Neuroligin1 Contributes to Neuropathic Pain by Promoting Phosphorylation of Cofilin in Excitatory Neurons

Abstract

Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4–L6 spinal dorsal horn in Vglut2-cre+/– mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre+/– mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.

Stress Elicits Contrasting Effects on Rac1-Cofilin Signaling in the Hippocampus and Amygdala

“…Finally, it may be noted that the blots of p-Cofilin depicted in panels 3A and 3F have a low signal to noise ratio, which gives the impression of a higher background resulting in a smear-like appearance. However, comparisons with Cell Signaling Technology (CST) datasheets for the respective antibodies, as well as previous articles where similar blots for phosphoproteins have been presented (Ouyang et al, 2021 ) suggest that this is caused by a low signal-to-noise ratio.…”

Dopamine D2 Receptor Activation Blocks GluA2/ROS Positive Feedback Loop to Alienate Chronic-Migraine-Associated Pain Sensitization

“…Growing evidence shows that the α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) play a crucial role in chronic pain [ 6 , 7 ], and they were proven to mediate the initial rapid transmission of injurious messages in the primary sensory neurons and facilitate central sensitization in neuropathic pain [ 8 , 9 ]. AMPARs are composed of four subunits (GluA1-4), of which GluA1-containing AMPAR is Ca 2+ -permeable while GluA2-containing AMPAR is Ca 2+ -impermeable [ 10 , 11 ].…”