Effects of Sensory Behavioral Tasks on Pain Threshold and Cortical Excitability

Background/Objective

Transcutaneous electrical stimulation has been proven to modulate nervous system activity, leading to changes in pain perception, via the peripheral sensory system, in a bottom up approach. We tested whether different sensory behavioral tasks induce significant effects in pain processing and whether these changes correlate with cortical plasticity.

Methodology/Principal Findings

This randomized parallel designed experiment included forty healthy right-handed males. Three different somatosensory tasks, including learning tasks with and without visual feedback and simple somatosensory input, were tested on pressure pain threshold and motor cortex excitability using transcranial magnetic stimulation (TMS). Sensory tasks induced hand-specific pain modulation effects. They increased pain thresholds of the left hand (which was the target to the sensory tasks) and decreased them in the right hand. TMS showed that somatosensory input decreased cortical excitability, as indexed by reduced MEP amplitudes and increased SICI. Although somatosensory tasks similarly altered pain thresholds and cortical excitability, there was no significant correlation between these variables and only the visual feedback task showed significant somatosensory learning.

Conclusions/Significance

Lack of correlation between cortical excitability and pain thresholds and lack of differential effects across tasks, but significant changes in pain thresholds suggest that analgesic effects of somatosensory tasks are not primarily associated with motor cortical neural mechanisms, thus, suggesting that subcortical neural circuits and/or spinal cord are involved with the observed effects. Identifying the neural mechanisms of somatosensory stimulation on pain may open novel possibilities for combining different targeted therapies for pain control.     

Agonists of Orally Expressed TRP Channels Stimulate Salivary Secretion and Modify the Salivary Proteome

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Highlights

• •Salivary secretion was increased by mouth rinsing with TRP channel agonists.
• •The salivary proteome varied over time and was changed by TRP channel stimulation.
• •Immunoreactive Cystatin S was increased in saliva after TRPV1 stimulation.

     

Temperature Coefficients of the Electrical Thresholds of Taste Sensations

Each papilla in an enlarged photograph of the tip of the tongue was identified electrically as belonging to one of the four basic taste sensations. The temperature coefficient of the threshold for electrical stimulation was observed for single papillae. The results seem to divide the four basic taste sensations into two different groups: sour-salty and sweet-bitter. This is the same division that has been reported with other methods.     

In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists

Background

GPCRs regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal.

Methods and Findings

In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOR-eGFP) in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. An initial treatment with the high (SNC80) or low (AR-M100390) internalizing agonist equally reduced CFA-induced inflammatory pain. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system. This loss of function was temporary, since full DOR-eGFP receptor responses were restored 24 hours after SNC80 administration. In contrast, treatment with AR-M100390 resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Finally SNC80 but not AR-M100390 produced DOR-eGFP phosphorylation, suggesting that the two agonists produce distinct active receptor conformations in vivo which likely lead to differential receptor trafficking.

Conclusions

Together our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo. This finding has both fundamental and therapeutic implications for slow-recycling GPCRs.     

温度感受器和触觉感受器的发现

2021年诺贝尔生理学或医学奖授予美国生理学家戴维·朱利叶斯(David Julius)和分子生物学家阿德姆·帕塔普蒂安(Ardem Patapoutian),以表彰他们在发现温度感受器和触觉感受器中所做出的突出贡献.机体对热、冷和机械压力等外界刺激的感知能力对于人们适应不断变化的环境至关重要,可以避免其遭受伤害.在D...     

