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Modified drug enters cells to provide long term pain relief

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US researchers have successfully altered a drug used to treat nausea - so that it enters cells and delivers long-lasting relief from pain.


Chemically modified versions of netupitant generated for the study blocked pain signals in laboratory mice for at least eight hours, and could now help to develop valuable new human analgesics without significant side effects.


Led by scientists at NYU College of Dentistry, the research team tweaked both the lipophilicity and acidity of netupitant – creating analogues that were able to enter cellular endosomes and block pain signalling in the neurokinin-1 receptor (NK1R).


In doing so, they not only confirmed the theory that endosomal signalling of NK1R and other G-protein-coupled receptors (GPCRs) plays a key role in how we experience pain, but also established useful criteria for designing new, targeted painkillers.


“Sustained signaling in endosomes is necessary for the hyperexcitability of pain-sensing neurons involved in chronic pain,” said study senior author Nigel Bunnett.


“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 development of novel painkillers with fewer side-effects could be highly beneficial in treating a number of conditions, including burn injuries, diabetic neuropathy and cancer. However, clinical trials exploring NK1R as a target for treating pain returned disappointing results during the 1990s and early 2000s. In their research paper, the NYU-led research group theorised that this may have been due to previous drugs targeting GCPRs at the cell surface, where “plasma membrane signaling of GPCRs is usually tightly regulated and may not exclusively mediate long-lasting pathology.”


Instead, they sought to “define the criteria for designing GPCR antagonists that disrupt endosomal signalosomes”, given that endosomal signalling “has been implicated in certain physiological and pathological processes, including hormonal control and pain transmission. Thus GPCRs in endosomes, rather than at the cell surface, might be the optimal therapeutic target.”


To overcome the differences in drug potency between humans and mice, the group genetically engineered laboratory mice whose NK1Rs were replaced by a full-length human variant. To further test the link between endosomal NK1R signalling and pain, they also engineered mice to carry a shorter human variant associated with diminished GCPR signalling.


They then injected the mice with capsaicin – the active ingredient in hot peppers – in order to induce a pain response. They subsequently administered analogues of netupitant, and another anti-nausea drug, aprepitant, and found that modified netupitant “had more potent, efficacious, and sustained antinociceptive effects.” Whereas aprepitant inhibited the animals’ pain responses for two hours, the netupitant analogues PS29 and PS34 “completely prevented capsaicin-evoked mechanical allodynia for 4 h, with antinociceptive effects for at least 8 h.”


The group also found that the mice with the truncated NK1R variant displayed “attenuated SP (Substance P) induced activation of spinal neurons and diminished nociception – again “support(ing) the hypothesis that efficient coupling to G proteins, βARRs, and the endocytic machinery are necessary for SP-evoked pain.”


Bunnett said that the NYU-led group would continue its work in this area – but also expressed hope that the research could have applications for developing a wide variety of drugs that target a range of endosomal GPCRs.


“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,” he added.




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