The premise of this proposal is that activation of spinal cord microglia and astrocytes by immune system products can produce pain facilitation. These spinal cord glia recognize and become activated by foreign substances such as bacteria and viruses via specific receptor-mediated processes. Glia, but not neurons, recognize and become activated by HIV-1. Recognition by glia of HIV-1 is through receptor mediated binding of the HIV-1 envelope glycoprotein gp120. Such glial activation leads to the release of a variety of neuroactive substances, including proinflammatory cytokines (interleukin-1[IL1], IL6 & tumor necrosis factor), nerve growth factor nitric oxide and excitatory amino acids. These substances would be expected to lead to hyperalgesia and allodynia. This is potentially relevant to pain in AIDS as it suggests that: (a) pain of known peripheral origin in AIDS patients may be exaggerated by the ongoing HIV-1 induced spinal glial activation & (b) pain of unknown origin in AIDS patients may be created by spinal glial activation. This project will examine the role of spinal microglia and astrocytes in pain facilitation produced by intrathecal administration of gp120. A multidisciplinary approach will be used to examine a single intrathecal gp120 model. Using this model, the effects of gp120 on behavioral indices of pain response, on levels of presumptive glially produced pain enhancing endproducts and on immunohistochemical and mRNA expression for these same endproducts will be tested. This approach will be used to examine the potential mediators in pain facilitation known to be produced by intrathecal gp120: nerve growth factor, proinflammatory cytokines, nitric oxide and excitatory amino acids. In addition, it will be determined whether gp120 increases expression of activation markers in spinal glia, and whether disruption of glial function will block gp120-induced changes in pain response, end products and mRNA.
|Milligan, Erin D; Watkins, Linda R (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23-36|
|Schoeniger-Skinner, Diana K; Ledeboer, Annemarie; Frank, Matthew G et al. (2007) Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120. Brain Behav Immun 21:660-7|