Physiological and Behavioral Effects of Zinc and Temperature on Coho Salmon (Oncorhynchus kisutch)

Pacific salmon species including the U.S. federally endangered coho salmon (Oncorhynchus kisutch) and the U.S. federally threatened steelhead trout (Oncorhynchus mykiss) have declined at an alarming rate in the last 40 years. Two of the main causes for the decline in coastal coho populations include increases in temperature and contaminant loads in coastal watersheds. Zinc, in particular, is one of the most common contaminants in aquatic systems. Using an experimental mesocosm design, we examined physiological, biochemical, and behavioral responses of coho salmon to excess dietary zinc and increased temperatures, with the ultimate goal of relating results to wild populations of coho salmon and steelhead in the Navarro River, California. Fish were obtained from a hatchery and divided into four treatments: low water temperature-no dietary zinc, high temperature-no zinc, low temperature-zinc, and high temperature-zinc. Each treatment had four replicate tanks. Zinc concentrations in liver increased during exposure to a high zinc diet. Iron concentrations in liver increased during simultaneous exposure to high zinc diet and increased temperature, and growth was reduced in this experimental treatment. Expression of hsp-70 was not significantly different between treatments, but showed decreasing trends with high dietary zinc and high temperature. Feeding rate increased with exposure to a high zinc diet. Comparison with steelhead trout samples from the Navarro River, California, showed levels of zinc, iron, and hsp-70 greater than those found in the experimental Coho salmon. All comparisons between the hatchery coho salmon and wild steelhead should be viewed with caution due to the differences between species, the laboratory and natural environment, and the genetic differences between wild and hatchery fish.     

Spatial Features of Vibrotactile Masking Effects on Airpuff-Elicited Sensations in the Human Hand

It was recently shown that the cutaneous sensitivity to airpuffs is decreased by a low-frequency vibrotactile masker in the hairy skin, and by a low-frequency but especially by a high-frequency masker in the glabrous skin. In the current study, the spatial features of this masking effect were determined in four healthy human subjects, using a reaction time paradigm. The masking effect decreased monotonically with increasing interstimulus distance, and identically in longitudinal and transverse (i.e., lateral) directions in the palm or dorsal surface of the hand. The masking effect was stronger in the glabrous than in the hairy skin, especially in the fingers. In the glabrous skin, the spread of masking effect produced by a high-frequency masker was more extensive than that produced by a low-frequency masker. The mechanical spread of high-frequency vibration was less extensive than that of low-frequency vibration in the skin. In the glabrous skin, a masker applied to the tip of the finger produced a stronger masking effect on sensations in the base of the finger than when the masker was located at the base and the test stimulus was located at the tip. It is concluded that mechanical spread of vibration in the skin is of minor importance in explaining the masking effects. Different peripheral neural mechanisms underlie the airpuff-elicited sensations in the hairy and glabrous skin. The afferent inhibitory mechanisms are stronger for signals coming from the glabrous skin of the fingers than for signals coming from the hairy skin. Furthermore, the peripheral innervation density and size of the cortical representational areas may be of importance in determining the magnitude of the masking effect.     

果蝇TRP离子通道C端一个新钙调蛋白结合位点的鉴定和分析

瞬时受体电位(TRP)通道是一类钙离子透过性的阳离子通道蛋白家族,参与了视觉、味觉、温度感受等重要的生物学过程。之前的研究表明,钙离子既能够正反馈也能够负反馈地调节瞬时受体电位通道的活性,而这种调节可能是通过钙调蛋白（calmodulin,CaM）与TRP通道的相互作用来进行的。为了阐明这一调控机制,我们首先需要对钙调蛋白与瞬时受体电位通道之间的相互作用进行详细的生化研究。在此项研究中,通过大肠杆菌表达系统,表达和纯化了果蝇瞬时受体电位通道羧基末端不同长短的蛋白片段,并发现了一个新的钙调蛋白结合位点。通过快速蛋白液相色谱、静态光散射以及等温量热滴定技术,鉴定了这一钙调蛋白结合位点与果蝇瞬时受体电位通道之间的相互作用,发现它们在钙离子依赖的条件下,可以形成亲和力非常强的稳定的蛋白复合物（解离常数在01～1微摩尔范围）。此外,通过合成多肽的方法,鉴定了果蝇瞬时受体电位通道913～939片段为该钙调蛋白结合位点的核心区域。最后,通过突变实验,进一步明确了果蝇瞬时受体电位通道922位的酪氨酸以及923位的缬氨酸为其钙调蛋白结合位点的关键氨基酸。总而言之,本研究发现和鉴定了果蝇瞬时受体电位通道上一个新的钙依赖的钙调蛋白结合位点,这一发现将为研究瞬时受体电位通道的体内功能提供生化基础,为阐明钙离子通过钙调蛋白调节瞬时受体电位通道的分子机制做出贡献。     

