Neuropilin-1: A Target for Redefining Chronic Pain Therapies Through Non-Opioid Mechanisms

Pain is an intrinsic part of the human experience, serving as a vital signal for injury or illness. However, for millions worldwide, chronic pain becomes a debilitating condition, overshadowing daily life and defying effective treatment. Traditional therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, often fall short. NSAIDs frequently fail to provide sufficient relief for severe or persistent pain, while opioids, despite their potency, are fraught with risks of addiction, tolerance, and life-threatening side effects. This therapeutic gap underscores an urgent need for novel, effective, and safer alternatives to manage pain.

A promising target in this quest has been nerve growth factor (NGF), a protein integral to pain signaling pathways. NGF interacts with its high-affinity receptor, tropomyosin receptor kinase A (TrkA), on sensory neurons, triggering processes that amplify pain signals. Decades of research have established NGF as a critical mediator in various pain conditions, including inflammatory, neuropathic, and cancer-associated pain. Clinical trials exploring monoclonal antibodies to neutralize NGF have shown significant analgesic effects. However, these trials faced a critical roadblock: some participants developed worsening joint conditions, leading regulatory bodies like the FDA to withhold approval for these treatments. This setback highlighted the complexity of targeting NGF, as its systemic inhibition can disrupt not only pain pathways but also its essential roles in tissue repair and homeostasis.

Given these challenges, researchers led by Professor Nigel Bunnett at New York University sought to address a fundamental question: could pain signaling pathways involving NGF be modulated more selectively? Their focus turned to neuropilin-1 (NRP1), a lesser-known but increasingly recognized co-receptor for NGF and TrkA. NRP1, initially identified for its role in vascular and neural development, has been implicated in amplifying NGF-TrkA interactions, making it a potential linchpin in pain signaling. Unlike broad NGF inhibition, targeting NRP1 offered a theoretically safer and more localized approach, preserving NGF’s beneficial effects while disrupting its nociceptive, or pain-inducing, functions.  Initially, the team sought to determine whether NRP1 interacts directly with NGF and TrkA to form a functional signaling complex. Using molecular modeling and biophysical assays, they demonstrated that NGF binds to NRP1 with high affinity, forming a ternary NGF-TrkA-NRP1 complex with a precise stoichiometric arrangement. This discovery was confirmed by advanced cell imaging techniques, where fluorescently tagged NGF and NRP1 localized together on sensory neurons. By engineering mutations to disrupt this binding, they observed significantly diminished NGF-TrkA signaling, directly linking NRP1 to pain pathway activation.

To test the functional implications of NRP1 in sensory neurons, the researchers used mouse and human dorsal root ganglia (DRG) neurons—key players in pain perception. When neurons were exposed to NGF, their excitability increased, as evidenced by heightened responses to pain-inducing stimuli. However, when NRP1 inhibitors, such as EG00229, were applied, this excitability was markedly reduced. These inhibitors also blocked NGF-induced sensitization of TRPV1, a receptor known to amplify pain signals. The researchers concluded that NRP1 serves as a critical facilitator of NGF-driven neuronal activation. Moving to animal models, the team examined how inhibiting NRP1 impacts pain behaviors in mice. They injected NGF into the mice’s hind paws, which triggered pain responses such as increased sensitivity to heat and mechanical pressure. Remarkably, co-administration of NRP1 inhibitors significantly diminished these responses, confirming that NRP1 plays a direct role in NGF-induced nociception. Furthermore, when NGF was injected into inflamed tissues, which mimic conditions like arthritis, the same inhibitors alleviated pain symptoms without affecting baseline sensitivity. This suggested that targeting NRP1 selectively disrupts pathological pain signaling while preserving normal sensory functions. One of the most intriguing findings came from experiments involving GIPC1, an intracellular adaptor protein that links NRP1 to the cellular machinery responsible for TrkA trafficking. By silencing GIPC1 in neurons or inhibiting its activity pharmacologically, the researchers observed a disruption in TrkA’s transport to the cell membrane and signaling endosomes. This disruption led to weakened NGF-induced neuronal responses and reduced pain behaviors in mice, further highlighting NRP1’s role as a co-receptor dependent on GIPC1. Finally, the authors explored the broader implications of NRP1 in pain mechanisms. They found that overexpressing NRP1 in cultured neurons enhanced NGF-TrkA signaling, leading to heightened activation of downstream pathways like ERK phosphorylation, a molecular hallmark of pain signaling. Conversely, genetic or pharmacological inhibition of NRP1 dampened these pathways, reducing both rapid ion channel sensitization and longer-term gene expression changes that drive chronic pain.

In conclusion, the study by Professor Nigel Bunnett  and colleagues is a landmark in the ongoing quest to advance pain management. By identifying NRP1 as a pivotal co-receptor in the NGF-TrkA signaling pathway, the researchers have illuminated a novel therapeutic target that could address chronic pain without the drawbacks of opioids or NGF-neutralizing monoclonal antibodies. This research bridges a critical gap in understanding how pain signaling can be modulated more selectively, paving the way for therapies that minimize systemic effects while offering substantial relief to patients. One of the most significant implications of the authors’ work lies in its potential to overcome the limitations of NGF-targeted therapies. While NGF has long been established as a key player in pain mechanisms, global inhibition of NGF leads to adverse side effects, including joint deterioration in patients with osteoarthritis. This research suggests that targeting NRP1 specifically within sensory neurons could bypass these risks. By focusing on the localized modulation of NGF-TrkA interactions, NRP1 inhibitors hold the promise of alleviating pain without disrupting NGF’s protective roles in tissue repair and other physiological processes.

Furthermore, the study’s findings offer a new framework for addressing diverse pain conditions. Chronic pain encompasses a wide spectrum, including inflammatory, neuropathic, and cancer-related pain, each with distinct underlying mechanisms. The discovery that NRP1 inhibition dampens NGF-induced pain in both acute and inflammatory contexts suggests its broad applicability across these pain types. This versatility is especially critical in conditions where other treatments fail or are contraindicated due to patient-specific factors. From a clinical perspective, this research sets the stage for developing non-opioid pain therapies with fewer side effects. Opioids, the mainstay of chronic pain treatment, carry severe risks of addiction, tolerance, and respiratory depression. The ability to target NRP1 offers a pathway to pain relief that avoids these dangers entirely, addressing the urgent public health crisis of opioid dependency. Another critical implication is the potential to combine NRP1 inhibitors with existing treatments to achieve synergistic effects. By selectively inhibiting NGF’s pain-driving actions, NRP1-targeted therapies could enhance the efficacy of other analgesics, providing multi-modal pain relief tailored to individual needs. Such combinations could reduce the doses of other medications, further minimizing side effects. Beyond pain management, this study has broader biomedical implications. NRP1’s role as a co-receptor for other growth factors, including VEGF-A, positions it as a potential target in related conditions such as cancer and inflammatory diseases. The ability to manipulate NRP1’s interactions with specific ligands could lead to therapeutic advances not only in pain but also in angiogenesis-related disorders, where its involvement is well-documented.