatory and inhibitory responses within the VP. These are likely to be partially mediated by enkephalin and substance P (SP), which are also released by these afferents, and are known to modulate VP neurons. However, less is known about the potentially differential effects stimulation of these afferents has on subpopulations of neurons within the VP and the cellular mechanisms by which they exert their effects. The current study aimed to research this further using brain slices containing the VP, stimulation of the NAc afferents, and multi-electrode array (MEA) recordings of their VP targets. Stimulation of the NAc afferents induced a pause in the tonic firing in 58% of the neurons studied in the VP, while 42% were not affected. Measures used to reveal the electrophysiological difference between these groups found no significant differences in firing frequency, coefficient of variation, and spike half-width. There were however significant differences in the pause duration between neurons in the dorsal and ventral VP, with stimulation of NAc afferents producing a significantly longer pause (0.48 ± 0.06 s) in tonic firing in dorsal VP neurons, compared to neurons in the ventral VP (0.21 ± 0.09 s). Pauses in the tonic firing of VP neurons, as a result of NAc afferent stimulation, were found to be largely mediated by GABAA receptors, as the application of picrotoxin significantly reduced their duration. Opioid agonists and antagonists were found to have no significant effects on the pause in tonic activity induced by NAc afferent stimulation. However, NK-1 receptor antagonists caused significant decreases in the pause duration, suggesting that SP may contribute to the inhibitory effect of NAc afferent stimulation via activation of NK-1 receptors.

The vagus nerve somatosensory evoked potential in the intact brain: state-of-evidence and some representative vignettes

Objective Scalp-recorded evoked potentials elicited by applying afferent electrical stimulation at the tragus region of the human external ear have shown inconsistent results. We aim to disentangle discrepant findings and interpretations, and put forward novel physiological explanations on the origin of the vagus nerve somatosensory evoked potentials (VSEP). Methods We systematically search and critically appraise in PubMed, Web of Science, and Scielo databases the scientific reports publishing VSEP findings elicited by afferent electrical stimulation at the tragus region from individuals without brain disorders. Eligible studies published from January 2000 to April 2020 were extracted. The following information was identified from each article: number of participants; age; gender; stimulating/recording and grounding electrodes as well as stimulus side, intensity, duration, frequency, and polarity. Information about physiological parameters and neurobiological variables was also extracted. Representative vignettes with novel scalp responses induced by stimulating the tragus were also included to add support to our conclusions. Results 140 healthy participants were identified from six selected reports. Mean age ranged from 24.3 to 61.5 years. Stimulating and recording aspects were miscellaneous among studies. Scalp responses marked as the VSEP were recorded in 76% of participants, and showed high variability, low validity and poor reproducibility. Age correlated with response latencies. There were not gender differences in scalp response parameters. Cardiovascular function was unaltered by tragus stimulation. Vignettes showed that the VSEP was scalp muscle responses. Conclusion VSEP did not fulfil evoked potential guidelines. VSEP corresponded to volume conduction propagating from muscles surrounding scalp recording sites.

Altered Interoceptive Perception and the Effects of Interoceptive Analgesia in Musculoskeletal, Primary, and Neuropathic Chronic Pain Conditions.

Chronic pain (CP) severely disrupts the daily life of millions. Interoception (i.e., sensing the physiological condition of the body) plays a pivotal role in the aetiology and maintenance of CP. As pain is inherently an interoceptive signal, interoceptive frameworks provide important, but underutilized, approaches to this condition. Here we first investigated three facets of interoceptive perception in CP, compared with pain-free controls. We then introduce a novel interoceptive treatment and demonstrate its capacity to reduce pain severity in CP, potentially providing complementary analgesic treatments. Study 1 measured interoceptive accuracy, confidence and sensibility in patients (N = 60) with primary, secondary musculoskeletal, and neuropathic CP. Compared with matched controls, CP participants exhibited significantly lower interoceptive accuracy and interoceptive confidence. Pain severity was predicted positively by interoceptive accuracy, anxiety and depression, and negatively by interoceptive confidence. Study 2 tested a promising new interoceptive treatment for CP, in a single-blind between-subjects design (N = 51) with primary, secondary musculoskeletal, and neuropathic CP patients. The treatment specifically activates the C-Tactile system, by means of controlled stimulation of interoceptive unmyelinated afferents, at 3 cm/s with a force of 2.5 mN. This treatment led to significant pain reduction (mean 23%) in the CP treatment group after only 11 min, while CP controls who received comparable but non-interoceptive stimulation reported no change in pain intensity. These studies highlight the importance of interoceptive approaches to CP and demonstrate the potential of this novel method of C-Tactile stimulation to provide complementary analgesic treatments.

