A southern grasshopper mouse approaches and prepares to attack an Arizona bark scorpion. Photo: Matthew and Ashlee Rowe.

The bark scorpion is, according to Wikipedia, the most venomous scorpion in North America, wielding an intensely painful – and potentially lethal – sting that stuns and deters snakes, birds and other predators. People unfortunate enough to have experienced the sting say that it produces an immediate burning sensation, followed by prolonged throbbing pain that can last for hours.

But the grasshopper mouse is completely resistant to the bark scorpion's venom. In fact, it actively preys upon scorpions and other poisonous creatures. As the film clip below shows, it responds to the bark scorpion's sting by licking its paw for a second or two, before resuming its attack, then killing and eating the scorpion, starting with the stinger and the bulb containing the venom. Researchers have now established exactly why this is – paradoxically, the venom has an analgesic, or pain-killing, effect on the grasshopper mouse.



The animal's secret lies in two proteins, the sodium channels Nav1.7 and Nav1.8, which are found in a subset of sensory nerve fibres called nociceptors. These cells express numerous other proteins that are sensitive to damaging chemicals, excessive mechanical pressure, and extremes in temperature, and have fibres that extend from just beneath the skin surface into the spinal cord.

The sensor proteins relay these signals to Nav1.7 and Nav1.8, which then change their structure in response, so that their pores, which span the nerve cell membrane, open up, allowing sodium ions to flood into the cell. This causes the nociceptors to generate nervous impulses, which are transmitted along the fibre into the spinal cord. From there, the signals are relayed to second-order sensory neurons, which then carry the signals up into the brain, where they are interpreted as pain.

Ashlee Rowe of the University of Texas in Austin and her colleagues started off by injecting scorpion venom, formaldehyde and salt water into the hind paws of southern grasshopper mice and common house mice, and compared their behavioural responses.

The house mice licked their paws furiously for several minutes after being injected with venom or formaldehyde, but not when they were injected with salt water. By contrast, the grasshopper mice seemed completely oblivious to the venom, and barely licked their paws at all after being injected with it. They found the formaldehyde to be far more irritating, and the venom actually reduced the amount of time they spent licking their paws when the two were injected together.

Next, the researchers isolated sensory neurons from both types of mice and grew them in Petri dishes. They then added scorpion venom to the dishes and used microelectrodes to measure the electrical activity of the cells. This showed that the venom strongly activated cells from the house mice, making them fire with rapid bursts of nervous impulses, but actually prevented cells from the grasshopper mice from firing. Further investigation revealed that the scorpion venom directly binds to, and potently inhibits, Nav1.8 sodium channels from the grasshopper mice, but not the house mice.

Rowe and her colleagues performed a final series of experiments to determine how this happens at the molecular level. They sequenced the Nav1.8 gene from the grasshopper mouse, and compared it to that of the common mouse, to identify multiple DNA sequence variations that confer insensitivity to scorpion venom. All the mutations encode amino acid residues in or around the pore region of the Nav1.8 protein, replacing neutral residues with acidic ones that are attracted to water.

As a result of these tiny structural changes, scorpion venom binds to Nav1.8 and switches it off, perhaps by plugging the pore or making it impermeable to sodium ions in some other way, thus blocking the transmission of pain signals into the spinal cord.

The researchers confirmed the importance of the pore region by using genetic engineering to replace this segment of the common mouse gene with the corresponding segment from the grasshopper mouse gene. This made the resulting protein resistant to the venom, whereas substituting the pore DNA sequence in the grasshopper gene with that from the common mouse gene rendered it highly sensitive to the venom.

The ability to detect pain is critical for survival, as it alerts organisms to potentially life-threatening injuries. Venomous creatures have capitalised on this, by evolving neurotoxins that inflict pain by activating nociceptors in one way or another, thus detering would-be predators from attacking again. The grasshopper inhabits the deserts of North America and Mexico, and probably evolved resistance to venom as a physiological adaptation, which enabled it to eek out an existence in such an extreme environment by feasting on venomous prey.

Previous work has identified Nav1.7 as a key player in pain signalling, and researchers have identified a number of rare mutations in the gene encoding it, which make people either completely or partially insensitive to pain. Drugs that block Nav1.7 activity could therefore be effective pain-killers, and various research groups have been researching and developing such drugs. The new findings identify Nav1.8 as another potential target, and provide another potential route for the development new analgesic drugs.

Reference: Rowe, A. H., et al. (2013). Voltage-Gated Sodium Channel in Grasshopper Mice Defends Against Bark Scorpion Toxin. Science, 342: 441-446. DOI: 10.1126/science.1236451