NaV1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas

Abstract: Peripheral nerve injury can result in formation of a neuroma, which is often associated with heightened sensitivity to normally innocuous stimuli as well as spontaneous dysesthesia and pain. The onset and persistence of neuropathic pain have been linked to spontaneous ectopic electrogenesis in axons within neuromas, suggesting an involvement of voltage-gated sodium channels. Sodium channel isoforms NaV1.3, NaV1.7 and NaV1.8 have been shown to accumulate in chronic painful human neuromas, while, to date, only NaV1.3 has been reported to accumulate within experimental neuromas. Although recent evidence strongly support a major contribution for NaV1.7 in nociception, the expression of NaV1.7 in injured axons within acute neuromas has not been studied. The current study examined whether NaV1.7 accumulates in experimental rat neuromas. We further investigated whether activated (phosphorylated) mitogen-activated protein (MAP) kinase ERK1/2, which is known to modulate NaV1.7 properties, is co-localized with NaV1.7 within axons in neuromas. We demonstrate increased levels of NaV1.7 in experimental rat sciatic nerve neuromas, 2weeks after nerve ligation and transaction. We further show elevated levels of phosphorylated ERK1/2 within individual neuroma axons that exhibit NaV1.7 accumulation. These results extend previous descriptions of sodium channel and MAP kinase accumulation within experimental and human neuromas, and suggest that targeted blockade of NaV1.7 or ERK1/2 may provide a strategy for amelioration of chronic pain that often follows nerve injury and formation of neuromas. [Copyright &y& Elsevier]