title: Pharmacologically inhibiting GluR2 internalization alleviates neuropathic pain.
abstract: Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments, so it is critical to find new drugs for this condition. Recently, the cellsurface trafficking of pain-related receptors has been suggested as an important mechanism underlying persistent neuropathic pain. Here, we used the short peptide GluA2-3y, which specifically inhibits the GluA2-dependent endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and tested its anti-nociceptive effect in the periaqueductal grey (PAG) of intact rats and rats with neuropathic pain. Intra-PAG injection of 0.15, 1.5, 7.5, and 15 pmol of GluA2-3y induced dose-dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats, suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation. Furthermore, GluA2-3y had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation. Interestingly, the intra-PAG injection of 15 pmol GluA2-3y had an analgesic effect similar to 10 μg (35 nmol) morphine in rats with neuropathic pain. Taken together, our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation, and inhibiting GluA2 endocytosis with GluA2-3y has potent analgesic effects in rats with neuropathic pain. These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain.
authors.affiliation: Beijing Engineering Research Center of Food, Environment, and Health, Minzu University of China, Beijing, 100081, China.|College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China.
authors.forename: Tao-Yan
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Laboratory of Neurobiology and State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China. chengy4@mail.nih.gov.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Beijing Engineering Research Center of Food, Environment, and Health, Minzu University of China, Beijing, 100081, China. zhongsijia01@163.com.|College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China. zhongsijia01@163.com.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qin
authors.affiliation: Laboratory of Neurobiology and State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Long-Chuan
authors.initials: LC
authors.lastname: Yu
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides / Q000494:pharmacology; D008297:Male; D009437:Neuralgia / Q000503:physiopathology*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D057846:Cell-Penetrating Peptides; D018091:Receptors, AMPA; C000595429:Tat-GluA2(3Y) peptide; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPA receptor; GluA2-3y; hindpaw withdrawal latency; internalization; morphine; periaqueductal grey