The Integrity of the TRP Domain Is Pivotal for Correct TRPV1 Channel Gating

Transient receptor potential vanilloid subtype I (TRPV1) is a thermosensory ion channel that is also gated by chemical substances such as vanilloids. Adjacent to the channel gate, this polymodal thermoTRP channel displays a TRP domain, referred to as AD1, that plays a role in subunit association and channel gating. Previous studies have shown that swapping the AD1 in TRPV1 with the cognate from the TRPV2 channel (AD2) reduces protein expression and produces a nonfunctional chimeric channel (TRPV1-AD2). Here, we used a stepwise, sequential, cumulative site-directed mutagenesis approach, based on rebuilding the AD1 domain in the TRPV1-AD2 chimera, to unveil the minimum number of amino acids needed to restore protein expression and polymodal channel activity. Unexpectedly, we found that virtually full restitution of the AD1 sequence is required to reinstate channel expression and responses to capsaicin, temperature, and voltage. This strategy identified E692, R701, and T704 in the TRP domain as important for TRPV1 activity. Even conservative mutagenesis at these sites (E692D/R701K/T704S) impaired channel expression and abolished TRPV1 activity. However, the sole mutation of these positions in the TRPV1-AD2 chimera (D692E/K701R/S704T) was not sufficient to rescue channel gating, implying that other residues in the TRP domain are necessary to endow activity to TRPV1-AD2. A biophysical analysis of a functional chimera suggested that mutations in the TRP domain raised the energetics of channel gating by altering the coupling of stimuli sensing and pore opening. These findings indicate that inter- and/or intrasubunit interactions in the TRP domain are essential for correct TRPV1 gating.     

Scavenging Effects of Dopamine Agonists on Nitric Oxide Radicals

Abstract: It has recently been considered that free radicals are closely involved in the pathogenesis of Parkinson's disease (PD), and the level of nitric oxide radical (^•NO), one of the free radicals, is reported to increase in PD brain. In the present study, we established a direct detection system for ^•NO in an in vitro ^•NO-generating system using 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)- N -methyl-1-propanamine as an ^•NO donor and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO) by electron spin resonance (ESR) spectrometry and examined the quenching effects of the dopamine agonists pergolide and bromocriptine on the amount of ^•NO generated. ^•NO appeared to be scavenged by pergolide and, to a lesser extent, by bromocriptine. In the competition assay, the 50% inhibitory concentration values for pergolide and bromocriptine were estimated to be ∼23 and 200 µ M , respectively. It was previously reported that in vivo treatment of pergolide and bromocriptine completely protected against the decrease in levels of striatal dopamine and its metabolites in the 6-hydroxydopamine-injected mouse. Considering these findings, pergolide and probably bromocriptine may also protect against dysfunction of dopaminergic neurons because of its multiple effects; not only does it stimulate the presynaptic autoreceptors, but it also directly scavenges ^•NO radicals and hence protects against ^•NO-related cytotoxicity. This ESR spectrometry method using carboxy-PTIO may be useful for screening other drugs that can quench ^•NO.     

Comparative Efficacy of GABAA and GABAB Receptor Agonists in Pain Alleviation in a Spinal Cord Injury Model of Neuropathic Pain

Neurophysiology - We investigated the effectiveness of intrathecal introduction of GABAA and GABAB receptor agonists in reversing pain modalities in a central model of neuropathic pain. In adult...     

