title: VPS26A-SNX27 Interaction-Dependent mGluR5 Recycling in Dorsal Horn Neurons Mediates Neuropathic Pain in Rats.
abstract: Retromer, which crucially contributes to endosomal sorting machinery through the retrieval and recycling of signaling receptors away from degradation, has been identified as a critical element for glutamatergic-receptor-dependent neural plasticity at excitatory synapses. We observed it accompanied by behavioral allodynia; neuropathic injury time-dependently enhanced VPS26A and SNX27 expression; VPS26A-SNX27 coprecipitation; and VPS26A-positive, SNX27-positive, and VPS26A-SNX27 double-labeled immunoreactivity in the dorsal horn of Sprague Dawley rats that were all sufficiently ameliorated through the focal knock-down of spinal VPS26A expression. Although the knock-down of spinal SNX27 expression exhibited similar effects, spinal nerve ligation (SNL)-enhanced VPS26A expression remained unaffected. Moreover, SNL also increased membrane-bound and total mGluR5 abundance, VPS26A-bound SNX27 and mGluR5 and mGluR5-bound VPS26A and SNX27 coprecipitation, and mGluR5-positive and VPS26A/SNX27/mGluR5 triple-labeled immunoreactivity in the dorsal horn, and these effects were all attenuated through the focal knock-down of spinal VPS26A and SNX27 expression. Although administration with MPEP adequately ameliorated SNL-associated allodynia, mGluR5 expression, and membrane insertion, SNL-enhanced VPS26A and SNX27 expression were unaffected. Together, these results suggested a role of spinal VPS26A-SNX27-dependent mGluR5 recycling in the development of neuropathic pain. This is the first study that links retromer-associated sorting machinery with the spinal plasticity underlying pain hypersensitivity and proposes the possible pathophysiological relevance of endocytic recycling in pain pathophysiology through the modification of glutamatergic mGluR5 recycling.
  
  
  CONCLUSIONS
  VPS26A-SNX27-dependent mGluR5 recycling plays a role in the development of neuropathic pain. The regulation of the VPS26A-SNX27 interaction that modifies mGluR5 trafficking and expression in the dorsal horn provides a novel therapeutic strategy for pain relief.
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Tzer-Bin
authors.initials: TB
authors.lastname: Lin
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan, Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Cheng-Yuan
authors.identifier: http://orcid.org/0000-0002-5732-9814
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan, Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Chun
authors.initials: MC
authors.lastname: Hsieh
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsueh-Hsiao
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan, Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan, and.
authors.forename: Jen-Kun
authors.initials: JK
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Yat-Pang
authors.initials: YP
authors.lastname: Chau
authors.affiliation: Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan.
authors.forename: Gin-Den
authors.identifier: http://orcid.org/0000-0001-8613-5499
authors.initials: GD
authors.lastname: Chen
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan, hsien.yu@gmail.com.
authors.forename: Hsien-Yu
authors.identifier: http://orcid.org/0000-0002-9471-8130
authors.initials: HY
authors.lastname: Peng
mesh_terms: D000818:Animals; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C578937:Grm5 protein, rat; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; C477690:Snx27 protein, rat; C498296:VPS26A protein, human; D033921:Vesicular Transport Proteins
keywords: SNX27; VPS26; allodynia; mGluR5; neuropathic pain; retromer