LIDo banner

Apply now

Find out more about the different routes to entry and our eligibility criteria

Marlene E. Da Vitoria Lobo: Hypoxia-induced carbonic anhydrase mediated dorsal horn neuron activation and induction of neuropathic pain

Neuropathic pain, such as that seen in diabetes mellitus, results in part from central sensitisation in the 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 causative factors 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 neurons, depicted by increased expression of hypoxia markers such as hypoxia inducible factor 1α, glucose transporter 3, and carbonic anhydrase 7. Furthermore, inducing hypoxia through intrathecal delivery of dimethyloxalylglycine leads to the activation of dorsal horn 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 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.

Chronic pain is a significant burden faced by patients, with pain not restricted to a single condition but developing because of an array of differing health and disease-related afflictions. Forty-three percent of the United Kingdom17 and 25% of the global population20 suffer from chronic pain, which can arise either idiopathically, as a consequence of another disease (eg, diabetes68), or as a consequence of therapyo (eg, chemotherapy46). Neuropathic pain arises due to damage to the somatosensory sensory system with the modulation of intrinsic sensory neural circuits fundamental to the maintenance of nociception4 and presented as a hypersensitivity to evoked sensory stimuli (eg, allodynia or hyperalgesia) as well as ongoing pain18,30. There is a severe lack of effective analgesic management in the clinic.6

Click here to read full publication