NeuroVoices: Nigel Bunnett, PhD, BSc, on Identifying a Novel Therapeutic Target for Chronic Pain

Nigel Bunnett, PhD, BSc

Chronic pain is a significant focus within neurology, as it often stems from disorders of the nervous system, such as neuropathies, migraines, and central pain syndromes. Advances in neurology have shed light on the mechanisms behind chronic pain, including the role of specific receptors and neural pathways, paving the way for targeted therapies. More recently, a study published in the Journal of Clinical Investigation has located a new receptor for nerve growth factor (NGF) that plays and critical role in pain signaling, even though it does not signal on its own.

Led by Nigel Bunnett, PhD, BSc, researchers identified neurpilin-1 (NRP1) as a novel co-receptor for NGF, which enhances pain signaling by facilitating the activation of TrkA, a key receptor associated with pain. Additionally, the study uncovered the critical role of the intracellular protein GIPC1 in assembling and stabilizing this receptor complex, enabling NGF to more effectively trigger pain responses. As part of a new iteration of NeuroVoices, Bunnett, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry, sat down to provide insights on the discovery and the next steps in this research.

Bunnett, a basic scientist with an interest in studying the signaling mechanisms of chronic pain, gave commentary on the implications of these findings, pointing to the therapeutic potential of targeting NRP1 and GIPC1. Furthermore, he addressed the broader implications of this research for managing various forms of pain and discussed the process for designing treatments that disrupt this pain-signaling complex.

NeurologyLive: What was the idea behind this study? Why was this of interest to you and your colleagues?

Nigel Bunnett, PhD, BSc: Chronic pain is a major medical problem and a significant cause of human suffering. About 20% of the global population experiences chronic pain at some point in their lives. The current therapies, such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs), are often ineffective and come with life-threatening side effects. For example, in the US alone, over 100,000 people died of drug overdoses last year, and a large portion of these deaths were attributable to opioids. So, we wanted to better understand the mechanisms of chronic pain and develop new, non-opioid therapies that avoid the side effects of opioids and NSAIDs.

What are the greatest takeaways from the study from a clinical perspective?

Yes, so this study focuses on nerve growth factor (NGF). NGF is a validated target for treating chronic pain. Large clinical trials have tested monoclonal antibodies against NGF for arthritis pain. Although these antibodies were effective in relieving pain, they were not approved due to worsened joint damage in some patients. We wanted to explore the mechanisms by which NGF causes pain, with the goal of developing treatments that avoid the side effects of monoclonal antibodies targeting NGF.

The study identified two new co-receptors for NGF that are essential for it to cause pain. The first is neuropilin-1, which binds NGF with low affinity and brings it to the cell surface, facilitating its activation of a second receptor called TrkA. TrkA is the signaling receptor that mediates pain. Neuropilin-1 acts in two ways: it binds NGF and associates with TrkA, helping bring it to the cell surface where it can signal more effectively.

We found that inhibiting neuropilin’s function—using various methods—strongly reduced NGF’s ability to activate neurons, make them hyper-excitable, and cause pain in preclinical models. Importantly, this process occurs in both mice and human nociceptors, providing a translational component.

The second protein we identified is GIPC1, an intracellular protein that interacts with both neuropilin-1 and TrkA. It effectively "glues" the complex together, enabling NGF to more efficiently evoke pain. So, these two mediators—neuropilin-1 and GIPC1—are potentially new therapeutic targets for pain. Both proteins are enriched in nociceptors, the cells responsible for detecting and transmitting painful signals. By targeting these proteins specifically in nociceptors, we hope to avoid the systemic side effects seen with monoclonal antibody therapies.

Coming into the study, how much was previously known about neuropilin-1, and what did this study add?

Neuropilin-1 has been known for quite a while as a protein that interacts with several growth factors, such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF). It has also been implicated in cancer. However, it was never before identified as a receptor for NGF. NGF itself was the first growth factor ever discovered and has been known for years to play a role in neuronal development and growth. Later, it was found to contribute to pain, making it a significant therapeutic target.

Despite its promise, previous attempts to target NGF—such as with monoclonal antibodies—failed due to side effects like joint damage. By identifying neuropilin-1 as a new NGF receptor, this study opens up new possibilities for targeting this system to treat chronic pain. I believe this discovery could rekindle interest in NGF-related research and therapies.

What are the next steps following this research?

Nerve growth factor has been implicated in many types of pain, including inflammatory joint pain, arthritis pain, cancer pain, surgical pain, and neuropathic pain. NGF is released by diseased, damaged, or injured tissues and signals neurons to cause pain. In my lab, we’re focusing on the structure of the NGF-neuropilin-TrkA complex. We're designing molecules to prevent this complex from assembling efficiently. We’ve identified and patented new structures that block NGF’s ability to cause pain, and that’s the direction we’re pursuing.

Could this research lead to more discussions about preventing chronic pain?

Absolutely, this research could pave the way for reversing chronic pain. Since NGF is implicated in many forms of chronic pain, blocking its ability to excite neurons could reverse pain. It might also be possible to prevent chronic pain from developing by treating patients very early on with these therapies, potentially stopping pain from becoming chronic. However, that’s a challenging goal.

One final point I’d like to add is that neuropilin-1 and GIPC1 not only play a role in NGF-mediated pain but likely also contribute to pain mediated by other receptor tyrosine kinases and G protein-coupled receptors. This means they could be broad therapeutic targets for various types of pain.

REFERENCE
1. Peach CJ, Tonello R, Damo E, et al. Neuropillin-1 inhibition suppresses nerve-growth factor signaling and nociception in pain models. Journal of Clin Investig. Published online November 26, 2024. doi:10.1172/JCI183873