Researchers have identified a novel receptor for nerve growth factor (NGF) that is crucial in the pain signaling process, despite not functioning as a signaling entity on its own, according to a recent study. These discoveries could pave the way for innovative treatments for arthritis and various types of inflammatory and cancer-related pain, while minimizing the adverse effects that have hindered the success of recent clinical therapies.
Scientists at the NYU Pain Research Center have unveiled a new receptor for nerve growth factor that significantly contributes to pain signaling, even though it operates without signaling independently, as detailed in a study published in the Journal of Clinical Investigation. This research offers hope for creating effective treatments for arthritis and other inflammatory and cancer-related pain that do not carry the side effects associated with some current therapies.
“Nerve growth factor is unique because it’s among the few targets validated by patients for pain management,” stated Nigel Bunnett, a professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and the leading author of the study. “Our aim was to identify methods to bypass side effects, thus paving the way for safer, non-opioid pain therapies for arthritis and other types of chronic pain.”
Nerve growth factor is a protein essential for the growth of neurons. It is a strong inducer of pain in both animals and humans, released by cells from injured or diseased tissues. Pain signals are transmitted when nerve growth factor binds to a receptor known as tropomyosin receptor kinase A (TrkA).
Monoclonal antibodies—laboratory-created proteins that imitate natural antibodies and latch onto specific proteins for disease treatment—have shown potential in chronic pain management by specifically targeting and neutralizing nerve growth factor. In extensive clinical trials, these antibodies provided better relief from osteoarthritis pain than placebos or alternative medications; however, some patients faced worsened joint damage, which prevented approval for these treatments.
Understanding how a non-signaling receptor influences pain signals
Through a series of experiments with mouse and human neurons, the researchers discovered a new receptor for nerve growth factor known as neuropilin-1 (NRP1), a protein found in neurons and various other cell types.
The research team observed that nerve growth factor contains a segment of amino acids recognized to enable binding with NRP1. They noted that NRP1 was present in the same cells as the TrkA receptor for nerve growth factor.
By examining pain-responsive neurons, they found that NRP1 could bind nerve growth factor strongly; furthermore, blocking NRP1 in neurons from both species prevented nerve growth factor from sending pain signals. This led the researchers to determine that NRP1 serves as a co-receptor for nerve growth factor, even though, unlike TrkA, NRP1 does not initiate signaling on its own.
“Our discoveries indicate that neuropilin-1 is essential for nerve growth factor to transmit pain signals, albeit indirectly,” Bunnett remarked.
In deeper cellular investigations, the team identified two mechanisms that clarify NRP1’s role in pain. Firstly, through binding with nerve growth factor, NRP1 boosts the local concentration of nerve growth factor available to TrkA, the signaling receptor. Additionally, NRP1 acts as a molecular chaperone—a type of protein that assists in the movement of other proteins within the cell—by interacting with TrkA and facilitating its transfer from the cell’s interior to the plasma membrane’s surface. This action enhances the presence of TrkA at the cell surface, enabling it to recognize nerve growth factor and initiate pain signaling.
Subsequently, the researchers utilized molecular modeling to better understand the interactions among nerve growth factor, TrkA, and NRP1 at the cellular surface. The model indicates that two molecules each of nerve growth factor, TrkA, and NRP1 work together to form a complex responsible for pain signaling.
Finally, the researchers identified a protein named G Alpha Interacting Protein C-terminus 1 (GIPC1), which appears vital in linking TrkA and NRP1 in pain signaling. GIPC1 connects TrkA and NRP1 to a specific molecule that carries the pain signaling complex into the cell’s interior, potentially leading to persistent or chronic pain.
A “springboard” for pain management interventions
Based on the newly identified role of NRP1 in pain signaling, the researchers see various opportunities to use this information to adapt existing therapies and create new treatment options.
One possibility is to block NRP1 using existing compounds, as inhibitors of NRP1—including monoclonal antibodies—are already available for cancer treatment.
“We can evaluate these monoclonal antibodies targeting NRP1 in pain models,” Bunnett said. “By focusing on receptors located at the surface of pain-sensing neurons, these treatments may reduce side effects typical of other monoclonal antibodies that neutralize all nerve growth factor in the body.”
The researchers are also exploring their newfound comprehension of the pain signaling complex, pinpointing the interaction sites for nerve growth factor, TrkA, and NRP1 while developing peptides to disrupt these interactions. In their study published in the Journal of Clinical Investigation, they designed one such peptide that inhibited the interaction between nerve growth factor and NRP1, successfully stopping pain in cellular models.
“This understanding can serve as a starting point to create new peptide-based analgesics that prevent the formation of this pain signaling complex,” Bunnett remarked.
Additional contributors to the study include Chloe Peach (currently at the University of Nottingham), Raquel Tonello, Elisa Damo, Renato Bruni, Harsh Bansia, Ana-Maria Manu, Hyunggu Hahn, Alex Thomsen, Brian Schmidt, Steve Davidson, and Amedee des Georges from the NYU Pain Research Center at NYU College of Dentistry; Kimberly Gomez, Aida Calderon-Rivera, and Rajesh Khanna from the University of Florida College of Medicine; and Laura Maile from the University of Cincinnati.
This research received partial funding from the National Institutes of Health and the Department of Defense, with support numbers specified. Bunnett is a founding scientist of Endosome Therapeutics Inc., and his lab’s research is also funded in part by Takeda.
