"No pain, no gain": The impact of autonomous sensory meridian response on pain perception.

Autonomous sensory meridian response (ASMR) is a phenomenon characterised by a static-like tingling sensation spreading from the scalp and neck to the periphery in response to a variety of audio, visual, and tactile triggers resulting in a highly relaxed state and boosted positive affect. The limited literature on this phenomenon points to a potential of ASMR to alleviate pain. Emerging evidence also suggests that ASMR may be linked to increased sensory sensitivity more broadly. This study aimed to objectively address these claims by administering an algometer (measure of pain tolerance), and a visual analog scale (VAS) (measure of subjective pain sensitivity) to ASMR experiencers and controls at baseline, following an ASMR video, and a control video. Findings indicate that ASMR experiencers have a higher pain sensitivity than controls; however, there was no difference between the two groups in terms of pain tolerance. In addition, any potential analgesic properties associated with experiencing ASMR may reflect protective properties of ASMR buffering against the increased pain sensitivity among ASMR experiencers relative to controls.

Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).

The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.