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Validated chronic migraine biomarkers could improve diagnostic, prognostic, and predictive abilities for clinicians and researchers, as well as increase knowledge on migraine pathophysiology.
Learn More >Binding of arrestin to phosphorylated G-protein-coupled receptors (GPCRs) controls many aspects of cell signaling. The number and arrangement of phosphates may vary substantially for a given GPCR, and different phosphorylation patterns trigger different arrestin-mediated effects. Here, we determine how GPCR phosphorylation influences arrestin behavior by using atomic-level simulations and site-directed spectroscopy to reveal the effects of phosphorylation patterns on arrestin binding and conformation. We find that patterns favoring binding differ from those favoring activation-associated conformational change. Both binding and conformation depend more on arrangement of phosphates than on their total number, with phosphorylation at different positions sometimes exerting opposite effects. Phosphorylation patterns selectively favor a wide variety of arrestin conformations, differently affecting arrestin sites implicated in scaffolding distinct signaling proteins. We also reveal molecular mechanisms of these phenomena. Our work reveals the structural basis for the long-standing "barcode" hypothesis and has important implications for design of functionally selective GPCR-targeted drugs.
Learn More >Up to 20% of people who undergo total knee replacement surgery have ongoing pain and discomfort. The aim of this study was to understand what role the concepts of embodiment (of both having a body and experiencing the world through one's body) and incorporation (integrating something into one's body) might have in understanding experiences of pain and discomfort after total knee replacement.
Learn More >A noxious stimulus following a more intense stimulus often feels less painful than continuous noxious stimulation. This effect, known as offset analgesia (OA), may be due to descending inhibitory control, to changes in peripheral neural transmission, or both. The timing and location of noxious thermal stimulation were manipulated to better understand the peripheral and central contributions to OA.
Learn More >Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive, vibration-sensing neurons are associated with Meissner's corpuscles in the skin. In the present study, we found that USH2A, a transmembrane protein with a very large extracellular domain, was found in terminal Schwann cells within Meissner's corpuscles. Pathogenic USH2A mutations cause Usher's syndrome, associated with hearing loss and visual impairment. We show that patients with biallelic pathogenic USH2A mutations also have clear and specific impairments in vibrotactile touch perception, as do mutant mice lacking USH2A. Forepaw rapidly adapting mechanoreceptors innervating Meissner's corpuscles, recorded from Ush2a mice, showed large reductions in vibration sensitivity. However, the USH2A protein was not found in sensory neurons. Thus, loss of USH2A in corpuscular end-organs reduced mechanoreceptor sensitivity as well as vibration perception. Thus, a tether-like protein is required to facilitate detection of small-amplitude vibrations essential for the perception of fine-grained tactile surfaces.
Learn More >The hippocampus is an important region for the interaction between depression and pain. Studies show that the P2X4 receptor plays key role in neuropathic pain. This work investigated the potential implication of the P2X4 receptor in the hippocampus in comorbidity of chronic pain and depression. The rat model induced by chronic constriction injury (CCI) plus unpredictable chronic mild stress (UCMS) was used in this study. Our data showed that CCI plus UCMS treatment resulted in abnormal changes in pain and depressive-like behaviors in the rat, accompanied by the upregulated expression of P2X4, NLRP3 (NOD-like receptor protein 3) inflammasome, and interleukin-1β and the activation of p38 MAPK in the hippocampus. The P2X4 antagonist 5-BDBD reversed these abnormal changes in the hippocampus, relieved hippocampal neuronal damage, and alleviated the abnormal pain and depressive-like behaviors in the CCI plus UCMS treated rats. These findings suggest that the P2X4 receptor in the hippocampus may mediate and significantly contribute to the pathological processes of comorbid pain and depression.
Learn More >In this brief report, we demonstrate that the Ca3.3 T-type voltage-gated calcium channel subtype is involved in our FRICT-ION model of chronic trigeminal neuropathic pain. We first showed that the gene encoding Ca3.3 is significantly upregulated in whole trigeminal ganglia of FRICT-ION mice compared to controls at week 10 post-injury. We confirmed protein upregulation of Ca3.3 compared to controls using Western blot analysis of whole trigeminal ganglia tissues. Finally, we demonstrated that intraperitoneal injection of a selective TAT-based Ca3.3 blocking peptide in FRICT-ION mice significantly reduces Ca3.3 protein expression at the peak anti-allodynic effect (4 hrs post-injection) of the attenuated neuropathic pain behavior. We also suggest that blockade of Ca3.3 may be more effective in attenuating trigeminal neuropathic pain in female than male FRICT-ION mice. Therefore, blocking or attenuating Ca3.3 function may be an effective strategy for treatment of trigeminal neuropathic pain.
Learn More >Itch in patients with chronic kidney disease (CKD) is common, often very distressing and associated with depression, reduced quality of life, and increased death. The most common first-line treatment has been the use of antihistamines despite the lack of substantial evidence for its use for uraemic itch. Few recommendations and guidelines exist for treatment.
Learn More >Our knowledge of the pathophysiology of migraine and the molecules implicated in the disorder have evolved over time. Among these, calcitonin gene-related peptide has shown a crucial role that led to the development of therapies specifically targeting the molecule. Four monoclonal antibodies targeting the calcitonin gene-related peptide pathway are currently available after the US FDA approval of eptinezumab for the indication of migraine prevention. This is the only one of the class to be administered intravenously. The pharmacology of eptinezumab and the four studies that led to the approval, two Phase II and two Phase III clinical trials, are reviewed in this paper. Eptinezumab has demonstrated efficacy, tolerability and safety in patients with episodic and chronic migraine. Studies including migraineurs who have failed previous preventives, and comparison with other options administered quarterly, as well as real-world experience data will all be welcome.
Learn More >The purpose of this study was to compare disability in people with HIV and peripheral neuropathy with those without neuropathy and explore how neuropathy and other relevant factors are associated with disability.
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