A Bayesian approach to analysing cortico-cortical associative stimulation induced increases in the excitability of corticospinal projections in humans

Repeated pairing of transcranial magnetic stimulation (TMS) over left and right primary motor cortex (M1), at intensities sufficient to generate descending volleys, produces sustained increases in corticospinal excitability. In other paired associative stimulation (PAS) protocols, in which peripheral afferent stimulation is the first element, changes in corticospinal excitability achieved when the second stimulus consists of brief bursts of transcranial alternating current stimulation (tACS), are comparable to those obtained if TMS is used instead (McNickle and Carson 2015). The present aim was to determine whether associative effects are induced when the first stimulus of a cortico-cortical pair is tACS, or alternatively subthreshold TMS. Bursts of tACS (500 ms; 140 Hz; 1 mA) were associated (180 stimulus pairs) with single magnetic stimuli (120% resting motor threshold rMT) delivered over the opposite (left) M1. The tACS ended 6 ms prior to the TMS. In a separate condition, TMS (55% rMT) was delivered to right M1 6 ms before (120% rMT) TMS was applied over left M1. In a sham condition, TMS (120% rMT) was delivered to left M1 only. The limitations of null hypothesis significance testing are well documented. We therefore employed Bayes factors to assess evidence in support of experimental hypotheses—defined precisely in terms of predicted effect sizes, that these two novel variants of PAS increase corticospinal excitability. Although both interventions induced sustained (~ 20–30 min) increases in corticospinal excitability, the evidence in support of the experimental hypotheses (over specified alternatives) was generally greater for the paired TMS-TMS than the tACS-TMS conditions.

Low-Threshold Mechanosensitive VGLUT3-Lineage Sensory Neurons Mediate Spinal Inhibition of Itch by Touch.

Innocuous mechanical stimuli, such as rubbing or stroking the skin, relieve itch through the activation of low-threshold mechanoreceptors. However, the mechanisms behind this inhibition remain unknown. We presently investigated whether stroking the skin reduces the responses of superficial dorsal horn neurons to pruritogens in male C57BL/6J mice. Single-unit recordings revealed that neuronal responses to chloroquine were enhanced during skin stroking, and this was followed by suppression of firing below baseline levels after the termination of stroking. Most of these neurons additionally responded to capsaicin. Stroking did not suppress neuronal responses to capsaicin, indicating state-dependent inhibition. Vesicular glutamate transporter 3 (VGLUT3)-lineage sensory nerves compose a subset of low-threshold mechanoreceptors. Stroking-related inhibition of neuronal responses to chloroquine was diminished by optogenetic inhibition of VGLUT3-lineage sensory nerves in male and female Vglut3-cre/NpHR-EYFP mice. Conversely, in male and female Vglut3-cre/ChR2-EYFP mice, optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited firing responses of spinal neurons to pruritogens after the termination of stimulation. This inhibition was nearly abolished by spinal delivery of the κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride, but not the neuropeptide Y receptor Y1 antagonist BMS193885. Optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited pruritogen-evoked scratching without affecting mechanical and thermal pain behaviors. Therefore, VGLUT3-lineage sensory nerves appear to mediate inhibition of itch by tactile stimuli.SIGNIFICANCE STATEMENT Rubbing or stroking the skin is known to relieve itch. We investigated the mechanisms behind touch-evoked inhibition of itch in mice. Stroking the skin reduced the activity of itch-responsive spinal neurons. Optogenetic inhibition of VGLUT3-lineage sensory nerves diminished stroking-evoked inhibition, and optogenetic stimulation of VGLUT3-lineage nerves inhibited pruritogen-evoked firing. Together, our results provide a mechanistic understanding of touch-evoked inhibition of itch.

