Pain in experimental autoimmune encephalitis: a comparative study between different mouse models

Abstract

BackgroundPain can be one of the most severe symptoms associated with multiple sclerosis (MS) and develops with varying levels and time courses. MS-related pain is difficult to treat, since very little is known about the mechanisms underlying its development. Animal models of experimental autoimmune encephalomyelitis (EAE) mimic many aspects of MS and are well-suited to study underlying pathophysiological mechanisms. Yet, to date very little is known about the sensory abnormalities in different EAE models. We therefore aimed to thoroughly characterize pain behavior of the hindpaw in SJL and C57BL/6 mice immunized with PLP139-151 peptide or MOG35-55 peptide respectively. Moreover, we studied the activity of pain-related molecules and plasticity-related genes in the spinal cord and investigated functional changes in the peripheral nerves using electrophysiology.MethodsWe analyzed thermal and mechanical sensitivity of the hindpaw in both EAE models during the whole disease course. Qualitative and quantitative immunohistochemical analysis of pain-related molecules and plasticity-related genes was performed on spinal cord sections at different timepoints during the disease course. Moreover, we investigated functional changes in the peripheral nerves using electrophysiology.ResultsMice in both EAE models developed thermal hyperalgesia during the chronic phase of the disease. However, whereas SJL mice developed marked mechanical allodynia over the chronic phase of the disease, C57BL/6 mice developed only minor mechanical allodynia over the onset and peak phase of the disease. Interestingly, the magnitude of glial changes in the spinal cord was stronger in SJL mice than in C57BL/6 mice and their time course matched the temporal profile of mechanical hypersensitivity.ConclusionsDiverse EAE models bearing genetic, clinical and histopathological heterogeneity, show different profiles of sensory and pathological changes and thereby enable studying the mechanistic basis and the diversity of changes in pain perception that are associated with distinct types of MS.

Effects of active immunisation with myelin basic protein and myelin-derived altered peptide ligand on pain hypersensitivity and neuroinflammation

“…These results suggest that oligodendrocytes and myelin integrity are not likely to play a role in this animal model. While nonpeptidergic IB4-binding C fibre staining has been shown to decrease in neuropathic pain (Bailey andRibeiro-da-Silva, 2006, Munglani et al, 1995), an increased IB4+ immmunoreactivity in the spinal cord of proeolipid protein (PLP) 139-151 -immunised SJL/J mice exhibiting neuropathic pain behaviours has been reported (Lu et al, 2012), and our results show no change in IB4 immunoreactivity in the spinal cord. Thus, the role of non-peptidergic IB4-binding C fibres in neuropathic pain associated with EAE appears unclear.…”

“…Accumulating evidence suggests inflammation and reactive gliosis are key features of EAE (Olechowski et al, 2009, Lu et al, 2012. Herein, we observed a significantly enhanced Iba-1+ immunoreactivity in the dorsal and ventral horns of the lumbar spinal cord of MBP-treated rats compared to the co-immunised and control rats.…”

Loss of Allograft Inflammatory Factor-1 Ameliorates Experimental Autoimmune Encephalomyelitis by Limiting Encephalitogenic CD4 T-Cell Expansion

“…Expression of Aif-1 increases above basal levels in these cell types (16)(17)(18) in neuro-inflammatory disease models (19). Conceivably, increased expression of Aif-1 during EAE pathogenesis (20,21) could promote T cell, macrophage and/or microglial proinflammatory functions and overall disease activity. Alternatively, Aif-1-dependent microglial phagocytosis (23) and clearance of cellular debris could be important as means to limit inflammation and enhance regenerative processes (11 mice, the Aif-1-deficient mice had lower incidence and severity of induced disease.…”

“…Aif-1 expression is induced in microglial cells in different stages of EAE in rat and mouse models (20,21) Figure 1B) throughout the disease evaluation period. Although the timing of disease onset and time to peak disease were similar in both groups ( tent with the decreased incidence and severity of disease.…”

“…The significance of increased Aif-1 expression in neuroinflammatory diseases such as EAE (20,21) has not been characterized. Overexpression of Aif-1 in MOLT-4 T cells increases proliferation, migration and activation (17) and in macrophage cell lines enhances production of interleukin (IL)-6, IL-12 and IL-10 (22).…”