The core idea of this proposal is that, while mediators released by activated immune cells are adaptive when directed against microbes, these same mediators can be pathological when they act on neurons. It is clear from animal studies that """"""""innocent bystander"""""""" damage can occur from immune activation near, but not directed at, peripheral nerves. Indeed, most human neuropathies are associated with immune activation rather than by physical (mechanical) trauma. These inflammatory neuropathies involve damage of peripheral nerves by immune cells and chronic pain. The overall goal of this proposal is to understand low-threshold mechanical allodynia (lowering of response threshold to mechanical stimuli) induced by immune activation and release of immune cells products in and around one healthy sciatic nerve (sciatic inflammatory neuritis (SIN). Unilateral and bilateral allodynia are rapidly induced by 4 and 160 ug peri-sciatic zymosan, respectively. We propose that SIN triggers a linear chain of events, resulting in allodynia: immune cells (activated by zymosan) release substances that alter peripheral nerve function, which in turn alters spinal cord function. Using a multidisciplinary approach, we will examine the basic elements of this chain of events & see how they interact to produce unilateral & bilateral allodynias. We will test peri-sciatically & intrathecally administered antagonists on behavioral indices of mechanical allodynia. We will then examine levels of SIN-induced pain enhancing endproducts from immune cells & spinal cord (measured by colorimetric assays & ELISAs), immunohistochemical expression of these endproducts in immune cells, sciatic nerve & spinal cord (by double-label immunohistochemistry & FACS flow cytometry), & changes in messenger RNA for these same endproducts in immune cells & spinal cord. Thus, this multidisciplinary approach will be used to examine the potential mediators of allodynia at the level of the immune cells (Specific Aim I), at the level of the sciatic nerve (Specific Aim II), & at the level of the spinal cord (Specific Aim III).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040696-03
Application #
6639709
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Nunn, Michael
Project Start
2001-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$229,804
Indirect Cost
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Milligan, Erin D; Watkins, Linda R (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23-36
Ledeboer, Annemarie; Liu, Tongyao; Shumilla, Jennifer A et al. (2007) The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol 2:279-291
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
Ledeboer, Annemarie; Mahoney, John H; Milligan, Erin D et al. (2006) Spinal cord glia and interleukin-1 do not appear to mediate persistent allodynia induced by intramuscular acidic saline in rats. J Pain 7:757-67
Ledeboer, Annemarie; Gamanos, Michael; Lai, Wenmin et al. (2005) Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 22:1977-86
Watkins, L R; Maier, S F (2005) Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med 257:139-55
Ledeboer, Annemarie; Sloane, Evan M; Milligan, Erin D et al. (2005) Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115:71-83
Wieseler-Frank, Julie; Maier, Steven F; Watkins, Linda R (2005) Immune-to-brain communication dynamically modulates pain: physiological and pathological consequences. Brain Behav Immun 19:104-11
Milligan, Erin D; Langer, Stephen J; Sloane, Evan M et al. (2005) Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 21:2136-48
Milligan, E; Zapata, V; Schoeniger, D et al. (2005) An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci 22:2775-82

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