How a map of cell signaling networks could identify new targets for pain drugs

Researchers developing drugs for pain disorders have been studying "nociceptive neurons" that are responsible for detecting environmental changes such as injury and translating them into pain signals to the brain. But pain signaling involves far more complex networking beyond these sensory cells.    

By leveraging a computational analysis of RNA sequencing data sets, scientists at the University of Texas (UT) at Dallas created maps of the pain “interactome,” which display networks of signaling connections between target tissues and nociceptive neurons.

Using the maps, the team identified Novartis’ cancer drug Tykerb as a possible candidate for managing pain due to its ability to block the ErbB family of proteins, including the epidermal growth factor receptors (EGFRs). The results were published in the journal Science Signaling.

Some members of the team have formed a startup called Doloromics to explore using the pain interactome to identify novel targets for developing pain drugs. The company recently won backing from genomic sequencing giant Illumina via its Illumina Accelerator.

Previous studies have identified several molecular players involved in pain, but they have mostly focused on solo gene expression factors within specific tissues. The UT Dallas team believes a wider network of cross-tissue interaction could be at play in pain-related diseases. So, the researchers set out to understand how interactions between various cells and neurons contribute to chronic pain.

RELATED: UCSD spinout pursues gene therapy for chronic pain following positive data in mice

Using mouse and human RNA sequencing data sets, the researchers developed interactome maps displaying relationships between sensory neurons and several cell types. They examined how colon nociceptors in the mouse interact with normal and inflamed cells associated with colitis, for example. They also studied how macrophages taken from the joints of people with rheumatoid arthritis interact with human neurons as well as how pancreatic tumors drive cancer-related pain.

One common theme emerged from these analyses: The abundance of the growth factor HBEGF, which acts on its corresponding receptor EGFR in nociceptive neurons, suggests it mediates interactions between diseased tissue and nociceptors.

In mice, the researchers showed that HBEGF likely enhanced pain signals in mouse neurons and that the effect could be blocked by the ErbB antagonist Tykerb.

RELATED: Scorpion toxin uncovers insights into pain that could inspire non-opioid treatments

The opioid epidemic has inspired scientists around the world to search for better alternatives to manage pain. A team at the University of California, San Diego suggested using the gene editing tools CRISPR and zinc finger nucleases to suppress a gene that encodes for a sodium ion channel protein called NaV1.7 in neurons. And researchers from the University of Queensland and the University of California, San Francisco recently set their eyes on a toxin from scorpions, showing the molecule’s impact on the TRPA1 protein, otherwise known as the “wasabi receptor,” could inspire new treatments for chronic pain.

The UT team believes their interactome maps provide a toolkit for understanding multiple ligand-receptor interactions involved in pain. That could uncover several targets and new strategies for pain relief.

“We anticipate that continuing advances in sequencing techniques, such as spatial transcriptomics, and their application to human disease tissues will enable targeted therapeutic discoveries using this interactome framework,” the researchers wrote in the study.