Chronic neuropathic pain, such as allodynia, defined as painful sensation to usually non-painful stimuli, is mediated by pathologically activated glial cells residing in both sensory dorsal root ganglia (DRG) and in the spinal cord. These cells secrete the pro-inflammatory factors, IL-1b and TNF-a, as well as chemokines, such as CCL2, that attract circulating leukocytes to the DRG and spinal cord regions. These leukocytes cross the blood-nerve and -spinal barriers, a process facilitated by the activation of the b-2 (b2)-integrin, lymphocyte function-associated antigen-1 (LFA-1), providing an additional source of IL-1b and TNF-a exacerbating neuronal pain signaling processes. Underlying factors that may predispose individuals to allodynia are generally not well recognized. Increasing evidence indicates that prenatal alcohol exposure (PAE) can produce long-lasting alterations to immune function and neuroimmune interactions, increasing the risk for a number of chronic immunologic disorders such as diabetes and rheumatoid arthritis. Specifically, PAE is thought to pathologically prime immune-like glial cells (satellite cells, astrocytes and microglia) disrupting their nutritive role in support of neuronal function during development and into adulthood. Whether PAE leads to heightened and enduring glial reactivity throughout adulthood leading to aberrant neuroimmune signaling is not well understood. The objective of this proposal is to examine whether moderate PAE can heighten allodynic responses in adult offspring using a well-established rodent model of chronic peripheral neuropathic pain, and by applying this model system, to understand underlying PAE-related aberrant neuroimmune interactions. Our overarching hypothesis states that: PAE produces chronic gliopathy and DRG and spinal leukocyte accumulation that mediate pathological pain in rats.
The Specific Aims of the proposal are to: (1) identify the magnitude and role of DRG & spinal leukocyte accumulation in the development of neuropathic pain in adult PAE rats, and (2) identify the DRG and spinal cytokine/chemokine, glial activation and b2-integrin expression profile in PAE neuropathic rats. The studies could provide novel insights into whether an adverse in utero environment intersects with vulnerability to developing adult onset allodynia, as well identifying potential neuroimmune makers for discerning vulnerability to neuropathological pain, and more broadly, to disorders with an underlying neuroinflammatory component. These studies could also inform future studies targeting the development of interventional approaches for the amelioration of neuropathic pain in individuals predisposed to this chronic disabling neurologic disorder.
Fetal alcohol spectrum disorders occur following ethanol exposure during pregnancy and are a major public health problem. Moderate fetal alcohol exposure (FAE) can lead to subtle characteristics such as cognitive and behavioral deficits that persist through adulthood. The effects of FAE on the developing central nervous system (CNS), including glial cells are significant, as glia become dysfunctional for neuronal support. However, glia, as immune-like cells produce proinflammatory cytokines like interaluekin-1b (IL-1b) and tumor necrosis factor- alpha (TNF-a) that can lead to neuropathology. Whether FAE leads to chronic gliopathy that in turn, generates adult-onset chronic CNS neuroimmune aberrant signaling is not well understood. Chronic neuropathic pain (allodynia; non-pain light touch coded as painful) is mediated by glially-derived IL-1b TNF-a and CCL2 cytokines/chemokines (chemo-tactic signaling cytokines) that induce peripheral immune cell trafficking into sensory ganglia and spinal cord. The goal of the proposed study is to examine allodynia as a model system to understand potential neuroimmune mechanisms underlying chronic disease due to prenatal alcohol exposure.
