Scientists identify a new receptor for nerve growth factor, offering a potential breakthrough in pain treatment.

A groundbreaking study published in the Journal of Clinical Investigation by researchers at the NYU Pain Research Center has identified neuropilin-1 (NRP1) as a novel co-receptor for nerve growth factor (NGF), an important protein in pain signaling. This discovery could pave the way for safer and more effective treatments for arthritis, inflammatory pain, and cancer pain.

The Role of Nerve Growth Factor in Pain

Nerve growth factor (NGF) is a protein that promotes neuron development and plays a critical role in pain signaling. It binds to the receptor tropomyosin receptor kinase A (TrkA) to transmit pain signals. However, recent therapies targeting NGF with monoclonal antibodies, while effective in reducing pain, failed clinical trials due to side effects such as joint damage.

Neuropilin-1: A Non-Signaling Co-Receptor

The researchers discovered that NRP1 binds NGF with high affinity, acting as a co-receptor alongside TrkA. While NRP1 does not directly signal, it amplifies pain signaling by increasing NGF’s local concentration near TrkA and serving as a molecular chaperone that facilitates TrkA’s movement to the cell surface. This enhances TrkA’s ability to recognize NGF and transmit pain signals.

Pain Signaling Complex and Molecular Insights

Using molecular modeling, the team showed that NGF, TrkA, and NRP1 form a pain signaling complex involving two molecules of each. They also identified G Alpha Interacting Protein C-terminus 1 (GIPC1) as a critical protein linking NRP1 and TrkA, enabling sustained pain signaling.

Implications for Pain Treatment

The findings offer multiple avenues for developing new pain therapies:

• Blocking NRP1: Existing NRP1 inhibitors, such as monoclonal antibodies developed for cancer treatment, could be repurposed to target pain without systemic side effects.

• Peptide-Based Analgesics: The researchers created a peptide that disrupts the interaction between NGF and NRP1, effectively blocking pain signaling in cellular studies.

A Promising Future for Non-Opioid Pain Management

These discoveries provide a foundation for designing safer, targeted treatments for chronic pain. By focusing on the NRP1-TrkA complex, researchers aim to circumvent the challenges faced by previous NGF-targeted therapies.

The study’s senior author, Dr. Nigel Bunnett, emphasized the potential of these findings: “We can use this information as a springboard to develop new peptide-based analgesics that prevent this signaling complex from forming.”

Study Contributors

The research was conducted by an interdisciplinary team from NYU Pain Research Center, the University of Florida College of Medicine, and the University of Cincinnati, among others.

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