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Enhanced version of anti-nausea drug enables cellular access for extended pain relief


Neurokinin-1 receptor signaling from endosomes

A recent study led by NYU College of Dentistry's Pain Research Center highlights that modifying the chemical properties of an anti-nausea medication enables it to access the interior compartments of cells, resulting in long-lasting pain relief. Published in the Proceedings of the National Academy of Sciences (PNAS), the research emphasizes that pain signaling occurs within cells rather than at their surface, underscoring the importance of drugs capable of reaching cell receptors.


G protein-coupled receptors (GPCRs), a significant protein family regulating various bodily processes and targeted by a third of clinically used drugs, include a subset of receptors that play a crucial role in pain. One such receptor is the neurokinin-1 (NK1) receptor, activated by a pain-transmitting neuropeptide known as substance P.


While several FDA-approved drugs targeting the NK1 receptor effectively prevent chemotherapy- or surgery-related nausea and vomiting, earlier attempts to utilize these drugs for pain relief proved unsuccessful in clinical trials during the 1990s and early 2000s.


One potential reason for the previous ineffectiveness of NK1 receptor-targeting pain drugs is their limited blockade of surface cell receptors. However, the researchers at NYU Pain Research Center have demonstrated that pain signaling through GPCRs occurs not at the cell surface but within specialized compartments called endosomes.


''Sustained signaling in endosomes is necessary for the hyperexcitability of pain-sensing neurons involved in chronic pain. 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 specifically examined two drugs, aprepitant and netupitant, which are NK1 receptor antagonists commonly used to prevent nausea and vomiting. While studying NK1 receptors in the laboratory provides the advantage of having clinically approved drugs that target the receptor, it also presents challenges due to significant differences between the NK1 receptor in mice and humans. To address this issue, the researchers genetically modified mice to express the human NK1 receptor.


Previously, Bunnett and colleagues demonstrated that enclosing aprepitant within nanoparticles facilitated drug delivery to endosomes, effectively blocking pain. However, in this study, the effects of aprepitant on endosomal signaling were only transient based on cellular studies, and its pain-relieving properties in mice were limited to short durations.


The modification of the second drug, netupitant, demonstrated greater potential in the study. The researchers made chemical alterations to enhance its ability to penetrate a cell's lipid membrane. They also modified the molecule's charge to ensure it remained trapped inside the acidic environment of an endosome once it entered.


These modifications enabled the modified netupitant to efficiently enter cells, reach the endosomes, and effectively block NK1 receptor signaling within the endosomes. Its impact was significantly prolonged compared to both aprepitant and the regular form of netupitant. Moreover, the modified netupitant exhibited a more potent and long-lasting analgesic effect in mice.


In a separate experiment, the researchers investigated mice with a distinct type of NK1 receptor located on the outer membrane of the cell instead of within. These mice displayed greater pain resistance compared to those with human NK1 receptors within the cell, emphasizing the crucial role of endosomes in pain signaling and the necessity for treatments capable of penetrating cells.


The research team is actively pursuing further investigations in animal models and continuing this line of research to develop novel pain therapies that target G protein-coupled receptors (GPCRs) within endosomes.


Bunnett, the lead researcher, remarked, "Although our focus was on the neurokinin-1 receptor, our findings likely have broader implications for many G-protein coupled receptors, as numerous receptors exhibit sustained signaling within cells, necessitating drugs that can enter cells and block receptors in endosomes."


Additional authors involved in the study include Alan Hegron, Chloe J. Peach, Raquel Tonello, Shavonne Teng, Rocco Latorre, Dane D. Jensen, Alex R. B. Thomsen, and Brian L. Schmidt from NYU College of Dentistry; Philipp Seemann, Harald Huebner, Dorothee Weikert, and Peter Gmeiner from Friedrich-Alexander Universität Erlangen-Nürnberg in Germany; and Jeanette Rientjes, Nicholas A. Veldhuis, Daniel P. Poole, and Wendy L. Imlach from Monash University in Australia.




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