Biology subjects

Hulse, R. P.

Publications and source records attributed to Hulse, R. P..

4 recordsLinked to original sources

bioRxiv2023

Angiotensin II type 1 receptor activation facilitates pain hypersensitivity via dorsal horn pericyte mediated vasoconstriction

Vascular disturbance is a key factor in the development of neurological disease, with reduced integrity of the capillary network in the dorsal horn implicated in activation of nociceptive neural circuits and induction of pain hypersensitivity. Pericytes regulate capillary health and tone, with pericyte dysfunction in cerebral tissue associated with neurodegenerative disorders. Our work demonstrates that nociceptive processing is influenced by angiotensin II type 1 (AT1) receptor mediated pericyte contractility in the dorsal horn. Intravital imaging of the mouse spinal cord demonstrated angiotensin II induced cessation of spinal cord capillary perfusion. Intrathecal administration of angiotensin II induced pericyte contractility and narrowing of capillary diameter, which was accompanied by mechanical allodynia and heat hyperalgesia. Angiotensin II mediated pericyte activation and reduction of spinal cord blood flow, was prevented by inhibition of AT1 receptor via losartan treatment. In addition, losartan either systemically or intrathecally administered, prevented angiotensin II induced pain in male and female adult mice. This was associated with protection of the dorsal horn capillary endothelium, with intrathecal co-treatment with losartan preventing loss of CD31 immunoreactivity in the dorsal horn following administration of angiotensin II. This investigation demonstrates that AT1 mediated pericyte regulation of the dorsal horn capillary network, is fundamental in modulating nociceptive processing and perception of pain. Here we identify a novel cellular and mechanistic target for the development of new analgesic.

neuroscience↗

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↗

bioRxiv2021

Hypoxia induced carbonic anhydrase mediated dorsal horn sensory neuron activation and induction ofneuropathic pain

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 1, 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.

neuroscience↗