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We previously demonstrated that automated, Web-based pain coping skills training (PCST) can reduce osteoarthritis pain. The present secondary analyses examined whether this program also changed coping strategies participants identified for use in hypothetical pain-related situations.
Learn More >Migraine occurs 2-3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes.
Learn More >Up to 90% of patients with postural tachycardia syndrome (PoTS) report headaches, and comorbid migraine headaches are common. Given this, pathophysiological interaction is possible, which may reveal key aspects of disease expression and treatment opportunities. We hypothesized that PoTS subjects-both with and without migraine-would show features of central sensitization, including allodynia and photophobia.
Learn More >Itch can be induced by activation of small-diameter dorsal root ganglion (DRG) neurons which express abundant intracellular fibroblast growth factor 13 (FGF13). Although FGF13 is revealed to be essential for heat nociception, its role in mediating itch remains to be investigated. Here, we reported that loss of FGF13 in mouse DRG neurons impaired the histamine-induced scratching behavior. Calcium imaging showed that the percentage of histamine-responsive DRG neurons was largely decreased in FGF13-deficient mice, and consistently, electrophysiological recording exhibited that histamine failed to evoke action potential firing in most DRG neurons from these mice. Given that the reduced histamine-evoked neuronal response was caused by knockdown of FGF13 but not by FGF13A deficiency, FGF13B was supposed to mediate this process. Furthermore, overexpression of histamine type 1 receptor H1R, but not H2R, H3R nor H4R, increased the percentage of histamine-responsive DRG neurons, and the scratching behavior in FGF13-deficient mice was highly reduced by selective activation of H1R, suggesting that H1R is mainly required for FGF13-mediated neuronal response and scratching behavior induced by histamine. However, overexpression of H1R failed to rescue the histamine-evoked neuronal response in FGF13-deficient mice. Histamine enhanced the FGF13 interaction with Na1.7. Disruption of this interaction by a membrane-permeable competitive peptide, GST-Flag-Na1.7CT-TAT, reduced the percentage of histamine-responsive DRG neurons, and impaired the histamine-induced scratching, indicating that the FGF13/Na1.7 interaction is a key molecular determinant in the histamine-induced itch sensation. Therefore, our study reveals a novel role of FGF13 in mediating itch sensation via the interaction of Na1.7 in peripheral nervous system.Scratching induced by itch brings serious tissue damage in chronic itchy diseases and targeting itch-sensing molecules is crucial for its therapeutic intervention. Here, we reveal that FGF13 is required for the neuronal excitation and scratching behavior induced by histamine. We further provide the evidence that the histamine-evoked neuronal response is mainly mediated by histamine type 1 receptor H1R, and is largely attenuated in FGF13-deficent mice. Importantly, we identify that histamine enhances the FGF13/Na1.7 interaction, and disruption of this interaction reduces histamine-evoked neuronal excitation and highly impairs histamine-induced scratching behavior. Additionally, we also find that FGF13 is involved in 5-HT-induced scratching behavior and hapten 1-fluoro-2,4-dinitrobenzene (DNFB)-induced chronic itch.
Learn More >Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared to matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR in Na1.8-positive neurons (), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. and deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR-dependent hyperexcitability of trigeminal neurons from WT female mice. deletion, LI-1 and inhibitors of adenylyl cyclase or protein kinase A prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N-terminus of PAR at Asn↓Arg, proximal to the canonical trypsin activation site. Lgmn activated PAR by biased mechanisms in HEK293 cells to induce Ca mobilization, cAMP formation and protein kinase A/D activation, but not β-arrestin recruitment or PAR endocytosis. Thus, in the acidified OSCC microenvironment Lgmn activates PAR by biased mechanisms that evoke cancer pain.Oral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared to matched normal oral tissue. Lgmn evokes pain-like behavior through PAR Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR Inhibitors of adenylyl cyclase and protein kinase A prevented the effects of Lgmn. Lgmn activated PAR to induce calcium mobilization, cAMP formation and activation of protein kinase D and A, but not β-arrestin recruitment or PAR endocytosis. Thus, Lgmn is a biased agonist of PAR that evokes cancer pain.
Learn More >Increased acute postoperative pain intensity has been associated with the development of persistent postsurgical pain (PPP) in mechanistic and clinical investigations, but it remains unclear which aspects of acute pain explain this linkage.
Learn More >The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients.
Learn More >For more than ten years, gene therapy for neurological diseases has experienced intensive research growth and more recently therapeutic interventions for multiple indicationsBeneficial results in several phase 1/2 clinical studies, together with improved vector technology have advanced gene therapy for the central nervous system (CNS) in a new era of development. While most initial strategies have focused on orphan genetic diseases, such as lysosomal storage diseases, more complex and widespread conditions like Alzheimer's disease, Parkinson's disease, epilepsy or chronic pain are increasingly targeted for gene therapy. Increasing numbers of applications and patients to be treated will require improving and simplifying gene therapy protocols to make them accessible to the largest number of affected people. While vectors and manufacturing are a major field of academic research and industrial development, there is a growing need to improve, standardize and simplify delivery methods. Delivery is the major issue for CNS therapies in general, and particularly for gene therapy. The blood brain barrier restricts the passage of vectors; and strategies to bypass this obstacle are a central focus of research. Here, we present the different ways that can be used to deliver gene therapy products to the CNS. We focus on results obtained in large animals that have allowed the transfer of protocols to human patients and have resulted in the generation of clinical data. We discuss the different routes of administration, their advantages and their limitations. We describe techniques, equipment and protocols and how they should be selected for safe delivery and improved efficiency for the next generation of gene therapy trials for CNS diseases.
Learn More >Migraine affects how the brain processes sensory information at multiple levels. The aberrant integration of visual and somatosensory stimuli is thought to underlie Alice in Wonderland Syndrome, a disorder often reported as being associated with migraine. However, there is still a lack of knowledge about the epidemiology of this syndrome in migraineurs and the association between Alice in Wonderland Syndrome episodes and migraine attacks. Therefore, we conducted a prospective cohort study to systematically evaluate the prevalence and the clinical features of Alice in Wonderland Syndrome in a large sample of patients with migraine.
Learn More >Rheumatoid arthritis (RA) is chronic, painful, disabling condition resulting in significant impairments in physical, emotional, and social health. We used different methods and perspectives to evaluate the responsiveness of PROMIS® short forms (SFs) and identify minimal and meaningful score changes.
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