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. 2015 Aug 6;31(5):611–616. doi: 10.1007/s12264-015-1556-2

Pharmacologically inhibiting GluR2 internalization alleviates neuropathic pain

Tao-Yan Liu 1,2, Yong Cheng 3,✉, Xiao-Yan Qin 1,2,✉, Long-Chuan Yu 3
PMCID: PMC5563682  PMID: 26248656

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.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s12264-015-1556-2 and is accessible for authorized users.

Keywords: periaqueductal grey, AMPA receptor, GluA2-3y, internalization, morphine, hindpaw withdrawal latency

Electronic supplementary material

12264_2015_1556_MOESM1_ESM.pdf (13.6KB, pdf)

Supplementary material, approximately 11 KB.

Footnotes

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s12264-015-1556-2 and is accessible for authorized users.

Contributor Information

Yong Cheng, Email: chengy4@mail.nih.gov.

Xiao-Yan Qin, Email: zhongsijia01@163.com.

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Supplementary Materials

12264_2015_1556_MOESM1_ESM.pdf (13.6KB, pdf)

Supplementary material, approximately 11 KB.

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