Searing pain can drive sufferers mad, and many poisonous animals such as spiders exploit this fact for their defence. When they feel threatened, they bite and inject venoms that are extremely painful, warding off any potential predator. Recent research published in Nature by David Julius and his co-workers from the University of California, San Francisco, has now identified toxins in a spider's venom that resemble molecules from hot chilli peppers, in that they target the same pain receptors as these molecules.
Pain is caused by the activation of specialized nerve cells carrying receptors that are susceptible to capsaicin, the molecule that causes the burn of hot chilli peppers. One of the scientific highlights of 1997 was when Michael Caterina and his colleagues showed that the capsaicin receptor is a heat-activated ion channel involved in the pain pathway. Subsequent research revealed that this receptor belongs to a family of proteins called transient receptor potential (TRP) channels. When a TRP channel in a nerve cell membrane is activated by capsaicin or heat, it opens and forms a pore; calcium ions flow into the cell, generating electrical signals that are transmitted to the brain, signalling pain.
While the components of spider venoms that cause paralysis, inflammation and shock have been extensively studied in the past, little is currently known about pain-generating molecules. Julius and his co-workers addressed the question of which molecules in the spider's venom actually produce pain by designing ingenious experiments allowing them to test many different types of venoms for their ability to activate TRP channels.
For this purpose, the team cultured human kidney cells, which had been genetically altered to produce different varieties of TRP channels on the cell surface. They monitored the activation of TRP channels using a fluorescent dye that lit up when calcium ions flooded into the cells. When the scientists tested the venom of Psalmopoeus cambridgei, a West Indian tarantula,they observed calcium influx in kidney cells carrying the capsaicin variety of TRP receptor. To isolate the venom molecules causing this response, they broke the venom down and identified three peptides, which they named vanillotoxins;each of them activated the capsaicin channel separately.
Next, the team wanted to know if the vanillotoxins also stimulated sensory nerve cells that have the capsaicin receptor on the cell surface. They added the isolated peptides to the laboratory culture of nerve cells from normal mice and from genetically manipulated mice lacking the capsaicin channel and measured their response. Again using the calcium-sensitive fluorescent dye,they observed significant calcium influx only in nerve cells from normal mice but not in those from deficient mice. Looking at the effect of the toxins in the live mice, the mutant mice lacking the capsaicin channel appeared to be insensitive to pain and inflammation that could be provoked in normal mice by capsaicin injection.
Julius and his team found out that organisms as distantly related as hot peppers and tarantulas produce molecules that activate the same receptor channel, producing strong pain. The discovery that vanillotoxins open these channels may provide new tools that could help in understanding TRP channel properties. Understanding the mechanisms that activate TRP channels may also help researchers exploring the pain receptors that are involved in certain types of chronic pain in humans.
