Role of VEGF-A in chronic pain

Chronic pain is highly debilitating and impacts greatly upon the patients' wellbeing and quality of life.Chronic pain arises due to disease or treatment that cause dysfunction to the sensory nervous system, including arthritis, diabetes and chemotherapy induced sensory neuropathy.In diabetic patients, for example, sensory neurons in the peripheral and central (spinal cord) nervous system become hyperactive.This is replicated in rodent models of neuropathic pain, with C fibre and A fibre nociceptors responding with an increase in neuronal evoked and ongoing activity [1] as well as the onset of central sensitisation in the spinal cord.However, effective treatment for chronic pain is still a huge unmet clinical need.Development of neuropathic pain is modulated by changes in expression and/or activity of voltage gated ion channels, neuropeptides and growth factors (such as upregulation of nerve growth factor in cancer and arthritic pain), which can influence sensory neuron excitability as well as altered structural components (sensory nerve fibre aberrant growth or degeneration) of the sensory neuron.Recent evidence now presents a prominent role for the angiogenic growth factor; vascular endothelial growth factor-A (VEGF-A) to impact upon the sensory nervous system, with nociceptive and neuroprotective roles acknowledged [2,3] .VEGF-A is widely recognised to regulate blood vessel function and integrity.However, alterations in VEGF-A expression and signalling profiles is strongly associated with a number of angiogenic related pathologies such as diabetes, arthritis and cancer, all of which are associated with chronic pain development.VEGF-A acts upon the sensory neuron by inducing sensory neuron axonal outgrowth and survival [2, 4, 5], and in early rodent studies highlighting a role of VEGF-A in inflammatory pain.The VEGF-A family consists of a number of differing isoform subtypes, with alternative splicing of exon 8 giving rise to VEGF-A xxx a (proximal splice site selection) and VEGF-A xxx b (exon 8b distal splice site selection) [6] .Differing exon content gives each of these isoforms distinct signalling and unique functional attributes compared to the sister isoforms [2,4].Therefore understanding the balance of these pro and anti-nociceptive VEGF-A isoforms and the control of exon 8 splice site selection is crucial in the development of analgesics.Recent investigations outline that the angiogenic growth factor, VEGF-A, is integral for the modulation of nociception and onset of chronic pain.Understanding these signalling events such as alternative splicing, is key to providing effective and novel analgesia to prevent sensory neuronal damage and chronic pain.