Hypoxia-induced carbonic anhydrase mediated dorsal horn neuron activation and induction of neuropathic pain

Lobo, Marlene E Da Vitoria; Weir, Nick; Hardowar, Lydia; Ojaimi, Yara Al; Madden, Ryan; Gibson, Alex; Bestall, Samuel M.; Hirashima, Masanori; Schaffer, Chris B.; Donaldson, Lucy Fife; Bates, David O.; Hulse, Richard P.

doi:10.1097/j.pain.0000000000002627

Cited by 10 publications

(18 citation statements)

References 76 publications

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“…In addition to MASTL, carbonic anhydrase 3, F-box leucine-rich repeat protein 4 (FBXL4), and NADH-ubiquinone oxidoreductase chain 4L also differed signi cantly between the two groups. Carbonic anhydrase 3 is an intracellular protein that acts as a metabotropic inhibitor of inositol triphosphate receptor 1 (ITPR1), which is essential for intracellular Ca 2+ release, synaptic function, chronic pain, and neuronal excitability (33), and studies have shown that inhibition of carbonic anhydrase activity reduces hypoxia-induced pain (34)(35)(36). In addition, it has been suggested that inhibitors of human carbonic anhydrase 3reduce abnormal pain caused by neuropathy in mice (37,38).…”

Section: Discussionmentioning

confidence: 99%

Proteomics of long-term neurodevelopmental disorders of rats exposed to early pain stimulation in the neonatal period

Zuo

et al. 2023

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Objective To screen the feasibility and value of quantitative proteomic tandem mass spectrometry labeling (TMT) technology for early pain stimulation leading to neurodevelopmental disorders during puberty in neonatal rats. Methods The rats were randomly divided into two groups at postnatal day one (P1), and the skin was pricked for seven consecutive days in the experimental group; the control group was stroked simultaneously. A Morris water maze experiment was performed at P45 and P48. The rats were sacrificed at P50, and the proteins extracted from the hippocampal tissues were analyzed by TMT quantitative proteomics. The differentially expressed proteins were identified as biologically relevant proteins after pain intervention. Results The Morris water maze experiment suggested that the experimental group of rats had a significantly longer escape latency at P45 and P48 than the control group (P<0.05). At P49, Rats in the experimental group crossed the traversing platform less often than the control group within 60 s. Hippocampal tissue proteomics analysis showed than 33 proteins were upregulated, and 37 were downregulated. The differentially expressed proteins were enriched in different GO subsets, the most significant of which were sucrose metabolic process, response to stilbenoid maltose metabolic process, disaccharide metabolic process, circulating immunoglobulin complex, haptoglobin-hemoglobin complex, hemoglobin complex, replisome, purine-rich negative regulatory element binding, biliverdin reductase activity, alpha-1,4-glucosidase activity, and retinal dehydrogenase activity. KEGG enrichment analysis was most significant for starch and sucrose metabolism, galactose metabolism, antigen processing and presentation, and TGF-beta signaling. The core proteins were identified by constructing protein interaction networks. Four essential differentially expressed proteins were screened, including microtubule-associated serine-/threonine-protein kinase, carbonic anhydrase 3, F-box and leucine-rich repeat protein 4, and NADH-ubiquinone oxidoreductase chain 4L. Conclusions TMT-labeled proteomics identified energy metabolic processes, developmental processes, cellular processes, bioregulation, and signaling as the main targets of distant neurodevelopmental disorders caused by painful stimulation. Microtubule-associated serine/threonine-protein kinase, carbonic anhydrase 3, F-box and leucine-rich repeat protein 4, and NADH-ubiquinone oxidoreductase chain 4L may be involved in the cognitive impairment of adolescence caused by early pain stimulation in neonatal rats.

