Importin α3 contribution to the pain transduction pathway

The recent opioid crisis in the USA has demonstrated the limitations in pain management options available at the moment. Therefore, investigating the biology of pain perception is vital to promote the development of more specific and non-addictive analgesic drugs, especially in the context of chronic pain.

Altered skin and muscle innervation, as a result of an unbalance of internal and external growth signals in neurons, is one of the causes of neuropathic pain.

Peripheral neurons survive and grow in response to neurotrophins, released by surrounding cells. It has been speculated that intracellular growth factors also contribute to and regulate neurotrophin signaling, but the current knowledge on this topic is severely lacking. Intriguingly, this signaling axis could be relevant in shaping nociception in the peripheral neurons.

In a recently published article (Marvaldi et al., 2020), knockout of importin α3 in dorsal root ganglia (DRG) neurons was shown to reduce neuropathic pain perception. Importin α3 is a shuttle protein of the karyopherin family that acts as an adaptor protein of KPNB1 for the delivery of transcription factors to the nucleus. Indeed, analysis has shown that importin α3 null mice have altered gene expression upon injury.

Our research aims to investigate which genes, found to have altered expressions in importin α3 null mice, are relevant for pain perception. In particular, we are planning to look for those genes that are differently modulated at the early and late stages of chronic pain. By comparing our findings to data collected from previously published articles, we will identify candidate proteins that may more likely be involved in the nociception pathways and then further characterize their roles through biochemical assays (both in vitro and in vivo).

Finally, we hope to unravel novel transcriptional networks controlling nociception, which could become new therapeutic targets to manage chronic pain patients.