Browsing by Author "Calvo Bascuñán, Margarita"

Now showing 1 - 7 of 7
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    Characterisation of the pathophysiology of neuropathy and sensory dysfunction in a mouse model of recessive dystrophic epidermolysis bullosa
    (LIPPINCOTT WILLIAMS & WILKINS, 2022) Schmidt, Daniela; Díaz Céspedes, Paula Estefany; Muñoz, Daniela; Espinoza Mihovilovic, Fernanda Mileva; Nystrom, Alexander; Fuentes, Ignacia; Ezquer, Marcelo; Bennett, David L.; Calvo Bascuñán, Margarita
    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic condition in which mutations in the type VII collagen gene (COL7A1) lead to decreased expression of this anchoring protein of the skin, causing the loss of stability at the dermo-epidermal junction. Most patients with RDEB experience neuropathic pain and itch due to the development of a small fibre neuropathy, characterised by decreased intraepidermal innervation and thermal hypoaesthesia. To understand the physiopathology of this neuropathy, we used a mouse model of RDEB (Col7a1(flNeo/flNeo)) and performed a detailed characterisation of the somatosensory system. Col7a1(flNeo/flNeo) mice showed a decrease in heat sensitivity, an increase in spontaneous scratching, and a significant decrease in intraepidermal nerve fibre density in the hindpaw; these changes were distal because there was no significant loss of unmyelinated or myelinated fibres in the nerve trunk. Of interest, we observed a decrease in axon diameter in both myelinated and unmyelinated fibres. This axonal damage was not associated with inflammation of the dorsal root ganglion or central projection targets at the time of assessment. These results suggest that in RDEB, there is a distal degeneration of axons produced by exclusive damage of small fibres in the epidermis, and in contrast with traumatic and acute neuropathies, it does not induce sustained neuroinflammation. Thus, this animal model emphasizes the importance of a healthy cutaneous environment for maintenance of epidermal innervation and faithfully replicates the pathology in humans, offering the opportunity to use this model in the development of treatments for pain for patients with RDEB.
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    Exploring neuroinflammation: A key driver in neuropathic pain disorders
    (2024) Scheuren, Paulina S.; Calvo Bascuñán, Margarita
    Inflammation is a fundamental part of the body's natural defense mechanism, involving immune cells and inflammatory mediators to promote healing and protect against harm. In the event of a lesion or disease of the somatosensory nervous system, inflammation, however, triggers a cascade of changes in both the peripheral and central nervous systems, ultimately contributing to chronic neuropathic pain. Substantial evidence links neuroinflammation to various conditions associated with neuropathic pain. This chapter will explore the role of neuroinflammation in the initiation, maintenance, and resolution of peripheral and central neuropathic pain. Additionally, biomarkers of neuroinflammation in humans will be examined, emphasizing their relevance in different neuropathic pain disorders.
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    Future perspectives: the next fifty years of the International Association for the Study of Pain
    (2023) Sommer, Claudia; Calvo Bascuñán, Margarita; Cervero, Fernando; Loeser, John D.
    The International Association for the Study of Pain (IASP) has become the leading professional association dedicated to promoting pain research and management. Through its many activities, including research funding, educational programs, advocacy initiatives, and global collaborations, the Association has significantly contributed to the understanding and treatment of pain. Looking into the future, the IASP is determined to continue its mission of reducing the burden of pain on individuals and societies worldwide. Here, we explore how current and past activities of the IASP will shape the future of pain research, treatment, education, and advocacy as well as provide a valuable service to its members across the world.
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    Harmonizing neuropathic pain research: outcomes of the London consensus meeting on peripheral tissue studies
    (2025) Villa, Sara; Aasvang, Eske K.; Attal, Nadine; Baron, Ralf; Bourinet, Emmanuel; Calvo Bascuñán, Margarita; Finnerup, Nanna B.; Galosi, Eleonora; Hockley, James R. F.; Karlsson, Pall; Kemp, Harriet; Koerner, Jannis; Kutafina, Ekaterina; Lampert, Angelika; Murk, Margarita; Nochi, Zahra; Price, Theodore J.; Rice, Andrew S. C.; Sommer, Claudia; Taba, Pille
    Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across laboratories. In this white paper, we report on a consensus meeting attended by neuropathic pain experts, designed to accelerate protocol alignment and harmonization of studies involving relevant peripheral tissues. The meeting was held in London in March 2024 and attended by 28 networking partners, including industry and patient representatives. We achieved consensus on minimal recommended phenotyping, harmonised wet laboratory protocols, statistical design, reporting, and data sharing. Here, we also share a variety of relevant standard operating procedures as supplementary protocols. We envision that our recommendations will help unify human tissue research in the field and accelerate our understanding of how abnormal interactions between sensory neurons and their local peripheral environment contribute towards neuropathic pain.
