PGE2/EP4 receptor and TRPV1 channel are involved in repeated restraint stress-induced prolongation of sensitization pain evoked by subsequent PGE2 challenge

Brain Res. 2019 Oct 15:1721:146335. doi: 10.1016/j.brainres.2019.146335. Epub 2019 Jul 11.

Abstract

Prevalence of prior stressful experience is linked to high incidence of chronic pain. Stress, particularly repeated stress, is known to induce maladaptive neuroplasticity along peripheral and central pain transmission pathways. These maladaptive neuroplastic events facilitate sensitization of nociceptive neurons and transition from acute to chronic pain. Pro-inflammatory and pain mediators are involved in inducing neuroplasticity. Pain mediators such as prostaglandin E2 (PGE2), EP4 receptor and transient receptor potential vanilloid-1 (TRPV1) contribute to the genesis of chronic pain. In this study, we examined the role of PGE2/EP4 signaling and TRPV1 signaling in repeated restraint stress-induced prolongation of sensitization pain, a model for transition from acute to chronic pain, in both in vivo and in vitro models. We found that pre-exposure to single restraint stress induced analgesia that masked sensitization pain evoked by subsequent PGE2 challenge. However, pre-exposure to 3d consecutive restraint stress not only prolonged sensitization pain, but also increased stress hormone corticosterone (CORT) in serum, COX2 levels in paw skin, and EP4 and TRPV1 levels in dorsal root ganglion (DRG) and paw skin. Pre-exposure to CORT for 3d, not 1d, also prolonged sensitization pain evoked by PGE2. Co-injection of glucocorticoid receptor (GR) antagonist RU486, COX2 inhibitor NS-398, EP4 receptor antagonist L161,982 or TRPV1 antagonist capsazepine prevented 3d restraint stress prolonged sensitization pain evoked by PGE2. In DRG cultures, CORT increased EP4 and TRPV1 protein levels through GR activation. These data suggest that PGE2/EP4 signaling and TRPV1 signaling in peripheral pain pathway contribute to repeated stress-predisposed transition from acute to chronic pain.

Keywords: Dorsal root ganglion; EP4 receptor; PGE2; Restraint stress; Sensitization pain; TRPV1 channel.

MeSH terms

  • Animals
  • Dinoprostone / metabolism
  • Dinoprostone / physiology
  • Ganglia, Spinal / metabolism
  • Hyperalgesia / metabolism
  • Male
  • Neuralgia / metabolism
  • Nociceptors / metabolism
  • Pain / metabolism*
  • Pain Measurement
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism*
  • Receptors, Prostaglandin E, EP4 Subtype / physiology
  • Sensory Receptor Cells / drug effects
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • TRPV Cation Channels / metabolism*
  • TRPV Cation Channels / physiology

Substances

  • Receptors, Prostaglandin E, EP4 Subtype
  • TRPV Cation Channels
  • TRPV1 receptor
  • Trpv1 protein, rat
  • Dinoprostone