Kappa opioid receptor (KOR) agonists possess adverse dysphoric and psychotomimetic effects, thus limiting their applications as non-addictive anti-pruritic and analgesic agents. Here, we showed that protein kinase C (PKC) inhibition preserved the beneficial antinociceptive and antipruritic effects of KOR agonists, but attenuated the adverse condition placed aversion (CPA), sedation, and motor incoordination in mice. Using a large-scale mass spectrometry-based phosphoproteomics of KOR-mediated signaling in the mouse brain, we observed PKC-dependent modulation of G protein-coupled receptor kinases and Wnt pathways at 5 min; stress signaling, cytoskeleton, mTOR signaling and receptor phosphorylation, including cannabinoid receptor CB1 at 30 min. We further demonstrated that inhibition of CB1 attenuated KOR-mediated CPA. Our results demonstrated the feasibility of in vivo biochemical dissection of signaling pathways that lead to side effects.Startle stimuli evoke lower responses when presented during the early as compared to the late cardiac cycle phase, an effect that has been called 'cardiac modulation of startle' (CMS). The CMS effect may be associated with visceral-afferent neural traffic, as it is reduced in individuals with degeneration of afferent autonomic nerves. The aim of this study was to investigate whether the CMS effect is due a modulation of only early, automatic stages of stimulus processing by baro-afferent neural traffic, or if late stages are also affected. We, therefore, investigated early and late components of auditory-evoked potentials (AEPs) to acoustic startle stimuli (105, 100, 95 dB), which were presented during the early (R-wave +230 ms) or the late cardiac cycle phase (R +530 ms) in two studies. In Study 1, participants were requested to ignore (n = 25) or to respond to the stimuli with button-presses (n = 24). In Study 2 (n = 23), participants were asked to rate the intensity of the stimuli. We found lower EMG startle response magnitudes (both studies) and slower pre-motor reaction times in the early as compared to the late cardiac cycle phase (Study 1). We also observed lower N1 negativity (both studies), but higher P2 (Study 1) and P3 positivity (both studies) in response to stimuli presented in the early cardiac cycle phase. This AEP modulation pattern appears to be specific to the CMS effect, suggesting that early stages of startle stimulus processing are attenuated, whereas late stages are enhanced by baro-afferent neural traffic.With increasing popularity of internet streaming portals, the question why people develop excessive binge-watching behavior has become a focus of scientific research. The possible negative consequences of this behavior and its proximity to behavioral addictions are discussed. Since deficits of response inhibition and performance monitoring have been associated with substance use and addictive behaviors, we examined the hypothesis whether frequent binge watching is characterized by alterations in these processes. The current study examined response inhibition in a go/nogo task and performance monitoring in a flanker task using electroencephalography. Participants reported frequent binge-watching episodes (HBW, n = 35) or no binge-watching behavior (NBW, n = 33) during the past four weeks. Compared to the NBW group, HBW showed larger P3a and P3b during response inhibition and larger error-related negativity (ERN) for errors in the flanker task. Group differences in behavioral measures were not observed. The neurocognitive profile associated with frequent binge watching differs from externalizing disorders, such as substance use disorders and addictive behaviors, which are more likely to be associated with diminished amplitudes during response inhibition and performance monitoring. Current findings of increased activity in performance monitoring and inhibition tend to be associated with internalizing disorders. Therefore, symptoms such as anxiety and worry may play a role in the development of binge-watching behavior.Although previous studies have reported the association between large-scale brain networks alterations and pathological anxiety, abnormalities in the dynamic interaction among the triple network model in anxiety disorders and, especially, in trait anxiety is still poorly explored. Thus, the main aim of the current study was to investigate triple network functional dynamics in subjects with high trait anxiety during resting state (RS) through electroencephalography (EEG) connectivity. Twenty-three individuals with high-trait-anxiety (HTA) and forty-five participants with low-trait-anxiety (LTA) were enrolled. Biricodar EEG analyses were conducted by means of the exact Low-Resolution Electromagnetic Tomography software (eLORETA). Compared to LTA participants, HTA subjects showed a decrease of alpha connectivity within the salience network (SN), between the dorsal anterior cingulate cortex (dACC) and both left and right anterior insula (AI). Furthermore, SN functional connectivity strength was negatively correlated with higher trait anxiety, even when controlling for potential confounding variables (e.g., depressive and obsessive-compulsive symptoms). Taken together, our results point out a specific functional connectivity pattern in HTA individuals, which consists in a dysfunctional communication within the SN, specifically in the AI-dACC pathway. This functional pattern could underline, at rest, saliency detection and brain correlates of altereted emotion regulation and cognitive control processes typically involved in anxiety.Psychological stress is a risk factor for cardiovascular disease. Individual differences in cardiovascular responses to stress may be an underlying mechanism. The literature examining the relationships between frequency and perceptions of life stress with cardiovascular reactivity to acute stress in the laboratory is inconclusive. Recent work highlights the need to measure cardiovascular reactivity across multiple stress exposures to obtain more comprehensive profiles of reactivity by assessing adaptation over time. The aims of the current study were to examine the relationships between frequency and perceptions of stressful life events with cardiovascular reactivity, as well as adaptation of cardiovascular reactivity over time. Four hundred and fifty-three healthy, young adults (mean (SD) age = 19.5 (1.3) years, 62% female, 66.2% Caucasian, 17.7% Hispanic) completed a single laboratory visit, which included two identical, stress-testing protocols, each consisting of a 10-minute baseline and 4-minute stress task.