A Photo Stability Indicating HPLC technique for Validation of Netupitant and Palonosetron in Bulk and Formulations

Analytical chemistry is the science that seeks ever improved means of measuring the chemical composition of natural and artificial materials.Netupitant Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 receptors. Palonosetron is a selective serotonin 5-HT3 receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally and peripherally in turn inhibits the visceral afferent stimulation of the vomiting center.The mobile phase used was orthophosphoric and acetate 70% buffer pH 3 and 30% methanol.The assay of Netupitant and Palanosetron was performed with tablets and the % assay was found to be 100.08 and 100.04, The linearity was found to be linear with a correlation coefficient of 0.999, the precision 0.8 and 0.3 for Netupitant and Palanosetron which shows that the method is precise.The validation of developed method shows that the accuracy is well within the limit, which shows that the method is capable of showing good accuracy and reproducibility. The LOD and LOQ for Netupitant were found to be 3.02 and 9.98 and LOD and LOQ for Palanosetron was found to be 3.00 and 10.00. Thus, it shows that the method is stability indicating, sensitive, accurate, robust and precise. Hence, the developed HPLC method can be successfully applied to the pharmaceutical dosage form and can be used for routine analysis.
 
 

Prefrontal Cortex-Driven Dopamine Signals in the Striatum Show Unique Spatial and Pharmacological Properties.

Dopamine (DA) signals in the striatum are critical for a variety of vital processes, including motivation, motor learning, and reinforcement learning. Striatal DA signals can be evoked by direct activation of inputs from midbrain DA neurons (DANs) as well as cortical and thalamic inputs to the striatum. In this study, we show that in vivo optogenetic stimulation of prelimbic (PrL) and infralimbic (IL) cortical afferents to the striatum triggers an increase in extracellular DA concentration, which coincides with elevation of striatal acetylcholine (ACh) levels. This increase is blocked by a nicotinic ACh receptor (nAChR) antagonist. Using single or dual optogenetic stimulation in brain slices from male and female mice, we compared the properties of these PrL/IL-evoked DA signals with those evoked by stimulation from midbrain DAN axonal projections. PrL/IL-evoked DA signals are undistinguishable from DAN evoked DA signals in their amplitudes and electrochemical properties. However, PrL/IL-evoked DA signals are spatially restricted and preferentially recorded in the dorsomedial striatum. PrL/IL-evoked DA signals also differ in their pharmacological properties, requiring activation of glutamate and nicotinic ACh receptors. Thus, both in vivo and in vitro results indicate that cortical evoked DA signals rely on recruitment of cholinergic interneurons, which renders DA signals less able to summate during trains of stimulation and more sensitive to both cholinergic drugs and temperature. In conclusion, cortical and midbrain inputs to the striatum evoke DA signals with unique spatial and pharmacological properties that likely shape their functional roles and behavioral relevance.SIGNIFICANCE STATEMENT Dopamine signals in the striatum play a critical role in basal ganglia function, such as reinforcement and motor learning. Different afferents to the striatum can trigger dopamine signals, but their release properties are not well understood. Further, these input-specific dopamine signals have only been studied in separate animals. Here we show that optogenetic stimulation of cortical glutamatergic afferents to the striatum triggers dopamine signals both in vivo and in vitro These afferents engage cholinergic interneurons, which drive dopamine release from dopamine neuron axons by activation of nicotinic acetylcholine receptors. We also show that cortically evoked dopamine signals have other unique properties, including spatial restriction and sensitivity to temperature changes than dopamine signals evoked by stimulation of midbrain dopamine neuron axons.

