Osaka University researchers have made a crucial breakthrough in our knowledge of how chronic pain disorders evolve. The researchers explain how a protein previously linked to neuron proliferation and cell adhesion is also important in the development of pain sensitization.
Neuropathic pain is a chronic condition caused by prior nerve injury or certain diseases such as diabetes, cancer, and multiple sclerosis. Patients with this condition frequently exhibit hypersensitivity to typically non-painful stimuli such as touch or repetitive movement, with pain commonly presenting as acute scorching sensations, numbness, or pins and needles. Analgesics are often ineffective in relieving pain.
In humans, the dorsal horn of the spinal cord serves as a sorting station for pain sensations. Signals from the body’s peripheral parts are processed and then transferred to the brain via secondary neurons.
This is an important location in the development of neuropathic pain; studies have connected the disorder to aberrant neuronal excitability in the dorsal horn of the spinal cord. However, it is unknown what causes these neurons to become abnormally stimulated.
Fibronectin Leucine-rich Transmembrane Protein-3
FLRT3, or fibronectin leucine-rich transmembrane protein-3, is a protein commonly found in both embryonic and adult nervous systems. And while researchers don’t know exactly what role it plays in adult tissues, FLRT3 has been implicated in synapse formation and cell adhesion in the developing brain.
However, reports of FLRT3 expression in the dorsal horn following nerve injury prompted Osaka University researchers to investigate the possibility that FLRT3 could be involved in neuropathic pain.
“We examined FLRT3 expression in the dorsal horns of adult rats after peripheral nerve injury. Interestingly, even though Flrt3 gene expression was only observed in the dorsal root ganglion, high levels of FLRT3 protein were found in the dorsal horn,”
explained the lead author of the study, Moe Yamada.
Mechanical Allodynia
“When we then injected purified FLRT3 into the subarachnoid space so that it reaches the cerebrospinal fluid or overexpressed the protein in the dorsal root ganglion using a viral vector, the treated rats developed touch sensitivity, called mechanical allodynia,”
added Yamada.
Fortunately, when they blocked FLRT3 activity with antibodies or gene silencing, the mechanical allodynia symptoms caused by nerve damage almost completely disappeared. The results suggest that FLRT3 is made by neurons in the dorsal root ganglion that are damaged. This makes neurons more excitable throughout the dorsal horn, which makes the pain more noticeable.
“This is a novel role for FLRT3, and provides new avenues to explore in the search for effective treatments for neuropathic pain,”
senior author Toshihide Yamashita said.
Abstract
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 DRG, FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated Flrt3 transcription in the DRG but not in the spinal cord. Intrathecal administration of FLRT3 protein to naive 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.
Reference:
- Moe Yamada, Yuki Fujita, Yasufumi Hayano, Hideki Hayakawa, Kousuke Baba, Hideki Mochizuki, Toshihide Yamashita. Increased expression of fibronectin leucine-rich transmembrane protein 3 in the dorsal root ganglion induces neuropathic pain in rats. Journal of Neuroscience 15 November 2023, 43 (46) 7879-7892; DOI:10.1523/JNEUROSCI.0579-23.2023
Last Updated on November 18, 2023