The Striking Nature of Venom

By Lauren Hinkel
BU News Service

A strike; venom rushes through your flesh, into your veins. A searing pain spreads throughout your body. Muscles tighten, and your heart beats erratically. Your nerves freeze, paralysis sets in, and your world fades to black. That is the power of venom. Dripping from fangs of snakes and barbs of underwater snails, venom efficiently kills its victims. Yet, this brew of hundreds of toxins also contains compounds with the potential to heal and save lives—powerful, natural painkillers.

Currently, opium-derived prescription painkillers like Vicodin flood the pharmaceutical market. By relieving pain, these potent drugs fill an important niche in medicine. They offer powerful relief to pain sufferers by mimicking the brain’s natural endorphins—chemicals that  produce feelings of pleasure and analgesia. Unfortunately, they also come with a high risk of psychological and physical addiction. Since 1999, the United States has seen a 300% increase in deaths due to painkiller abuse—over 15,000 deaths per year, more than cocaine and heroin combined. In light of this, the FDA recently recommended tighter federal restrictions on the most widely used painkillers—opioid analgesics such as Oxycontin (hydrocodone) and Vicodin.  As the rates of painkiller dependence in the United States soar and access to opioid painkillers diminishes, scientists and doctors are looking for less addictive alternatives, and venom is a prime candidate.

A single venomous bite injects hundreds of toxic amino acids and proteins into the flesh, each targeting a specific chain of molecular reactions necessary for life. The fact that each toxin targets a specific molecular pathway is exactly what makes venom so attractive for medical treatment.

As such, scientists can isolate individual venom toxins that interfere only with pain pathways in the nervous system. By selecting a protein that specifically binds to enzymes in this channel, scientists can turn off the flow of pain signals to the brain—like shutting off a faucet. With this high level of specificity, all other metabolic pathways continue to function normally, so addiction doesn’t result. Armed with this knowledge, scientists can harness the power of venom to treat medical conditions associated with specific metabolic pathways, such as chronic pain.

One promising venomous genus is the cone snail. The creature hunts like an undersea whaler. It baits its prey with a tentacle-like appendage. When the prey comes close enough, the cone snail shoots a harpoon infused with a neurologic venom called conotoxin into the fish, thereby capturing, paralyzing, and killing it.

Cone Snail. Flickr image by Ken Ichi

The cone snail harbors many more potential analgesic proteins and peptides in its venom. Dr. John-Paul Bingham of the University of Hawaii collects these proteins—building a venom bank on which he hopes to identify a protein or peptide capable of blocking pain. “There are 600 species [of cone snail] in the genus. Each snail produces about 100 peptides, and about 25-30% of these could be potential analgesics,” said Bingham. “Until we characterize them, we have no way of knowing their capabilities.” But it’s no small task. Individual cone snails within the same species can produce slightly different versions of a toxin based on their diet and geography. Taking this into account, he estimates that between 500,000 and 700,000 compounds could be potential analgesics.

Prialt (Ziconotide), a drug patented by Neurex Corp, is a painkiller isolated from the venom of a species of cone snail and is currently available on the pharmaceutical shelf. Prialt inhibits the transmission of pain signals to the brain by blocking calcium channels. But like many of the venom-derived analgesics, Prialt cannot be taken orally: it’s easily broken down by the body’s gastric juices before it can reach the nervous system and block pain. Many drugs of this class have to be injected directly into the spinal column or the location of pain—a cumbersome process for both patients and doctors.

Researcher David Craik and his group at the University of Queensland, Australia bypassed this problem by developing a painkiller that patients can take orally. The drug contains, a novel painkiller with a circular structure that is not degraded by the stomach’s acids. When tested on rats with injured legs, Craik’s oral, venom-derived drug inhibited calcium ion channels associated with pain transmission in the nervous system.  It proved to be 100 times more powerful at blocking pain than morphine, which is often used as an experimental standard.

Other species of animals harbor the potential for pain relief in their venom. The venom from the Black Mamba, a sub-Saharan African snake, contains protein keys that inhibit pain pathways. Sylvie Diochot, an engineer at the Institute of Pharmocologie Moleculaire and Cellulaire in France helped identify two venom toxins—named mambalgin-1 and -2—which block hydrogen ion flow through neuronal channels—muting pain signals to the brain.

In order to test the strength of the venom-derived painkiller, Diochot’s group developed a way to  measure pain in mice. The scientists injected either mambalgin-1 or -2 into a mouse-subject, and then tested for pain tolerance in two ways: by dipping the mouse’s paws in hot water or by injecting a paw with a painful substance. The group quantified the amount of pain experienced by measuring how fast the mice withdrew their paws from the water and how many times they licked the injured paw. The observed responses to both experiments were similar—the mice that received the mambalgins experienced a reduction in pain sensations comparable to the effects of morphine.

The mouse paw-licks pain metric has also been used to identify painkilling toxins in several other poisonous species. A team in Singapore working from the venom of the King Cobra found a peptide that blocks pain better than morphine without triggering tolerance or addiction. Similarly, Glenn King, a researcher at the University of Queensland, found a peptide in the venom of the Chinese Red-headed Centipede that blocked a sodium ion pain channel without impacting heart rate, blood pressure motor function, or dependence like morphine.

The beauty of venom is that it arises from millions of years of evolution, and humans can leverage this for medicinal purposes. Nature has a way of molding and perfecting biological structures to fit specific functions—like configuring a venomous protein to fit nicely into a molecular pain pathway.

In light of the FDA’s push for opioid restrictions, scientists and researchers could turn their gaze to the sea, forest or grasslands for alternatives. With over 20 million toxins, nature provides researchers with a reservoir of painkiller potential. By sifting through the muddled concoction of proteins, scientists could reveal medicinal treasures and unlock the striking nature of venom.