NRP1 regulates basal nociception: characterization of a peptidergic-specific NRP1 knockout mouse

Neuropilin-1 (NRP1) is a single pass transmembrane glycoprotein that can form a receptor complex with several tyrosine kinase receptors, including the vascular endothelial growth factor (VEGF) receptor. Previous studies have reported that binding of VEGFA to this receptor complex elicits mechanical allodynia and thermal hyperalgesia through potentiation of voltage-gated sodium and calcium channel activity. We find that Nrp1 mRNA and protein is widely distributed in naÏve mouse and rat DRG neurons, including peptidergic afferents. A CGRPcreER: NRP1 ^fl/fl transgenic mice was generated to investigate the role of peptidergic NRP1 in basal nociception. Following in vivo loss of NRP1, mice are hyposensitive to both noxious heat and mechanical stimuli. Under normal conditions, VEGFA elicits mechanical hypersensitivity, an effect that was absent in our NRP1 knockout mouse. Furthermore, VEGFA induced neuronal hyperexcitability was lost in CGRP expressing neurons isolated from this NRP1 knockout mouse. This study validates the NRP1 knockout mouse and confirms previous findings that VEGFA, often released during pathological pain conditions, requires peptidergic NRP1. Interestingly, we find that in the absence of ongoing injury or inflammation, peptidergic NRP1 regulates basal nociception and pain-like behaviors.

NRP1 is expressed in sensory neurons including the peptidergic subpopulation. Genetic deletion of NRP1 in healthy adults alters nociception without altering innervation; NRP1 knockout mice are hyposensitive to noxious heat and mechanical stimuli, but lose sensitivity to VEGFA, confirming it is a therapeutic target for growth factor mediated pain conditions.