Da Vitoria Lobo, M. | Search bioRxiv

bioRxiv2023

Neuroinflammation induces nerve growth factor dependent nociceptor sensitisation in a neonatal rodent model of platinum-based chemotherapy induced neuropathic pain

Chemotherapy-induced neuropathic pain (CINP) is a common adverse health related comorbidity that manifests later in life in paediatric patients treated for cancer. CIPN pathology progressively develops over time resulting in a delayed but long-lasting neuropathic pain. Current analgesic strategies are ineffective, aligning closely with our lack of understanding of CINP. Recent studies have indicated alterations in sensory neuronal maturation as component of CINP. The aim of this study was to investigate how cisplatin induces nerve growth factor mediated neuroinflammation and nociceptor sensitisation. In a rodent model of cisplatin induced survivorship pain, there was a significant infiltration of nerve growth factor positive macrophages into the dorsal root ganglia (DRG), demonstrating a robust neuroinflammatory response. Additionally, it was observed that CD11b/F480 positive monocyte/macrophages challenged with cisplatin expressed more NGF. Additionally, DRG derived primary sensory neuron cultures from neonatal mice demonstrated enhanced NGF-dependent TRPV1 mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured neurons were treated with conditioned media from cisplatin activated monocyte/macrophages. This elevated nociceptor activity was dose-dependently inhibited by a neutralising monoclonal antibody to NGF. Intraperitoneal administration of NGF neutralising antibody significant reduction in mechanical hypersensitivity was given to mice with cisplatin-induced juvenile survivorship pain there was a as well as suppression of cisplatin induced aberrant nociceptor intraepidermal nerve fibre density. These findings identify the NGF/TrkA signalling pathway as a potential novel therapeutic target for analgesia in adult survivors of childhood cancer.

neuroscience↗

bioRxiv2021

Quantifying spinal cord vascular permeability in the mouse using intravital imaging

Sensory perception and motor dexterity is coordinated by in part distinct anatomical centres in the spinal cord. Importantly the spinal cord is the first modulatory relay hub for coordinating sensory and motor inputs to allow control of an organisms response to a sensory experience and to orientate proprioceptive outputs. This is whilst communicating with higher centres within the brain to undertake greater complex neurophysiological function such as pain perception. This begins to outline the complexity of the nervous system communication. To allow this integral system to function efficiently neuronal homeostasis needs to be maintained with energy expenditure matched by proficient delivery of nutrients. This factor introduces the vascular system that extensively interacts in a multifaceted manner with differing aspects of the nervous system. Part of this multi-factoral interaction is through the heterogenic cellular makeup of the vascular network that delivers and modulates the molecular transport of such nutrients to spinal cord tissues, but also controlling penetration and migration of harmful pathogens and agents. Therefore the spinal cord is susceptible to any alterations in the microvessel integrity (e.g. vascular leakage) and/or function (e.g. cessated blood flow) of this vascular network, which principally occurs in times of pathology. Typically investigations into microvessel function have utilised histological and/or tracer based in-vivo assays. Methodologies such as evans blue extravasation have been used inconjunction with in-vitro cell biology assays such as transwell assays to determine microvessel integrity or function that only provides snapshots of developing vasculopathy. Adopting in-vivo imaging approaches, allow for real time functional measurements of the ongoing physiological function within the spinal cord, providing direct measurement of the vascular processes in play, including vascular architecture, blood flow and/or permeability. This technique in mouse allow for direct visualisation of cellular and/or mechanistic influence upon vascular function through utilising disease, transgenic and/or viral approaches. This combination of attributes allows for in depth real time understanding of the function of the vascular network within the spinal cord.

neuroscience↗