A stimulus rate that is not influenced by homosynaptic post-activation depression in chronic stroke

Purpose To determine a stimulus rate that is not influenced by homosynaptic post-activation depression for H-reflex studies in patients with chronic spasticity. Materials and methods A cohort of 15 chronic stroke patients with soleus spasticity who received inpatient treatment at our rehabilitation centre participated in this study. The effect of stimulus frequency related depression on H-reflex size was tested using four different stimulus rates (0.1, 0.2, 0.3 and 1 Hz). The affected sides stibial nerve was stimulated by a bipolar electrode. The H-reflex was recorded from the affected sideed sidee sidehe affected smine stimulus frequency related depression of H-reflex size, amplitude of the first H-reflex response (H1) was used as control and amplitude of the second H-reflex response (H2) as test. Results H2 amplitude for frequency of 1 Hz, 0.3 Hz, 0.2 Hz and 0.1 Hz were 74.3, 84.1, 85.5 and 92.7% of H1, respectively. Depression of H2 amplitude was statistically significant for 1 Hz, 0.3 Hz and 0.2 Hz (p < 0.001, p = 0.002, p = 0.024, respectively). Conclusions Higher frequency stimulation of Ia afferents than 0.1 Hz induced a stimulus frequency-related depression of H-reflex size in patients with chronic spasticity. The optimal stimulus rate for H-reflex was found to be 0.1 Hz.

Leptin Sensitizes NTS Neurons to Vagal Input by Increasing Postsynaptic NMDA Receptor Currents.

Leptin signaling within the nucleus of the solitary tract (NTS) contributes to the control of food intake, and injections of leptin into the NTS reduce meal size and increase the efficacy of vagus-mediated satiation signals. Leptin receptors (LepRs) are expressed by vagal afferents as well as by a population of NTS neurons. However, the electrophysiological properties of LepR-expressing NTS neurons have not been well characterized, and it is unclear how leptin might act on these neurons to reduce food intake. To address this question, we recorded from LepR-expressing neurons in horizontal brain slices containing the NTS from male and female LepR-Cre X Rosa-tdTomato mice. We found that the vast majority of NTS LepR neurons received monosynaptic innervation from vagal afferent fibers and LepR neurons exhibited large synaptic NMDA receptor (NMDAR)-mediated currents compared with non-LepR neurons. During high-frequency stimulation of vagal afferents, leptin increased the size of NMDAR-mediated currents, but not AMPAR-mediated currents. Leptin also increased the size of evoked EPSPs and the ability of low-intensity solitary tract stimulation to evoke action potentials in LepR neurons. These effects of leptin were blocked by bath applying a competitive NMDAR antagonist (DCPP-ene) or by an NMDAR channel blocker applied through the recording pipette (MK-801). Last, feeding studies using male rats demonstrate that intra-NTS injections of DCPP-ene attenuate reduction of overnight food intake following intra-NTS leptin injection. Our results suggest that leptin acts in the NTS to reduce food intake by increasing NMDAR-mediated currents, thus enhancing NTS sensitivity to vagal inputs.SIGNIFICANCE STATEMENT Leptin is a hormone that critically impacts food intake and energy homeostasis. The nucleus of the solitary tract (NTS) is activated by vagal afferents from the gastrointestinal tract, which promotes termination of a meal. Injection of leptin into the NTS inhibits food intake, while knockdown of leptin receptors (LepRs) in NTS neurons increases food intake. However, little was known about how leptin acts in the NTS neurons to inhibit food intake. We found that leptin increases the sensitivity of LepR-expressing neurons to vagal inputs by increasing NMDA receptor-mediated synaptic currents and that NTS NMDAR activation contributes to leptin-induced reduction of food intake. These findings suggest a novel mechanism by which leptin, acting in the NTS, could potentiate gastrointestinal satiation signals.

Attenuation of exaggerated blood pressure responses to exercise: a byproduct of improved vascular function with passive heat therapy?

Attenuation of exaggerated blood pressure responses to exercise: a byproduct of improved vascular function with passive heat therapy?