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The ability to sense physical forces is conserved across all organisms. Cells convert mechanical stimuli into electrical or chemical signals via mechanically activated ion channels. In recent years, the identification of new families of mechanosensitive ion channels-such as PIEZO and OSCA/TMEM63 channels-along with surprising insights into well-studied mechanosensitive channels have driven further developments in the mechanotransduction field. Several well-characterized mechanosensory roles such as touch, blood-pressure sensing and hearing are now linked with primary mechanotransducers. Unanticipated roles of mechanical force sensing continue to be uncovered. Furthermore, high-resolution structures representative of nearly every family of mechanically activated channel described so far have underscored their diversity while advancing our understanding of the biophysical mechanisms of pressure sensing. Here we summarize recent discoveries in the physiology and structures of known mechanically activated ion channel families and discuss their implications for understanding the mechanisms of mechanical force sensing.
Learn More >Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models.
Learn More >Central sensitization and impaired conditioned pain modulation (CPM) response have been reported to contribute to migraine progression. Migraine patients can present with allodynia possibly attributed to increased sensitivity of peripheral ends of nociceptors with both peripheral and central sensitization. Occipital nerve stimulation (ONS) works by stimulating the distal branches of C1, C2 and C3 possibly altering the nociceptive traffic to the trigemino-cervical complex, brainstem and supranuclear connections.
Learn More >Despite increasing evidence differentiating episodic and chronic migraine, little work has determined how currently utilized animal models of migraine best represent each distinct disease state.
Learn More >Chronic pain is one of the most prevalent causes of disability worldwide, and digital interventions may be one of the ways to meet this need. Randomised controlled trials have demonstrated that digital interventions can be effective in treating chronic pain. This study aimed to establish the clinical effectiveness of a web-based pain management programme (PMP), specifically whether it would lead to improved clinical outcomes and reduced health care costs in a real-world clinical setting.
Learn More >Intrathecal opioid pumps have been used in the management of severe chronic pain for more than 40 years. Numerous studies have shown significant therapeutic effects alongside tolerable side effects. In the last decades, life expectancy has increased in many countries in the world. With an aging population, the question arises whether effects equal to those in younger patients can also be achieved in elderly patients.
Learn More >The aim of this study was to describe the information access behaviours of clinicians involved in pain management with respect to their use of a pain evidence resource and to determine the areas of professional differences.
Learn More >In recent years, studying the central mechanism of itch has gained momentum. However, a proper meta-analysis has not been conducted in this domain. In this study, we tried to respond to this need. A systematic search and a meta-analysis were carried out to estimate the central mechanism of itch. The itch matrix comprises the thalamus and the parietal, secondary somatosensory, insular and cingulate cortices. We have shown that the basal ganglia (BG) play an important role in itch reduction. Finally, we explored itch processing in AD patients and observed that the itch matrix in these patients was different. In conclusion, this is the first meta-analysis on the central mechanisms of itch perception and processing. Our study demonstrated that different modalities of itch induction can produce a common pattern of activity in the brain and provided further insights into understanding the underlying nature of itch central perception.
Learn More >The sodium channel Nav1.7 is a master regulator of nociceptive input into the central nervous system. Mutations in this channel can result in painful conditions and produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting Nav1.7 has not yet produced a clinical drug. Recent work has illuminated the Nav1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Among the regulators of Nav1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound Nav1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2) mice in which Lys374 was replaced with Ala. CRMP2 mice had reduced Nav1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 mice to inflammatory, acute, or visceral pain. By contrast, in a neuropathic model, CRMP2 mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral Nav1.7 is a hallmark of chronic, but not physiological, neuropathic pain.
Learn More >To clarify whether photoreception of intrinsically photosensitive retinal ganglion cells (ipRGCs) is related to migraine, we investigated the relationship between hemodynamic responses related to neural activity and visual stimulation of ipRGCs. It has been established that photoreception in ipRGCs is associated with photophobia in migraine. However, the relationship between visual stimulation of ipRGCs and hemodynamic responses in the visual cortex has not been clarified. Hemodynamic responses in the visual cortex were measured using functional near-infrared spectroscopy (fNIRS) as signals reflecting changes in oxygenated and deoxygenated hemoglobin concentrations. Different types of visual stimulation generated by a metamerism method were applied to the peripheral field of the eye of patients with migraine (N = 20) and healthy participants (N = 21). The stimulation intensity on the retina was controlled using an artificial pupil. In the primary visual cortex of patients with migraine, statistically significant changes in fNIRS signals dependent on visual stimulation intensity applied to ipRGCs were observed (p < 0.01), while no such changes were observed in healthy participants. These results reveal that visual stimulation of ipRGCs projecting to the primary visual cortex is involved in hemodynamic responses in patients with migraine, suggesting that ipRGCs, in addition to photometric values related to cones, are associated with migraine.
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