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.
Highlights
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by widespread focal areas of inflammation, demyelination, gliosis, and neurodegeneration
The restrictions imposed by hind limb motor confounds on continual testing of mechanical allodynia in clinical EAE prompted us to use a technique developed for testing mechanical pain in the face [19], which is not affected by motor deficits
We found that stimulus-evoked and spontaneous pain in EAE may derive from unique pathological mechanisms, with the former arising in the absence of overt central lesion formation
Summary
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by widespread focal areas of inflammation, demyelination, gliosis, and neurodegeneration. Specific conditions include trigeminal neuralgia and Lhermitte’s phenomenon (neuropathic; due to ectopic impulse generation along primary afferents), ongoing extremity pain (neuropathic; secondary to lesion formation in the spino–thalamo–cortical pathways), painful tonic spasms and spasticity pain (mixed; mediated by nociceptors and arises secondary to lesions in the central motor pathways), pain associated with optic neuritis (nociceptive; originating from nervi nervorum), musculoskeletal pains (nociceptive; secondary to motor disorders), and migraine (nociceptive; resulting from predisposition or secondary to midbrain lesions) [7] As it stands, there is a dire need for effective and targeted therapies aimed at the amelioration of pain in MS. This is an issue that, at least in part, stems from a lack of reliable and translatable pain outcome measures in animal models of MS
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