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

Abstract

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.

Tumor necrosis factor alpha mediates orofacial discomfort in an occlusal dental interference model in rats: The role of trigeminal ganglion inflammation

“…Similar to our data, Hawkins showed that secondary traumatic stress increases GFAP and leads to trigeminal sensitization, and dental injuries can lead to GFAP activation through ocular inflammation . As GFAP is directly associated with neural damage, inflammation in any structure related to the trigeminal ganglion seems to lead to neuroinflammation and altered behavior due to discomfort in the head and neck region and the blockage of TNF‐α pathway was important to attenuates GFAP overexpression, neuroinflammation, and oral discomfort in this ODI experimental model.…”

CXCL10 and CXCR3 in the Trigeminal Ganglion Contribute to Trigeminal Neuropathic Pain in Mice

“…26,27 ERK activation in TG neurons is also induced by migraine or lingual nerve crush. 26,37,38 Our results showed that intra-TG injection of CXCL10 induced CXCR3dependent activation of ERK, but not p38 or JNK, in WT mice, suggesting that ERK is a downstream kinase of CXCL10/CXCR3. Inhibition of ERK activation by PD98059 (MEK inhibitor) has been shown to attenuate pIONL-induced mechanical allodynia and lingual nerve crush-induced pain hypersensitivity.…”

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

“…It has been shown that ligation of the ION induces the activation of ERK and p38, but not JNK in the TG [ 24 , 25 ]. ERK is also activated in TG neurons induced by migraine or lingual nerve crush [ 24 , 44 , 45 ]. We showed that the pIONL-induced ERK activation was reduced in Tlr8 −/− mice.…”