title: Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.
abstract: Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.
authors: Neuroscience Research Institute, Peking University, Beijing, China Clinical Molecular Laboratory, Peking University People's Hospital, Beijing, China Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Beijing, China.
authors: Xing
authors: X
authors: Xiao
authors: Xiao-Tao
authors: XT
authors: Zhao
authors: Ling-Chi
authors: LC
authors: Xu
authors: Lu-Peng
authors: LP
authors: Yue
authors: Feng-Yu
authors: FY
authors: Liu
authors: Jie
authors: J
authors: Cai
authors: Fei-Fei
authors: FF
authors: Liao
authors: Jin-Ge
authors: JG
authors: Kong
authors: Guo-Gang
authors: GG
authors: Xing
authors: Ming
authors: M
authors: Yi
authors: You
authors: Y
authors: Wan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005620:Freund's Adjuvant; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D002211:Capsaicin; D002118:Calcium