Many people live with chronic pain, and in some cases cannabis can provide relief. But the drug can also have a significant impact on memory and other cognitive functions. Now researchers report in ACS ‘ Journal of Medicinal Chemistry have developed a peptide which, in mice, ∆9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, to fight pain without the side effects.
According to the United States Centers for Disease Control and Prevention, about 20% of adults in the United States suffered from chronic pain in 2019. Opioids, a mainstay of severe pain management, are effective, but patients can easily becoming dependent on it. In some studies, medical marijuana has been helpful in relieving pain caused by migraines, neuropathy, cancer, and other conditions, but the side effects present barriers to widespread therapeutic use. Previously, researchers identified two peptides that disrupt an interaction between a target THC receptor and another receptor that binds to serotonin, a neurotransmitter that regulates learning, memory, and other cognitive functions. When the researchers injected the peptides into the brains of the mice, the mice had fewer memory problems caused by THC. Now, this team, led by Rafael Maldonado, David Andreu and his colleagues, wanted to improve these peptides to make them smaller, more stable, orally active and able to cross the blood-brain barrier.
Based on data from molecular dynamics simulations, the researchers designed two peptides that were less than half the length of the original peptides, but which retained their receptor binding and other functions. They also optimized peptide sequences to improve cell entry, stability, and the ability to cross the blood-brain barrier. Next, the researchers gave the mice the most promising peptide orally, with an injection of THC, and tested the mice’s pain threshold and memory. Mice treated with both THC and the optimized peptide reaped the benefits of THC for pain relief and also showed improved memory compared to mice treated with THC alone. Importantly, several treatments with the peptide did not elicit an immune response. These results suggest that the optimized peptide is an ideal drug candidate for reducing the cognitive side effects of cannabis-based pain management, according to the researchers.
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