Modified Anti-Nausea Drug Enters Cell for Pain Treatment

According to a new study headed by experts at NYU College of Dentistry’s Pain Research Center, changing the molecular characteristics of an anti-nausea drug allows it to enter an internal compartment of the cell and initiate the pain treatment.

The work, which was published in the Proceedings of the National Academy of Sciences (PNAS), demonstrates how pain signaling happens within cells rather than on the surface, emphasizing the need for medications that may reach receptors within cells.

G protein-coupled receptors (GPCRs) are a huge protein family that regulates various bodily processes and are the target of one-third of clinically utilized medications. A subset of these receptors is involved in pain, notably the neurokinin-1 (NK1) receptor, which is activated by substance P, a pain-transmitting neuropeptide.

A number of FDA-approved medications that target the NK1 receptor are used to treat nausea and vomiting caused by chemotherapy or surgery. Previously, scientists thought that the NK1 receptor would be a good target for pain treatment, however medicines targeting the receptor failed to pain treatment in human trials in the 1990s and early 2000s.

Because most medications inhibit receptors on the surface of cells, treatments targeting the NK1 receptor may not have been successful against pain. However, researchers at the NYU Pain Research Center discovered that GCPRs convey pain not from the cell’s surface, but from compartments within the cell known as endosomes.

Sustained signaling in endosomes is necessary for the hyperexcitability of pain-sensing neurons involved in chronic pain,” said Nigel Bunnett, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and the study’s senior author. “As a result, treating pain may require the development of drugs that penetrate cells, are retained in endosomes, and disrupt signaling inside the cell.”

The PNAS study focused on two medications, aprepitant and netupitant, which are both NK1 receptor antagonists used to treat nausea and vomiting. The benefit of studying NK1 receptors in the lab is that there are clinically available medications that target the receptor, but there are also obstacles because the NK1 receptor in mice and humans varies significantly. The researchers overcame this by genetically modifying mice to express the human NK1 receptor.

Bunnett and colleagues previously demonstrated that encapsulating aprepitant in nanoparticles may deliver the drug to endosomes to block pain, however in this study, aprepitant only temporarily disrupted endosomal signaling in cellular tests and temporarily reduced pain in mice.

The second medicine, netupitant, showed even more promise. The researchers altered the drug’s molecular characteristics to increase its ability to penetrate a cell’s lipid membrane. They also changed the charge of the molecule in an acidic environment such that when the medicine reached the acidic environment of an endosome, it would remain trapped inside and accumulate.

These modifications allowed the modified netupitant to easily infiltrate cells and reach the endosome, where it blocked NK1 receptor signaling for a considerably longer period of time. In mice, the modified netupitant had a more effective and long-lasting analgesic effect than aprepitant and the standard form of netupitant.

In another experiment, the researchers looked at mice having a different sort of NK1 receptor on the cell’s outer membrane rather than the inside. These mice were more pain resistant than animals expressing human NK1 receptors inside the cell, demonstrating the role of endosomes in pain communication and the need for medicines that can penetrate cells.

The researchers are continuing these and other experiments in animal models to create new pain treatments that inhibit GCPRs in endosomes.

“Although we focused on the neurokinin-1 receptor, our findings are likely applicable to many G-protein coupled receptors because many of them show sustained signaling within cells, and therefore require drugs that can enter cells and block the receptors in endosomes,” said Bunnett.

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