Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models
Chloe J. Peach, … , Rajesh Khanna, Nigel W. Bunnett
Chloe J. Peach, … , Rajesh Khanna, Nigel W. Bunnett
Published November 26, 2024
Citation Information: J Clin Invest. 2025;135(4):e183873. https://doi.org/10.1172/JCI183873.
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Research Article Cell biology Neuroscience

Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models

Abstract

Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain, yet failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a coreceptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 was coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppressed NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibited NGF/TrkA signaling, whereas NRP1 overexpression enhanced signaling. NGF bound NRP1 with high affinity and interacted with and chaperoned TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggested that the C-terminal R/KXXR/K NGF motif interacts with the extracellular “b” NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G α interacting protein C-terminus 1 (GIPC1), which scaffolds NRP1 and TrkA to myosin VI, colocalized in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogated NGF-evoked excitation of nociceptors and pain-like behavior. Thus, NRP1 is a nociceptor-enriched coreceptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via the GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited nonopioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain.

Authors

Chloe J. Peach, Raquel Tonello, Elisa Damo, Kimberly Gomez, Aida Calderon-Rivera, Renato Bruni, Harsh Bansia, Laura Maile, Ana-Maria Manu, Hyunggu Hahn, Alex R.B. Thomsen, Brian L. Schmidt, Steve Davidson, Amedee des Georges, Rajesh Khanna, Nigel W. Bunnett

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Figure 5

NRP1 inhibition abrogates NGF- and CFA-induced pain in mice.

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NRP1 inhibition abrogates NGF- and CFA-induced pain in mice. (A–M) NGF-i...
(A–M) NGF-induced pain in male (B–K) and female (L and M) mice. Effects of NRP1 inhibitors EG00229 (B and F; 1, 10, 30 μM/10 μl i.pl.), CendR (C and G; 0.2, 2 and 10 μM/10 μl i.pl.), compound 5 (D and H; Cpd5; 30 μM/10 μl i.pl.) or an antibody against the b1 domain of NRP1, vesencumab (E and I; 7 μg/10 μl i.pl.) in male mice. After baseline (B) measurements, inhibitors were coinjected with mouse NGF (50 ng/10 μl, i.pl.). Mechanical allodynia (B–E) and thermal hyperalgesia (F–I) were measured. n = 5–8 male mice per group. (J and K) AUC of EG00229 (30 μM/10 μl), CendR (2 μM/10 μl), compound 5 (30 μM/10 μl), and vesencumab (7 μg/10 μl) time courses. (L and M) Effects of NRP1 inhibitor EG00229 (30 μM/10 μl i.pl.) on NGF-induced nociception in female mice. Mechanical allodynia (L) and thermal hyperalgesia (M) were measured. n = 5–8 female mice per group. (N–T) CFA-induced inflammatory pain. Effects of EG00229 (O and R, 30 μM/10 μl) or vesencumab (P and S, 7 μg/10 μl). Inhibitors were injected (i.pl.) 48 hours after CFA (i.pl.). (Q and T) AUC of time courses. Mechanical allodynia (O–Q) and thermal hyperalgesia (R–T) were measured. n = 8–9 mice per group. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. PBS, control (Ctrl) peptide, or IgG Ctrl. (B–I, L, M, O, P, R, and S) Two-way ANOVA, Sídák’s multiple comparisons. (J, K, Q, and T) One-way ANOVA, Dunnett multiple comparisons.