Abstract
Spinal muscular atrophy (SMA) is a devastating motor neuron degeneration disease caused by a deficiency of the SMN protein. Majority of patients also suffer from chronic pain. However, the pathogenesis of pain in the context of SMA has never been explored. In this study, using various pain tests, we found that a mild SMA mouse model presents with multiple forms of pain hypersensitivity. Patch-clamp recording showed that nociceptive neurons in SMA mouse dorsal root ganglia (DRGs) are hyperexcitable and their sodium current densities are markedly increased. Using quantitative RT-PCR, western blotting and immunofluorescence, we observed enhanced expression of two main voltage-gated sodium channels Nav1.7 and Nav1.8 in SMA mouse DRGs, which is at least in part due to increase in both expression and phosphorylation of NF-κB p50/p65 heterodimer. Moreover, we revealed that plasma norepinephrine levels are elevated in SMA mice, which contributes to mechanical hypersensitivity via the β2-adrenergic receptor. Finally, we uncovered that β2-adrenergic signaling positively modulates expression as well as phosphorylation of p50 and p65 in SMA mouse DRGs. Therefore, our data demonstrate that SMA mice, similar to humans, also develop pain hypersensitivity, and highlight a peripheral signaling cascade that elicits the mechanical sensitization in the mouse model, suggesting potential targets for therapeutic intervention.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder
Pain hypersensitivity occurs in SMA mice
Heat sensitivity was assessed with the conventional hot plate test[28], which further indicates that thermal allodynia and hyperalgesia occur in SMA mice (Supplemental Fig. S2)
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. It is the most common genetic killer of infants, caused by mutations in the survival of motor neuron 1 (SMN1) gene[1]. Www.nature.com/scientificreports spinal cord motor neurons in SMA patients and mouse models, of severe forms[10,11,12]. Several groups provided strong evidence that cell-nonautonomous mechanisms account for or contribute to spinal cord motor neuron death and/or motor dysfunction in mouse and Drosophila models[13,14,15,16,17,18]. Chronic pain is an unpleasant sensation that persists over a long period of time It is a major comorbid condition in many diseases including neurological disorders[24]. Understanding of the specific pathophysiological mechanisms of pain associated with a disease should shed light on design of therapeutic approaches for pain relief
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