NYC Gazette

Researchers at the NYU Pain Research Center have identified a new receptor for nerve growth factor, potentially paving the way for innovative pain treatments. This discovery was detailed in a study published in the Journal of Clinical Investigation and could lead to new therapies for arthritis and other types of inflammatory and cancer-related pain.

"Nerve growth factor is unusual because it’s one of the few patient-validated targets for pain," stated Nigel Bunnett, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry, who is also the senior author of the study. "We wanted to think of a way of circumventing side effects in an effort to find safer, non-opioid therapies for arthritis and other forms of chronic pain."

Nerve growth factor, known to stimulate neuron development, also plays a significant role in transmitting pain signals by binding to tropomyosin receptor kinase A (TrkA). Recent attempts to use monoclonal antibodies targeting nerve growth factor showed promise but were hindered by adverse effects such as joint damage.

The researchers discovered neuropilin-1 (NRP1) as a co-receptor that binds with high affinity to nerve growth factor without signaling on its own. Blocking NRP1 inhibited nerve growth factor from signaling pain in neurons from both mice and humans. "Our findings suggest that neuropilin-1 is required for nerve growth factor to signal pain, even if it is indirectly regulating it," Bunnett explained.

Further studies revealed two mechanisms explaining NRP1's role: increasing local concentrations of nerve growth factor presented to TrkA and acting as a molecular chaperone aiding TrkA's movement within cells. The research team used molecular modeling to understand interactions between nerve growth factor, TrkA, and NRP1 at cell surfaces.

Additionally, they identified G Alpha Interacting Protein C-terminus 1 (GIPC1) as crucial in linking TrkA and NRP1, potentially contributing to sustained or chronic pain. Given these insights into NRP1's role in pain signaling, researchers are exploring ways to redeploy existing therapies or develop new ones by blocking NRP1 with established compounds like monoclonal antibodies used in cancer treatment.

"We could test these monoclonal antibodies that target NRP1 in models of pain," Bunnett suggested. He added that this specificity might avoid side effects associated with other treatments sequestering all nerve growth factors in the body.

The study authors include Chloe Peach from the University of Nottingham; Raquel Tonello; Elisa Damo; Renato Bruni; Harsh Bansia; Ana-Maria Manu; Hyunggu Hahn; Alex Thomsen; Brian Schmidt; Steve Davidson; Amedee des Georges from NYU Pain Research Center at NYU College of Dentistry; Kimberly Gomez; Aida Calderon-Rivera; Rajesh Khanna from University of Florida College of Medicine; Laura Maile from University of Cincinnati.

This research received support partly from National Institutes of Health grants (NS102722, DK118971, DE026806, DE029951, RM1DE033491, GM147088, GM133598, NS098772, NS120663, DA042852, NS134965) and Department of Defense grants (W81XWH1810431,W81XWH2210239). Nigel Bunnett is a founding scientist at Endosome Therapeutics Inc., with additional funding from Takeda supporting his laboratory work.

Founded in 1865 as New York University's dental school—NYU College Of Dentistry—is renowned globally today while educating nearly ten percent among American dentists annually through its diverse student body initiatives available online via dental.nyu.edu