Agrin downregulation induced by nerve injury contributes to neuropathic pain.
The elusiveness of neuropathic pain mechanisms is a major impediment in developing effective clinical treatments. Here we show that peripheral nerve injury decreased agrin expression in the ipsilateral spinal dorsal horn of rats displaying tactile allodynia. SCP1, an acetaminophen analog, suppressed allodynia and promoted agrin upregulation. Preemptive treatment with SCP1 also upregulated agrin, thereby preventing neuropathic pain development. Expression of 50 kDa agrin delivered by adeno-associated virus into the dorsal horn also suppressed allodynia and hyperalgesia. Allodynia suppression was a consequence of serine residue 896/897 phosphorylation of NMDA receptor NR1 subunits in the GABA interneurons of the dorsal horn. Agrin silencing by small interference RNA, administered with either AAV-Ag50 vector or SCP1, blocked allodynia suppression, agrin upregulation, and NR1 phosphorylation. In conclusion, 50 kDa agrin modulates neuropathic pain through NR1 phosphorylation in GABA neurons. This mechanism may open new approaches for treating not only neuropathic pain, but also epilepsy, tremors, and spasticity.
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, Louisiana 70112, USA. jcui@lsuhsc.edu
Jian-Guo
JG
Cui
Nicolas G
NG
Bazan
D018171:Agrin / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000293:injuries* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018171:Agrin; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid