Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

Brain Res. 2018 May 15;1687:162-172. doi: 10.1016/j.brainres.2018.03.003. Epub 2018 Mar 6.


The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.

Keywords: MAP kinase; Migraine; Secondary traumatic stress; Sensitization; Trigeminal ganglion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Central Nervous System Sensitization / physiology*
  • Disease Models, Animal
  • Female
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System / physiology
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Stress Disorders, Traumatic / pathology*
  • Stress Disorders, Traumatic / physiopathology
  • Swimming
  • Trigeminal Ganglion / pathology*
  • Trigeminal Nucleus, Spinal / pathology*


  • Nerve Tissue Proteins
  • MAP Kinase Kinase 4