Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats

Pain. 2015 Apr;156(4):597-608. doi: 10.1097/01.j.pain.0000460351.30707.c4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Capsaicin / pharmacology
  • Cell Culture Techniques
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Freund's Adjuvant / toxicity
  • Ganglia, Spinal / pathology*
  • Gene Expression Regulation / drug effects
  • Inflammation / chemically induced
  • Inflammation / complications
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pain / drug therapy*
  • Pain / etiology
  • Pain / pathology
  • Pain Threshold / drug effects
  • Patch-Clamp Techniques
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • TRPV Cation Channels / metabolism*

Substances

  • Enzyme Inhibitors
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Freund's Adjuvant
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Capsaicin
  • Calcium