PT  - JOURNAL ARTICLE
AU  - M.E. Da Vitoria Lobo
AU  - N. Weir
AU  - L. Hardowar
AU  - Y. Al Ojaimi
AU  - R. Madden
AU  - Alex Gibson
AU  - S.M. Bestall
AU  - C Schaffer
AU  - M. Hirashima
AU  - L.F Donaldson
AU  - D.O. Bates
AU  - R.P. Hulse
TI  - Hypoxia induced carbonic anhydrase mediated dorsal horn sensory neuron activation and induction of neuropathic pain
AID  - 10.1101/2021.06.08.447539
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.08.447539
4099  - http://biorxiv.org/content/early/2021/06/09/2021.06.08.447539.short
4100  - http://biorxiv.org/content/early/2021/06/09/2021.06.08.447539.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.