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Section: Discussionmentioning

confidence: 99%

Proteomics of long-term neurodevelopmental disorders of rats exposed to early pain stimulation in the neonatal period

Zuo

et al. 2023

Preprint

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“…In contrast, our work has presented that damage and cessation of blood flow in the spinal cord vasculature also initiates chronic pain states(Ved et al ., 2018 a ). This is further emphasised by the induction of hypoxia in the microenvironment of the dorsal horn neurons driving chronic pain states(Da Vitoria Lobo et al ., 2022). The spinal cord vasculature, which comprises of largely of endothelial cells (EC), degenerates either through endothelium apoptosis or regression, and is implicated in the onset of numerous neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

“…The spinal cord vasculature, which comprises of largely of endothelial cells (EC), degenerates either through endothelium apoptosis or regression, and is implicated in the onset of numerous neurological diseases. Our work presented to date highlights that if the endothelium degenerates exclusively, pain manifests(Ved et al ., 2018 a ; Da Vitoria Lobo et al ., 2022). However, it remains undefined the cellular and/or molecular events that underpin the diminishing health of the dorsal horn endothelium.…”

Section: Discussionmentioning

confidence: 99%

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

Hardowar,

Sheavyn,

McTernan

et al. 2023

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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.

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“…All rodents were habituated to the testing environment prior to nociceptive behavioural experimentation [3,22]. Mechanical withdrawal thresholds were acquired following application of Von Frey (vF) hairs to the plantar surface of the hindpaw.…”

Section: Methodsmentioning

confidence: 99%

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

Da Vitoria Lobo,

Hardowar,

Valentine

et al. 2023

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Chemotherapy-induced peripheral sensory neuropathy (CIPN) is a highly prevalent adverse health related comorbidity that manifests later in life in adult patients who have undergone paediatric cancer treatment with chemotherapeutic agents. Symptoms are typified by induction of neuropathic pain in a larger proportion of these patients. There is limited understanding of how this cisplatin induced sensory neuropathy develops and as a consequence current treatment approaches are not effective. The mechanisms that cause cisplatin-induced survivorship pain have yet to be elucidated; however, recent studies have indicated the involvement a key component, TrkA receptor signalling. The aim of this study was to investigate the effect of cisplatin mediated neuroinflammation and the dependence upon cisplatin induced nociceptor sensitisation upon nerve growth factor signalling. In a rodent model of cisplatin induced survivorship pain, there was a prominent induction of neuroinflammatory process in the dorsal root ganglia, demonstrated by infiltration of NGF positive CD45 positive macrophages. Isolated mouse splenocytes exposed to cisplatin led to increases in NGF expression. Primary cell cultures of sensory neurons from the dorsal root ganglia of neonatal mice treated with cisplatin demonstrated enhanced TRPV1 mediated nociceptor activity, which was NGF dependent. In addition, conditioned media from cisplatin treated splenocytes similarly increased nociceptor activity, which was inhibited in a dose dependent manner following NGF monoclonal antibody incubation. Administration of monoclonal NGF antibody invivo prevented cisplatin induced survivorship pain in mice depicted by reductions in mechanical hypersensitivity as well as suppression of cisplatin induced aberrant nociceptor intraepidermal nerve fibre density. These results indicate that cisplatin treatment induces nociceptor activation via NGF mediated neuroinflammation. The present findings provide a basis on which future studies into NGF/TrkA signalling inhibition may prove to have clinical significance as a therapy for CIPN in adult survivors of childhood cancer.

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Hypoxia-induced carbonic anhydrase mediated dorsal horn neuron activation and induction of neuropathic pain

Abstract: Supplemental Digital Content is Available in the Text.Reduced spinal cord blood flow leads to a hypoxia-mediated activation of hypoxia inducible factor 1α in dorsal horn neurons. This results in a carbonic anhydrase–dependent neuropathic pain.

Cited by 10 publications

References 76 publications

Proteomics of long-term neurodevelopmental disorders of rats exposed to early pain stimulation in the neonatal period

Proteomics of long-term neurodevelopmental disorders of rats exposed to early pain stimulation in the neonatal period

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

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

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