Browsing by Author "Bennett, David L. H."

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    A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy
    (2013) Huanga, Wenlong; Calvo Bascuñan, Margarita; Karu, Kersti; Olausen, Hans R.; Bathgate, Gabriella; Okuse, Kenji; Bennett, David L. H.; Rice, Andrew S. C.
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    Acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination: A report of three cases and review of the literature
    (2022) Abbott, Molly G.; Allawi, Zahra; Hofer, Monika; Ansorge, Olaf; Brady, Stefen; Fadic Ruiz, Ricardo; Torres Riveros, Gustavo Andres; Knight, Ravi; Calvo, Margarita; Bennett, David L. H.; Themistocleous, Andreas C.
    Small fiber neuropathy usually presents with gradual and progressive chronic length-dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford-AstraZeneca ChAdOx1-S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra-epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra-epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination are described. At follow up, neuropathic pain was present in two of the patients.
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    Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis.
    (2025) Soliman, Nadia; Moisset, Xavier; Ferraro, Michael C.; Ciampi de Andrade, Daniel; Baron, Ralf; Belton, Joletta; Bennett, David L. H.; Calvo, Margarita; Dougherty, Patrick; Gilron, Ian; Hietaharju, Aki J.; Hosomi, Koichi; Kamerman, Peter R.; Kemp, Harriet; Enax-Krumova, Elena K.; McNicol, Ewan; Price, Theodore J.; Raja, Srinivasa N.; Rice, Andrew S. C.; Smith, Blair H.; Talkington, Fiona; Truini, Andrea; Vollert, Jan; Attal, Nadine; Finnerup, Nanna B.; Haroutounian, Simon; NeuPSIG Review Update Study Group
    There remains a substantial unmet need for effective and safe treatments for neuropathic pain. The Neuropathic Pain Special Interest Group aimed to update treatment recommendations, published in 2015, on the basis of new evidence from randomised controlled trials, emerging neuromodulation techniques, and advances in evidence synthesis.
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    Studying Independent Kcna6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation
    (2021) Peck, Liam J.; Patel, Ryan; Diaz, Paula; Wintle, Yolanda M.; Dickenson, Anthony H.; Todd, Andrew J.; Calvo, Margarita; Bennett, David L. H.
    The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (Kcna6lacZ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent pre -synaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of "meganeur-ites," and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (Kcna6-/-) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce patho-logic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using lacZ. Nonetheless, in Kcna6-/-mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.
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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.