Peripheral and Central Neuroinflammatory Changes and Pain Behaviors in an Animal Model of Multiple Sclerosis

Abstract

Pain is a widespread and debilitating symptom of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. Although central neuroinflammation and demyelination have been implicated in MS-related pain, the contribution of peripheral and central mechanisms during different phases of the disease remains unclear. In this study, we used the animal model experimental autoimmune encephalomyelitis (EAE) to examine both stimulus-evoked and spontaneous pain behaviors, and neuroinflammatory changes, over the course of chronic disease. We found that mechanical allodynia of the hind paw preceded the onset of clinical EAE but was unmeasurable at clinical peak. This mechanical hypersensitivity coincided with increased microglial activation confined to the dorsal horn of the spinal cord. The development of facial mechanical allodynia also emerged in preclinical EAE, persisted at the clinical peak, and corresponded with pathology of the peripheral trigeminal afferent pathway. This included T cell infiltration, which arose prior to overt central lesion formation and specific damage to myelinated neurons during the clinical peak. Measurement of spontaneous pain using the mouse grimace scale, a facial expression-based coding system, showed increased facial grimacing in mice with EAE during clinical disease. This was associated with multiple peripheral and central neuroinflammatory changes including a decrease in myelinating oligodendrocytes, increased T cell infiltration, and macrophage/microglia and astrocyte activation. Overall, these findings suggest that different pathological mechanisms may underlie stimulus-evoked and spontaneous pain in EAE, and that these behaviors predominate in unique stages of the disease.

Regulatory T Cells and Their Derived Cytokine, Interleukin-35, Reduce Pain in Experimental Autoimmune Encephalomyelitis

“…despite no change in clinical EAE. Similar to other EAE studies (Duffy et al, 2016;Frezel et al, 2016;Wang et al, 2017), our findings further support the idea that pain behaviors are independent of clinical severity in EAE. Additionally, our results are consistent with a previous report demonstrating that intrathecal injection of CD4 ϩ CD25 ϩ Treg cells relieves mechanical allodynia in mice treated with the chemotherapeutic paclitaxel (Liu et al, 2014).…”

“…5B). Both stimulus-evoked pain (facial allodynia) and spontaneous pain (facial grimacing) were assessed, as described previously (Duffy et al, 2016). Facial allodynia was reduced in EAE mice injected with Treg cells compared with EAE mice injected with saline on days 22 ( p ϭ 0.002, H (2,21) ϭ 34.42) and 29 ( p ϭ 0.047, H (2,21) ϭ 22.9) after EAE induction (Fig.…”

“…Experimental autoimmune encephalomyelitis (EAE) is the most widely used animal model of MS and mice with EAE develop robust stimulus-evoked pain behaviors including thermal hyperalgesia, and mechanical and cold allodynia of the tail, hindpaws, forepaws, and face (Aicher et al, 2004;Olechowski et al, 2009;Rodrigues et al, 2009;Lu et al, 2012;Yuan et al, 2012;Schmitz et al, 2013;Duffy et al, 2016;Thorburn et al, 2016). Mice with EAE also develop spontaneous pain measured using the mouse grimace scale (MGS) (Duffy et al, 2016). Although the exact mechanisms underlying pain in MS and EAE are unclear, demyelination and neuroinflammation in nervous system areas involved in pain processing, such as the dorsal horn and spinothalamic pathway, have been implicated (Moalem and Tracey, 2006;Olechowski et al, 2009;Truini et al, 2013).…”

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

“…6; Mifflin et al, 2019), we silenced gene expression of CHOP (encoded by Ddit3) and Xbp1 in dissociated DRG neurons from EAE animals (Fig. 7A) (2,12)=5.020, p=0.0260, one-way ANOVA) ( Fig. 7G-I).…”

“…The role of the CNS as a modulator of pain in MS/EAE has been widely studied (7). However, only a handful of studies to date has investigated the contribution of the peripheral branch of the somatosensory nervous system to pain pathophysiology in EAE and MS (8)(9)(10)(11)(12)(13)(14).…”