Abstract
Among the many symptoms (motor, sensory, and cognitive) associated with multiple sclerosis (MS), chronic pain is a common disabling condition. In particular, neuropathic pain symptoms are very prevalent and debilitating, even in early stages of the disease. Unfortunately, chronic pain still lacks efficient therapeutic agents. Progress is needed (i) clinically by better characterizing pain symptoms in MS and understanding the underlying mechanisms, and (ii) preclinically by developing a more closely dedicated model to identify new therapeutic targets and evaluate new drugs. In this setting, new variants of experimental autoimmune encephalomyelitis (EAE) are currently developed in mice to exhibit less severe motor impairments, thereby avoiding confounding factors in assessing pain behaviors over the disease course. Among these, the optimized relapsing-remitting EAE (QuilA-EAE) mouse model, induced using myelin oligodendrocyte glycoprotein peptide fragment (35–55), pertussis toxin, and quillaja bark saponin, seems very promising. Our study sought (i) to better define sensitive dysfunctions and (ii) to extend behavioral characterization to interfering symptoms often associated with pain during MS, such as mood disturbances, fatigue, and cognitive impairment, in this optimized QuilA-EAE model. We made an in-depth characterization of this optimized QuilA-EAE model, describing for the first time somatic thermal hyperalgesia associated with mechanical and cold allodynia. Evaluation of orofacial pain sensitivity showed no mechanical or thermal allodynia. Detailed evaluation of motor behaviors highlighted slight defects in fine motor coordination in the QuilA-EAE mice but without impact on pain evaluation. Finally, no anxiety-related or cognitive impairment was observed during the peak of sensitive symptoms. Pharmacologically, as previously described, we found that pregabalin, a treatment commonly used in neuropathic pain patients, induced an analgesic effect on mechanical allodynia. In addition, we showed an anti-hyperalgesic thermal effect on this model. Our results demonstrate that this QuilA-EAE model is clearly of interest for studying pain symptom development and so could be used to identify and evaluate new therapeutic targets. The presence of interfering symptoms still needs to be further characterized.
Highlights
Multiple sclerosis (MS) is the most frequent chronic disease that generates neurological disability in young adults
The time course of the EAE score reproduced the clinical presentation of the QuilA-EAE model with alternating phases of relapse and remission (Figure 1B)
Post-hoc analysis showed a significant increase in latency in QuilA-EAE mice treated with pregabalin at 30 mg/kg (Tukey’s test, p < 0.01 vs. vehicle) (Figure 6B, right side). These results show an analgesic effect of the higher dose of pregabalin on heat hyperalgesia in QuilA-EAE but not control mice (CTL) mice
Summary
Multiple sclerosis (MS) is the most frequent chronic disease that generates neurological disability in young adults. It affects some 2–3 million people worldwide [1]. Neuropathic pain is more persistent and is one of the most common distressing conditions experienced by patients even in the early stages of the disease [3, 7]. Management recommendations for neuropathic pain in MS are similar to those for other causes of neuropathic pain. They include tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, and gabapentinoid anticonvulsants used as first-line drug therapy [2, 8, 9]. Randomized, double-blind, and placebo-controlled trials to evaluate the efficacy of these agents in the particular population of MS patients are lacking, and clinical reports suggest that pain in MS is inadequately relieved [10]
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