Genetic screen for neuropathic pain study in importin alpha3 knock out mice

Here we show that importin alpha (a) 3 (KPNA4) controls pain responsiveness in peripheral sensory neurons. An importin a3 knockout mouse showed reduced responsiveness to noxious heat or chemical pain, as well as greater tolerance to neuropathic pain. Similar findings were obtained upon acute knockdown of importin a3 in peripheral sensory neurons. Transcriptome analyses and immunohistochemistry indicated that importin a 3 deficient neurons were impaired in nuclear import of c-Fos. Forty days after spared nerve injury acute down-regulation of importin a3, c-FOS, Jun and the dominat negative AAV9 viruses rescue the neuropathic pain phenotype. In silico screens identified importin a3 deficiency mimicking drug leads that attenuated neuropathic pain and reduced c-Fos nuclear localization. Hence, perturbing c-Fos nuclear import by importin a3 can provide analgesia at peripheral loci in the nervous system Overall design: Treatments to combat neuropathic pain using the importin alpha3-cFOS signalling