Using FHF2 to Adjust the Gain on Pain

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The prevalence of chronic pain is higher in Veterans compared to the civilian population. Current treatments rely heavily on the use of opioids. The lack of adequate alternative treatments has led to overuse of opioids in the management of pain. These facts highlight the urgent need for alternative pain treatment options. The work outlined in this proposal will focus on voltage-gated sodium channel Nav1.7, an important component in human pain signaling. Single amino acid mutations in Nav1.7 cause at least two known diseases in humans related to pain. Mutations that lead to an increase in activity in the channel cause inherited erythromelalgia (IEM) a chronic pain syndrome that manifests as heat-induced burning pain in the distal extremities. Other mutations in the same channel that lead to decreased activity in Nav1.7 cause congenital insensitivity to pain (CIP) in which patients do not feel pain, i.e., they suffer from painless bone fractures, burns and childbirth. Because of this validation in human cases, Nav 1.7 has emerged as an attractive target in the treatment of chronic pain. The proposed research will build upon recently published work, which demonstrated that FGF homologous factor 2 (FHF2) interacts with Nav1.7, and that knockdown of FHF2 in native dorsal root ganglion (DRG) neurons results in increased Nav1.7 activity. This work will utilize a gene therapy approach to determine whether overexpression of FHF2 can confer loss-of-function attributes to Nav1.7 activity and thereby attenuate nociceptor excitability (a proxy for pain) after nerve injury. This proposal aims to further elucidate the mechanisms linking nerve damage to neuronal hyperexcitability. It has been shown that FHF2 is downregulated after nerve axotomy. Knockdown of FHF2 leads to gain-of- function changes in Nav1.7 activity, and Nav1.7 has been linked to neuronal hyperexcitability. We will utilize an RNA interference approach to knockdown FHF2 levels in an isoform dependent manner and measure the effects on neuronal excitability using multielectrode array analysis, in order to determine that FHF2 is an important factor in a mechanism that links nerve damage to hyperexcitability and pain. We will further investigate the mechanism underlying observed changes in excitability using current clamp electrophysiology. A deeper understanding of this mechanism might reveal additional opportunities to target the mechanism of FHF2 induced Nav1.7 modulation as a way of attenuating neuropathic pain after nerve injury. The ultimate goal of this research program is to discover an alternative way to treat chronic pain of neuropathic origin. This work will have applications for treating both trauma and burn related neuropathic pain, and if successful, will have an important impact on improving the quality of life of Veterans afflicted with pain.