Identification of a new functional domain of Nogo‐A that promotes inflammatory pain and inhibits neurite growth through binding to NgR1

Nogo‐A is a key inhibitory molecule to axon regeneration, and plays diverse roles in other pathological conditions, such as stroke, schizophrenia, and neurodegenerative diseases. Nogo‐66 and Nogo‐Δ20 fragments are two known functional domains of Nogo‐A, which act through the Nogo‐66 receptor (NgR1) and sphingosine‐1‐phosphate receptor 2 (S1PR2), respectively. Here, we reported a new functional domain of Nogo‐A, Nogo‐A aa 846‐861, was identified in the Nogo‐A‐specific segment that promotes complete Freund's adjuvant (CFA)‐induced inflammatory pain. Intrathecal injection of its antagonist peptide 846‐861PE or the specific antibody attenuated the CFA‐induced inflammatory heat hyperalgesia. The 846‐861 PE reduced the content of transient receptor potential vanilloid subfamily member 1 (TRPV1) in dorsal root ganglia (DRG) and decreased the response of DRG neurons to capsaicin. These effects were accompanied by a reduction in LIMK/cofilin phosphorylation and actin polymerization. GST pull‐down and fluorescence resonance energy transfer (FRET) assays both showed that Nogo‐A aa 846‐861 bound to NgR1. Moreover, we demonstrated that Nogo‐A aa 846‐861 inhibited neurite outgrowth from cortical neurons and DRG explants. We concluded that Nogo‐A aa 846‐861 is a novel ligand of NgR1, which activates the downstream signaling pathways that inhibit axon growth and promote inflammatory pain.