Grant: Project Grant

Normally the neurotransmitter glutamate acts at synapses on the cell surface of spinal cord neurons to signal pain. However, glutamate receptors are also found inside these neurons, including at the nucleus of the cell. We will use molecular biological techniques to show that glutamate receptors inside the cell are the key receptors underlying increases in pain sensitivity that occur after chronic inflammation or after nerve injury. We will also study whether changes in the activity of proteins which normally anchor glutamate receptors at the cell surface, which leads to the increase in the levels of these glutamate receptors at the nucleus of spinal cord neurons of animals with persistent pain, affects pain behaviour. Since it is likely that glutamate receptors inside spinal cord neurons are key in conditions of increased pain sensitivity, it may be possible, by targeting these receptors, to develop medications that specifically reduce chronic pain, without affecting other functions of glutamate receptors necessary for such processes as memory, normal pain reflexes, etc. Another approach would be to develop drugs which prevent the accumulation of glutamate at the nucleus of spinal cord neurons, by altering the function of proteins that affect their localization within the cell. Developing drugs that can specifically reduce increased pain sensitivity mediated by intracellular glutamate receptors should allow for more effective pain treatments, as well as reducing unwanted side-effects. This should improve the therapy of the nearly 20% of Canadians that suffer from chronic pain.