The nervous system modulates sensory information to assemble perception of pain, a component in everyday life that prevents us from causing damage to ourselves. However, chronic pain is a long-lasting condition affecting 44% of the United Kingdoms population, with ageing and metabolic dysfunction increasing susceptibility. It is an unpleasant affliction impacting greatly upon an individual quality of life, with current painkillers often ineffective. This highlights an unmet clinical need that requires the development of new analgesics and identification of novel molecular targets.
The dorsal horn within the spinal cord is a key modulatory hub for regulating this pain perception. Maintaining dorsal horn microenvironmental homeostasis is critical in controlling pain. We have identified decreases in spinal cord blood flow leads to reduced oxygen tension (hypoxia) within the dorsal horn. We believe this is a critical pathophysiological feature of chronic pain manifestation. We have identified expression of hypoxia inducible factor 1α (HIF1α) in dorsal horn neurons during states of chronic pain. HIF1α is a transcription factor that mediates cellular adaptation to metabolic disturbances. During hypoxia cellular metabolism becomes glycolysis dependent, driving acidosis. In these scenarios, expression of key pH buffering enzymes, such as carbonic anhydrases (CAR), are increased to overcome excess acid accumulation. However, increased CAR expression also leads to increased abundance of by-products including bicarbonate, themselves primary drivers of neuron activation and inducers of chronic pain.
It has proven difficult to decipher the molecular fingerprint of activated dorsal horn neural networks that contribute to chronic pain manifestation. How dorsal horn sensory neurons adapt to disturbances in oxygen availability is currently unknown. This investigation aims to determine hypoxia induced metabolic changes and transcriptional maladaptations, which are HIF1α dependent in dorsal horn neurons to identify key factors that cause chronic pain. In isolated spinal cord neurons metabolic disturbances (Seahorse XF24 and High resolution respirometry by Oroboros) and alterations in intracellular pH (fluorescent reporter assays) will be determined, in HIF1α knockout models and via pharmacological manipulation of CAR. HIF1α dependent alterations in the sensory neuron transcriptional profile will be evaluated to identify those neural processes that are influenced during prolonged periods of hypoxia. In addition, those identified neural mechanisms influenced by hypoxia, will be explored in rodent models of hypoxia induced pain and type 2 diabetic neuropathic pain to consider the impact upon nociceptive processing and pain behavioural phenotypes.
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