Testing the Effects of Classroom Supports on Children's Social and Behavioral Skills at Key Transition Points Using Latent Growth Modeling

Social and behavioral problems can interfere with a child's acquisition of age-appropriate skills, which may lead to antisocial behavior in adolescence and adulthood. Thus, determining how best to support positive skills during early childhood is critical. Using data from the first three phases of the NICHD Study of Early Child Care and Youth Development, I investigated whether participation in preschool, first, or third grade classrooms that were more emotionally supportive or academically focused resulted in better social skills and fewer problem behaviors at key transition points (i.e., preschool and third grade) than did participation in classrooms that were less supportive or less academically focused. Three findings are noteworthy. First, more emotionally supportive classrooms resulted in better social skills and fewer problem behaviors in preschool and third grade, even after correcting for observed family, child, and neighborhood selection factors; this effect did not exist for classrooms that were more academically focused. Second, immersion in classrooms that were more emotionally supportive at preschool, first, and third grade led to better social skills and fewer problem behaviors in preschool and third grade than did immersion in classrooms of average or below average emotional support across this period. Third, observed child factors, as opposed to family or neighborhood factors, seem to drive the pattern of findings. Effect sizes were small to modest. Implications for practice and future research are discussed.     

Perovskite Solar Cells go Outdoors: Field Testing and Temperature Effects on Energy Yield

Perovskite solar cells (PSC) have shown that under laboratory conditions they can compete with established photovoltaic technologies. However, controlled laboratory measurements usually performed do not fully resemble operational conditions and field testing outdoors, with day‐night cycles, changing irradiance and temperature. In this contribution, the performance of PSCs in the rooftop field test, exposed to real weather conditions is evaluated. The 1 cm² single‐junction devices, with an initial average power conversion efficiency of 18.5% are tracked outdoors in maximum power point over several weeks. In parallel, irradiance and air temperature are recorded, allowing us to correlate outside factors with generated power. To get more insight into outdoor device performance, a comprehensive set of laboratory measurements under different light intensities (10% to 120% of AM1.5) and temperatures is performed. From these results, a low power temperature coefficient of ?0.17% K^?1 is extracted in the temperature range between 25 and 85 °C. By incorporating these temperature‐ and light‐dependent PV parameters into the energy yield model, it is possible to correctly predict the generated energy of the devices, thus validating the energy yield model. In addition, degradation of the tested devices can be tracked precisely from the difference between measured and modelled power.     

Testing the Effects of Biogenic Amines and Alternative Topical Solvent Types on the Behavioral Repertoire of Two Web‐Building Spiders

Investigating the proximate mechanism underlying behavior has long been a primary goal of ethologists. With the recent focus on behavioral correlations (e.g., behavioral syndromes), a fundamental question arises regarding what mechanisms may drive positive relationships between functionally distinct behaviors. Understanding these mechanisms can inform critical questions, such as why distinct behaviors are often correlated, and can also lend insights into how behavioral similarities are conserved across species. Arthropods provide an idea system to study these questions as the biogenic amines, such as octopamine and serotonin, have long been known to mediate a large number of behaviors such as aggression, dominance, escape behavior, and others. Behaviorists have several ways in which they can manipulate these biogenic amines in vivo, including injection, feeding, and topical application. Topical application is potentially an optimal method for manipulating amine concentrations, given that it is minimally invasive and relatively precise. Here, we investigate the role of biogenic amines, octopamine, and serotonin, in mediating a range of similar and often correlated behaviors in two distantly related species of spiders, the western black widow, Latrodectus hesperus, and the funnel‐web spider, Agelenopsis pennsylvanica. Additionally, we investigate the behavioral effects associated with three commonly used carrier solvents: dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and acetone. We demonstrate that biogenic amines are involved both in mediating several behaviors, and also potentially the links between different behaviors. We also show that the same behaviors in different species are not affected by biogenic amines in the same manner, suggesting differences in the underlying neurophysiological mechanisms governing behavior. Furthermore, we discovered large and pervasive effects associated with both carrier solvents, thus calling into question the potential usefulness and interpretability of topical application methods in behavioral research.