Scorpion venom is a painkiller for the grasshopper mouse
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.
