Grant: Operating Grant

100,000,000 people worldwide suffer from the 'disease of pain'. This frequently reflects the presence of chronic, 'neuropathic' pain that can be initiated by traumatic nerve injury, diabetes or by infections such as AIDs or 'shingles'. Because this type of pain is resistant to most types of pain killers, there is an urgent need to understand the changes in the nervous system that accompany its onset, as only this can lead to the rational development of effective therapies. We study neuropathic pain in two ways. First, using procedures approved by the International Association for the Study of Pain, we subject rats to experimental nerve injury and study the changes in the electrical activity of nerve cells associated with pain processing in the spinal cord. These neurons become more prone to generate nerve impulses and this leads to a phenomenon known as 'central sensitization'. Secondly, we use 'organotypic' cultures where we maintain small slices of spinal cords in tissue culture for many weeks. Cultures are treated with known mediators of neuropathic pain to produce 'pain in a dish' and we again analyze neuronal electrical properties as signs of pain develop. We have found that brain derived neurotrophic factor (BDNF) may be responsible for many aspects of 'central sensitization' and hence for the onset of neuropathic pain. BDNF produces a complex array of changes in spinal cord physiology and we plan to determine the molecular basis for these changes. It is also likely that 'central sensitization' leads to increased release of neurotransmitters from the nerves that carry painful information into the spinal cord and brain. This likely involves changes in 'calcium channels' that regulate the tendency of nerves to release neurotransmitters. This process is incompletely understood and requires further analysis. By understanding such changes we will provide the theoretical basis for the development urgently needed new drugs for neuropathic pain.