Mechanistic Study Of Pain Hypersensitivity In An SMA Mouse Model

Spinal muscular atrophy(SMA)is a neuromuscular disease,characterized by loss of spinal cord α-motor neurons that results in widespread atrophy of skeletal muscles,especially those of the limbs and trunk.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 von Frey test and Hargreaves test,we found that a mild SMA mouse model has both mechanical and heat hypersensitivity.Patch-clamp recording shows that sodium current densities of SMA nociceptive neurons in dorsal root ganglia are increased,resulting in hyperexcitability of the cells.Using qRT-RCR and western blotting,we observed increase in expression of two main sodium channels Nav1.7 and Nav1.8,which is at least in part due to an increased expression of NF-κB heterodimer p50 and p65.Moreover,we revealed that plasma norepinephrine levels are elevated in SMA mice,which contributes to pain hypersensitivity via β2-adrenergic receptors.Finally,we uncovered that β2-adrenergic signaling positively modulates expression of p50 and p65.Our data demonstrate that SMA mice,similar to humans,also suffer from chronic pain,and more importantly,establish a detailed peripheral signaling cascade that induces pain in the mouse model,suggesting potential targets for therapeutic intervention.