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.
Neuropathic pain such as that seen in diabetes mellitus, results in part from central sensitisation in the spinal cord dorsal horn. However, the mechanisms responsible for such sensitisation remain unclear. There is evidence that disturbances in the integrity of the spinal vascular network can be a causative factor in the development of neuropathic pain. Here we show that reduced blood flow and vascularity of the dorsal horn leads to the onset of neuropathic pain. Using rodent models (type 1 diabetes and an inducible endothelial specific vascular endothelial growth factor receptor 2 knockout mouse) that result in degeneration of the endothelium in the dorsal horn we show that spinal cord vasculopathy results in nociceptive behavioural hypersensitivity. This also results in increased hypoxia in dorsal horn sensory neurons, depicted by increased expression of hypoxia markers hypoxia inducible factor 1𝛼, glucose transporter 3 and carbonic anhydrase 7. Furthermore, inducing hypoxia via intrathecal delivery of dimethyloxalylglycine leads to the activation of dorsal horn sensory neurons as well as mechanical and thermal hypersensitivity. This shows that hypoxic signalling induced by reduced vascularity results in increased hypersensitivity and pain. Inhibition of carbonic anhydrase activity, through intraperitoneal injection of acetazolamide, inhibited hypoxia induced pain behaviours. This investigation demonstrates that induction of a hypoxic microenvironment in the dorsal horn, as occurs in diabetes, is an integral process by which sensory neurons are activated to initiate neuropathic pain states. This leads to the conjecture that reversing hypoxia by improving spinal cord microvascular blood flow could reverse or prevent neuropathic pain.
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