A study in mice shows that a drug makes mammalian pain receptors more like those in birds and more resistant to some types of pain.
Researchers have discovered a possible new way to treat pain without using opioids. By targeting a specific area of a well-known pain receptor, they were able to reduce pain sensitivity in mice without affecting other functions of the receptor, such as heat sensitivity.
Their inspiration? chickens
Most chicken breeders know that squirrels and rats do not eat chicken feed with capsaicin, the chemical that makes hot peppers bitter. In mammals, capsaicin activates a pain receptor to cause a burning sensation. In most bird species, capsaicin has little effect.
“Birds turned out to be naturally resistant to capsaicin,” says Eric Gross, associate professor of anesthesiology, perioperative and pain medicine at the Stanford University School of Medicine.
This fact prompted Gross to wonder if humans might have a genetic variant that makes the receptor known as transient receptor potential cation channel subfamily V member 1, or TRPV1, more bird-like and more pain-resistant.
Bird and human pain receptors
in a study conducted in Journal of Clinical Research, Gross’ team and collaborators have identified a specific genetic variant of TRPV1 that reduces pain sensitivity in humans. Although this variant is extremely rare, the researchers were able to replicate the effects of the altered gene with a specially designed drug.
The researchers first used a computational approach to find genetic variants of human TRPV1 similar to avian TRPV1. When they tested these variants in genetically engineered cells, a variant known as K710N greatly reduced the receptor’s response to capsaicin.
“When we created this genetic variant, we were quite surprised that there was such a reduction in the activity of the TRPV1 response to capsaicin,” says Gross, senior author of the study. “It got to the point where we tried this a few times to make sure that’s really what we were seeing.”
Spicy chicken food for mice
Next, they used the CRISPR/Cas9 gene editing technique to create mice with the K710N mutation. The plan was to see if these rats would find the capsaicin-fortified bird food palatable, which normal rats refuse. The response was faster than the researchers had expected: as soon as the spicy bird food was placed on the floor of their cage, the normal mice lifted their paws as best they could to avoid touching the capsaicin; This suggests that even skin contact causes pain. K710N mice, meanwhile, lifted their claws much less and were comfortable enough to taste capsaicin-spiced birdseed.
Based on these and other behavioral responses, Gross estimates that the mutation reduces pain by about 50%.
TRPV1 receptors on our sensory neurons do more than create a burning sensation when we eat chili peppers. They also respond to other stimuli such as heat and physical injury, which play an important role in protecting us from danger, and regulate body temperature.
“You don’t want to completely eliminate the feeling of pain,” says Gross. “Whether they’re putting their hands on a hot stove or stepping on a Lego, you still want to have someone to experience that painful sensation.”
K710N mice enjoyed a happy environment; they felt less pain but were still able to detect noxious stimuli and maintain their normal body temperature. “We managed to turn it around rather than completely eliminate it,” Gross says.
TRPV1 has more functions in the body, such as protecting against organ damage. The researchers found that the K710N variant retained and even enhanced these protective benefits of TRPV1. For example, heart cells with the variant were less likely to die when temporarily deprived of oxygen.
A potential drug for pain
Understanding exactly how the K710N mutation changes the structure and function of TRPV1, the researchers were able to design a drug with the same effect. When they gave mice a peptide drug called V1-cal by injection or infusion, it reduced the mice’s sensitivity to capsaicin and reduced chronic pain from nerve damage. Just like the K710N mutation, the drug had little effect on the sensation of heat and the regulation of body temperature.
Compared to previous attempts to treat pain by targeting TRPV1, the new chicken-inspired drug works more selectively with fewer side effects.
“People have always used a direct approach, so they looked at ways to specifically activate or block the receptor,” Gross says. “This has been a challenge because activation of the receptor causes pain, while inactivation can cause undesirable changes in body temperature.”
High concentrations of capsaicin activate and eventually desensitize the receptor and have been used in analgesic creams or patches, but treatments increase pain before reducing it. On the other hand, drugs that block the receptor have failed in clinical trials because they cause people to overheat.
“The drug we developed modulates only a specific area of the receptor, rather than directly activating or deactivating the receptor,” he says. “We’re able to avoid side effects that have plagued drug discovery for TRPV1 for some time.”
Gross’ team hopes to modify the peptide to be more stable and relieve pain for longer. In the study, mice were given the drug by continuous infusion.
As an anesthesiologist, Gross often treats patients with post-operative pain. “We’re really excited to see if this is a potential therapeutic for post-surgical pain and help us move towards an opioid-free approach.”
Researchers from Anhui Medical University Second Hospital in China, Butantan Institute in Brazil, University Hospital Munster in Germany, and Emory University also contributed to the study.
The study was funded by the National Institutes of Health, Stanford Cardiovascular Institute, National Natural Science Foundation of China, Chinese Scholarship Council State Scholarship Fund, Anhui Medical University Second Hospital, Sāo Paulo Research Foundation, Coodernacāo de Aperfeiçoamento. Pessoal de Nível Superior-Brasil, Stanford Diabetes Research Center, American Heart Association and German Research Foundation.
Source: Stanford University