Striatal-enriched phosphatase 61 inhibited the nociceptive plasticity in spinal cord dorsal horn of rats

Neuroscience. 2017 Jun 3;352:97-105. doi: 10.1016/j.neuroscience.2017.03.048. Epub 2017 Apr 5.

Abstract

Striatal-enriched phosphatase 61 (STEP61) is a member of intracellular protein tyrosine phosphatases, which is involved in the regulation of synaptic plasticity and a line of neuropsychiatric disorders. This protein tyrosine phosphatase is also abundant in pain-related spinal cord dorsal horn neurons. However, whether and how this tyrosine phosphatase modulates the nociceptive plasticity and behavioral hypersensitivity remain largely unknown. The present study recorded the long-term potentiation (LTP) of primary afferent C fiber-evoked field potentials in vivo in superficial dorsal horn of rats, and tested the possible role of STEP61 in spinal LTP. We found that LTP induction significantly increased STEP61 phosphorylation at Ser221 residue, a key molecular event that has been shown to impair the phosphatase activity. The STEP61 hypoactivity allowed for the activation of three substrates, GluN2B subunit-containing N-methyl-d-aspartate-subtype glutamate receptors, Src-family protein tyrosine kinase member Fyn and extracellular signal-regulated kinase 1/2, through which the thresholds for LTP induction were noticeably decreased. To reinstate STEP61 activity, we overexpressed wild-type STEP61 [STEP61(WT)] in spinal dorsal horn, finding that STEP61(WT) completely blunted LTP induction. Behavioral tests showed that LTP blockade by STEP61(WT) correlated with a long-lasting alleviation of thermal hypersensitivity and mechanical allodynia induced by chronic constriction injury of sciatic nerves. These data implicated that STEP61 exerted a negative control over spinal nociceptive plasticity, which might have therapeutic benefit in pathological pain.

Keywords: Fyn; N-methyl-d-aspartate receptor; extracellular signal-regulated kinase; long-term potentiation; neuropathic pain; striatal-enriched protein phosphatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afferent Pathways / physiopathology
  • Animals
  • Butadienes / pharmacology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hyperalgesia / pathology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Nerve Fibers / physiology
  • Neuralgia / pathology*
  • Nitriles / pharmacology
  • Pain Measurement
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / enzymology*
  • Spinal Cord Dorsal Horn / pathology*
  • Transduction, Genetic

Substances

  • Butadienes
  • Enzyme Inhibitors
  • Nitriles
  • U 0126
  • Green Fluorescent Proteins
  • Fyn protein, rat
  • Proto-Oncogene Proteins c-fyn
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatases