A small snail may offer an alternative to opioids for pain relief. Scientists at the University of Utah have discovered a compound that blocks pain by targeting a pathway not associated with opioids. Research in rodents indicates that the benefits continue long after the compound has been cleared from the body. The findings were published online in the February 20 issue of Proceedings of the National Academy of Sciences.
The opioid crisis has reached epidemic proportions. Opioids are highly addictive and according to the Centers for Disease Control and Prevention, 91 Americans die every day from an opioid overdose. The medical community needs alternative therapies that do not rely on opioid pathways for pain relief.
“Nature has developed molecules that are extremely sophisticated and may have unexpected applications,” begins Baldomera Olivera, Ph.D., professor of biology at the University of Utah. “We were interested in using venoms to understand different pathways in the nervous system.”
Conus regius, a small marine cone snail common to the Caribbean Sea, packs a venomous punch, capable of paralyzing and killing its prey.
In this study, researchers found that a compound isolated from snail venom, Rg1A, acts on a pain pathway separate from that targeted by opioid drugs. Using rodent models, scientists have shown that nicotinic acetylcholine receptor (nAChR) ?9?10 functions as a pain pathway receptor and that RgIA4 is an effective compound to block this receptor. The pathway adds to a small number of non-opioid-based pathways that could be further developed to treat chronic pain.
Interestingly, the duration of pain relief is long, far exceeding the presence of the compound in the animal’s system.
The compound works its way through the body within 4 hours, but scientists have found that the beneficial effects persist. “We found that the compound was still working 72 hours after injection, still preventing pain,” said J. Michael McIntosh, MD, professor of psychiatry at Utah University of Health Sciences. The duration of the result may suggest that the snail compound has a restorative effect on certain components of the nervous system.
“What’s particularly exciting about these results is the prevention aspect,” McIntosh said. “Once chronic pain has developed, it is difficult to treat. This compound offers a potential new avenue to prevent pain from developing in the first place and offer new therapy to patients who are out of options. .”
Researchers will move to the next stage of preclinical testing to study the safety and efficacy of a new drug therapy.
Testing a new non-opioid compound
Previous research had shown RgIA to be effective in rodents, but the scientists wanted to make sure they had a compound that would work in humans. To do this, they used synthetic chemistry to design 20 analogues of the compound. Essentially, the scientists started with a key (RgIA) that fits into a lock (the pain pathway receptor ?9?10 nAChR). Using the key as a model, they developed new (analogous) keys with slightly different configurations.
The scientists found a key that best matched the lock: the RgIA4 analog tightly bound to the human receptor.
To test whether the compound relieved pain, the scientists gave it to rodents that were exposed to a chemotherapy drug that causes extreme sensitivity to cold, as well as hypersensitivity to touch. “Interactions that aren’t normally painful, like sheets rubbing against the body or pants against the leg, become painful,” McIntosh said.
While untreated rodents experienced pain after being exposed to the chemotherapy drug, rodents given the compound did not experience pain. Rodents that were genetically modified rodents also did not lack the pain pathway receptor.
Most pain relievers available today work through a limited number of pathways and are not sufficient to relieve chronic pain. “RgIA4 works in an entirely new pathway, which opens the door to new opportunities for treating pain,” McIntosh said. “We believe that drugs that work through this pathway may reduce the burden of opioid use.”