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Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.
Learn More >Neuroscience is one of the fastest growing fields and highlights the excitement about research, but it also demonstrates the impact that our large scientific community can make in prioritizing equity and inclusion throughout science. I discuss strategies at multiple systemic levels where opportunities and interventions could be implemented to enhance neuroscience workforce diversity.
Learn More >To provide a comprehensive overview of the measurement properties of patient-reported outcome measures (PROMs) used to assess sleep quality in adult patients with prevalent pain-related conditions.
Learn More >To evaluate the efficacy of gabapentin at 20 mg/kg per day in the treatment of vincristine-related neuropathic pain.
Learn More >Wnt signaling represents a highly versatile signaling system, which plays critical roles in developmental morphogenesis as well as synaptic physiology in adult life and is implicated in a variety of neural disorders. Recently, we demonstrated that Wnt3a is able to recruit multiple non-canonical signaling pathways to alter peripheral sensory neuron function in a nociceptive modality-specific manner. Furthermore, several studies recently reported an important role for Wnt5a acting via canonical and non-canonical signaling in spinal processing of nociception in a number of pathological pain disorders. Here, using diverse molecular, genetic, and behavioral approaches in mouse models of pain , we report a novel role for Wnt5a signaling in nociceptive modulation at the structural level. In models of chronic pain, using male and female mice, we found that Wnt5a is released spinally from peripheral sensory neurons, where it recruits the tyrosine kinase receptors Ror2 and Ryk to modulate dendritic spine rearrangement. Blocking the Wnt5a-Ryk/Ror2 axis in spinal dorsal horn neurons prevented activity-dependent dendritic spine remodeling and significantly reduced mechanical hypersensitivity induced by peripheral injury as well as inflammation. Moreover, we observed that peripheral Wnt3a signaling triggers the release of Wnt5a in the spinal cord, and inhibition of spinal Wnt5a signaling attenuates the functional impact of peripheral Wnt3a on nociceptive sensitivity. In conclusion, this study reports a novel role for the Wnt signaling axis in coordinating peripheral and spinal sensitization and shows that targeting Wnt5a-Ryk/ROR2 signaling alleviates both structural and functional mechanisms of nociceptive hypersensitivity in models of chronic pain There is a major need to elucidate molecular mechanisms underlying chronic pain disorders in order to develop novel therapeutic approaches. Wnt signaling represents a highly versatile signaling system, which plays critical roles during development and adult physiology, and it was implicated in several diseases, included chronic pain conditions. Using mouse models, our study identifies a novel role for Wnt5a signaling in nociceptive modulation at the spinal cord level. We observed that Wnt5a recruits Ror2 and Ryk receptors to enhance dendritic spine density, leading to nociceptive sensitization. Blocking the Wnt5a-Ryk/Ror2 interaction in the spinal dorsal horn prevented spine remodeling and significantly reduced inflammatory and neuropathic hypersensitivity. These findings provide proof-of-concept for targeting spinal Wnt signaling for alleviating nociceptive hypersensitivity .
Learn More >The sensation of pruritus, or itch, is associated with a variety of skin and medical disorders. Itch is transmitted through afferent C-fibers, and sodium channels play a key role in the transmission process. Local anesthetics, which block sodium channels, are used topically to treat itch, but generally have a short duration of action and are not selective for afferent nerves underlying the itch sensation. Accordingly, there is a substantial unmet need for safe, efficacious, long-acting treatments for chronic pruritus, including non-histaminergic itch. We investigated the dose-response, time to onset and duration of action of ASN008 topical gel, which targets small afferent sodium channels, in a murine model of pruritus in which scratching behavior is induced by intradermal injection of chloroquine into the nape of the neck of C57BL/6 mice. Topical application of ASN008 gel resulted in a concentration-dependent reduction of scratching behavior. Onset of action was ≤ 1 hour and duration of scratching inhibition was 15-24 hours. In a further study involving once-daily application for 5 days with chloroquine challenge on day 5, treatment with ASN008 gel again resulted in a concentration-dependent reduction of chloroquine-induced scratching, even when the gel was removed 3 hours after each daily application. In conclusion, topical ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once-daily treatment for a variety of pruritic conditions in humans, including non-histaminergic itch. SIGNIFICANCE STATEMENT: ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once or twice-daily treatment for a variety of pruritic conditions in humans, including non-histaminergic itch. ASN008 topical gel is currently under investigation in Phase 1 clinical studies to evaluate safety, tolerability, pharmacokinetics and preliminary anti-pruritic efficacy in atopic dermatitis patients (ClinicalTrials.gov ID: NCT03798561).
Learn More >Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN).
Learn More >Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats.
Learn More >Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies.
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