Human nociception genes mapped out

Dec 17 2012

By Piriya Mahendra, medwireNews Reporter

Researchers have uncovered a "network map" of genes that are involved in pain perception, which they say may help identify new analgesic drugs.

In a previous study, Greg Neely (Garvan Institute of Medical Research, Sydney, Australia) and Josef Penninger (Austrian Academy of Sciences, Vienna) screened 14,000 genes in the fruit fly genome and identified 580 genes associated with heat perception.

Along with another team of researchers, they used this functional genomics dataset in the current study to develop a conserved network map of heat pain/nociception and identify 400 equivalent genes in humans.

"By cross-referencing fly data with human information already in the public domain - like gene expression profiling or genetic association studies - we know we'll be able to pinpoint new therapeutic targets," explained Neely in a press statement.

The researchers found that the network is markedly enriched for multiple genes associated with human pain and predicts previously unidentified candidate pain pathways. They note that the network map demonstrated "exceptional" evolutionary conservation of molecular mechanisms across species.

"The fact that evolution has done such a remarkable job of conserving pain genes across species makes our fly data very useful, because much of it translates to rodents and people," explained Neely.

"We are able to test our hypotheses in mice, and if a gene or pathway or process functions as we predict, there is a good chance it will also apply to people."

A central node of the pain network is phospholipid signaling, which has been implicated in pain processing in previous studies. The role of phospholipid signaling in mammalian heat pain perception was further investigated by the researchers by analyzing the phenotype of mice with mutations in PIP5Kα and PI3Kγ (enzymes involved in phospholipid function).

Both groups of mice showed pronounced hypersensitivity to noxious heat and capsaicin-induced pain; the researchers showed through the PI3Kγ kinase dead knock-in mice that this mapped directly to PI3Kγ lipid kinase activity.

The researchers used single primary sensory neuron recording to find that PI3Kγ function is mechanistically linked to a negative regulation of TRPV1 (receptor for noxious heat and capsaicin) channel transduction.

"Pain affects hundreds of millions of people and is a research field badly in need of new approaches and discoveries," said Neely in a press statement.

The researchers conclude in PLoS Genetics: "This finding shows that our fly-based genetic pain network map is a valuable tool for the discovery of novel 'nociception genes' in mammals."

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