Regardless of the scale of peripheral nerve damage, human neonates usually suffer no chronic neuropathic pain. However, by early adulthood, this situation is starkly different, with rates of chronic pain related to the severity of nerve injury, genetic makeup and as yet undetermined risk factors. Rodents display similar age related traits in differential neuropathic hypersensitivity and we have used this phenomenon to perform a whole genome expression screen of the spinal dorsal horns ipsilateral to the injured sciatic nerve from neonates (with no hypersensitivity) and adults (with chronic pain-like symptoms). We found virtually all of the genes regulated in the adult, but not in the neonate were immune related, and within this group we found evidence for the presence of two cell types, microglia and T lymphocytes. As we had previously characterized the role of microglia, we further defined the role of T cells in this process. Preventing T cell function in adult animals resulted in marke decreases in pain-like behavior, suggesting that T cell migration into the nervous system was a crucial part of chronic neuropathic pain, a mechanism that has remained largely unrecognized to date. Here we wish to define this system further, by (1) blocking leukocyte action and infiltration in adult animals subject to peripheral nerve injury;(2) investigating the mechanisms f T cell recruitment to the sciatic nerve injury site (neuroma), the dorsal root ganglion, and the dorsal horn following nerve injury;(3) separating and defining the individual roles of the T helpe cell subtypes (Th1, Th2, Th17 and T regulatory) by gain and loss of function techniques.
Neuropathic pain is a chronic disease with few effective therapies that destroys the lives of those that suffer its devastating consequences. Its treatment thus represents a major unmet clinical need. We have found that immune cells from the blood (T cells) infiltrate the peripheral nervous system and spinal cord following injury to peripheral sensory nerves and contribute to this pain. We believe we have found an important new mechanism of neuropathic pain, one with existing therapies designed for other conditions that may prove beneficial in reducing chronic pain symptoms.
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