New Approach to Pain Relief: Getting NK1-Targeting Drugs Inside Cells
Researchers at New York University have taken the nausea drug netupitant and tweaked it for long-lasting pain relief by boosting its ability to enter cells. The work was reported in the Proceedings of the National Academy of Sciences (PNAS).
The study examined two drugs, aprepitant and netupitant. Both can block the signals that carry pain, but their entry into cells had been limited. Scientists engineered mice to express the human NK1 receptor, the target of these drugs, and then administered the modified compounds.
The results show that the active ingredient resides in nanoparticles. The modified netupitant demonstrated substantially greater pain-relieving effects in the mice. The researchers altered the chemical traits of the drug to improve its passage across the cell’s lipid membrane. They also designed versions that remain inside cells and accumulate when they encounter the acidic environment of cellular organelles.
Pain signaling happens inside nerve cells rather than solely at the cell surface. This makes it essential to develop medicines that reach internal targets. Potential targets include G protein coupled receptors like NK1. Such intracellular targeting is especially relevant for preventing nausea and vomiting prompted by chemotherapy or surgery. Earlier efforts to treat pain by focusing on the NK1 receptor faced setbacks in clinical trials during the 1990s and early 2000s. A key challenge was that many drugs acted on surface receptors rather than reaching internal sites where pain signals are processed.
By advancing intracellular delivery, the study points to a new class of pain therapies that can reach the inner workings of nerve cells. The findings suggest that formulating existing NK1-targeted drugs into nanoparticles and optimizing their membrane crossing could improve analgesic outcomes while potentially reducing side effects. The researchers emphasize that these results in mice lay the groundwork for further exploration in humans and for refining strategies to deliver medicines to intracellular targets in the nervous system.
Overall, the research highlights a shift in how pain medications can be designed: focusing not only on receptor binding on the cell surface but on enabling drugs to cross membranes and act where signals originate. This approach could also influence future treatments for chemotherapy-induced nausea, postoperative nausea, and other pain-related conditions by providing a more direct route to the intracellular machinery that governs pain perception. (Citation: PNAS; NYU researchers.)