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    Pregabalin for Neuropathic Pain and Itch in Recessive Dystrophic Epidermolysis Bullosa: A Randomized Crossover Trial
    (2024) Calvo Bascuñán, Margarita; Tejos Bravo, Macarena Verónica Montserrat; Passi Solar, Álvaro Rodrigo; Espinoza Mihovilovic, Fernanda Mileva; Fuentes Bustos, María Ignacia; Lara-Corrales, Irene; Pope, Elena
    Importance: Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience neuropathic pain and itch. There is a lack of evidence on any treatment for these symptoms in patients with RDEB. Objectives: To test the efficacy of pregabalin in the treatment of neuropathic pain and itch in patients with RDEB. Design, Setting, and Participants: A randomized, double-blinded, crossover trial of oral pregabalin (50-300 mg/d) vs placebo was conducted at 2 sites, Toronto (Canada) and Santiago (Chile) from January 1, 2019, to December 31, 2020. Patients eligible to participate were diagnosed with RDEB, aged 8 to 40 years, not pregnant or lactating (if female), and had evidence of probable neuropathic pain and itching defined as distal thermal sensory loss (confirmed by thermal roller), score of 4 or greater on the Douleur Neuropathique 4 questionnaire (DN4), and score greater than 4 on the 10-point visual analog scale [VAS]). Patients with a clinically important or poorly controlled medical or psychiatric condition or pregabalin intolerance or allergy were excluded. Of 41 patients screened, 3 were not eligible and 28 declined enrollment. Data analyses were performed in 2021 through 2023. Intervention: Participants received both pregabalin and matched placebo (titrated to a maximum-tolerated dose of 300 mg/day) in a randomized sequence so that comparisons could be made within participants and between groups. Main Outcomes and Measures: Difference in the mean pain and itch scores between pregabalin and placebo treatment (measured using VAS) before and after intervention. Results: In all, 10 participants were randomized to 2 groups, 6 patients (mean [SD] age, 26.7 [8.1] years; 3 females [50%]) in group 1, and 4 patients (mean [SD] age, 26.5 [7.8] years, 2 females [50%]) in group 2. Group 1 received a sequence of pregabalin-placebo while group 2 received placebo-pregabalin. Pregabalin significantly reduced mean (SD) pain scores by 1.9 (1.5) points when controlling for sequence and treatment period vs baseline, while placebo had 0.1 (2.0) points of reduction. The effect of pregabalin was a mild but significant reduction in itch compared to baseline (mean [SD] points, 0.9 [2.2]), whereas the placebo produced no reduction (0.1 [2.5]). The mean pregabalin dose was generally well tolerated. Conclusions and Relevance: The results of this randomized crossover trial indicate that pregabalin significantly reduced pain and itch scores from baseline compared to placebo in patients with RDEB. This feasibility study provided preliminary data on the efficacy of pregabalin in managing pain and itch in RDEB and gathered essential data to inform the design of a larger cohort trial.
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    Regulation of Pain Perception by Microbiota in Parkinson Disease
    (2024) Manjarres Farías, Zulmary Alicia; Calvo Bascuñán, Margarita; Pacheco, Rodrigo
    Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology.
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    The local molecular signature of human peripheral neuropathic pain
    (2025) Sandy-Hindmarch, Oliver P.; Chang, Pao-Sheng; Scheuren, Paulina S.; De Schoenmacker, Iara; Hubli, Michele; Loizou, Constantinos; Wirth, Stephan; Mahadevan, Devendra; Wiberg, Akira; Furniss, Dominic; Calvo Bascuñán, Margarita; Bennett, David L. H.; Denk, Franziska; Baskozos, Georgios; Schmid, Annina B.
    Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature (MARCO, CD163, STAB1), indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163+MARCO+ macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+ subset implicated.