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Papers of the Week

Papers: 27 Jul 2019 - 2 Aug 2019

Animal Studies

2019 Sep 18

J Neurosci



Increased expression of fibronectin leucine-rich transmembrane protein 3 in the dorsal root ganglion induces neuropathic pain in rats.


Yamada M, Fujita Y, Hayano Y, Hayakawa H, Baba K, Mochizuki H, Yamashita T
J Neurosci. 2019 Sep 18; 39(38):7615-7627.
PMID: 31346030.


Neuropathic pain is a chronic condition that occurs frequently after nerve injury and induces hypersensitivity or allodynia characterized by aberrant neuronal excitability in the spinal cord dorsal horn. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) is a modulator of neurite outgrowth, axon pathfinding, and cell adhesion, which is upregulated in the dorsal horn following peripheral nerve injury. However, the function of FLRT3 in adults remains unknown. Therefore, we aimed to investigate the involvement of spinal FLRT3 in neuropathic pain using rodent models. In the dorsal horns of male rats, FLRT3 protein levels increased at day 4 after peripheral nerve injury. In the dorsal root ganglion (DRG), FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated transcription in the DRG, but not in the spinal cord. Intrathecal administration of FLRT3 protein to naïve rats induced mechanical allodynia and GluN2B phosphorylation in the spinal cord. DRG-specific FLRT3 overexpression using adeno-associated virus also produced mechanical allodynia. Conversely, a function-blocking FLRT3 antibody attenuated mechanical allodynia after partial sciatic nerve ligation. Therefore, FLRT3 derived from injured DRG neurons increases dorsal horn excitability and induces mechanical allodynia.Neuropathic pain occurs frequently after nerve injury and is associated with abnormal neuronal excitability in the spinal cord. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) regulates neurite outgrowth and cell adhesion. Here, nerve injury increased FLRT3 protein levels in the spinal cord dorsal root, despite the fact that transcripts were only induced in the dorsal root ganglion (DRG). FLRT3 protein injection into the rat spinal cord induced mechanical hypersensitivity, as did virus-mediated FLRT3 overexpression in DRG. Conversely, FLRT3 inhibition with antibodies attenuated mechanically induced pain after nerve damage. These findings suggest that FLRT3 is produced by injured DRG neurons and increases neuronal excitability in the dorsal horn, leading to pain sensitization. Neuropathic pain induction is a novel function of FLRT3.