Painful neuropathy is a major complaint in many disease states, particularly in diabetic mellitus patients. The impact of disease or physical injury on neuronal systems leads to an array of neuronal alterations. These principally result in neuronal cell death and neural degeneration highlighted by nerve regression and neuronal apoptosis, events that affect neuronal signalling and neurotransmission and are highly correlated to pain. A large proportion of patients with painful neuropathy are diabetics, and this neuropathy significantly affects their quality of life. Damage to the peripheral nerves is not only associated with pain, numbness or altered sensation, but also with a lack of motor control and coordination (when motor neurons are damaged, or proprioception is impaired), and impact on autonomic functions (e.g. salivary secretion), all of which also profoundly affect quality of life. In neurodegenerative disease peripheral nerve fibres are compromised, resulting eventually in the standard clinical hallmarks of neuropathy – regression of epidermal nerve fibre terminals and pain. The sensory nerve terminal regression found in type I diabetes is as a result of a poor neuroprotective/regenerative ability. This is likely to be attributable to loss of necessary growth/support factors such as NGF, vascular endothelial growth factor-A (VEGF) and brain derived neuroptrophic factor (BDNF). Therefore administration of the specific isoforms of growth factors such as VEGF165b, which has neuroprotective actions in vitro and in vivo, maybe beneficial. Systemic treatment of diabetic rats with VEGF165b prevented the development of diabetic neuropathy, which is typified by enhanced nociception to mechanical, thermal and chemical stimuli, as well as neuronal loss of cutaneous nerve terminals and sensory neuronal apoptosis in vivo. When damage to peripheral nerve trunks occurs, the degeneration of damaged fibres results in changes in the sensory properties of intact nerve fibres, often resulting in pain. Some key molecules have been particularly implicated in diabetic neuropathy, such as TRPA1, a channel fundamental to the sensitisation of neurones in chronic pain states. TRPA1 activity is increased in diabetic neuropathy. This can contribute to both sensitisation and death of nociceptors when it activated by mitochondrial dysfunction, oxidative stress and other endogenous diabetic metabolites. VEGF165b treatment inhibits the hyperglycaemic induced potentiation of TRPA1 activity. These findings demonstrate that manipulation of VEGF expression maybe a useful tool in treating diabetic complications, and in particular neuropathy.