| First Author | Rozas P | Year | 2016 |
| Journal | Pain | Volume | 157 |
| Issue | 6 | Pages | 1346-1362 |
| PubMed ID | 26894912 | Mgi Jnum | J:315407 |
| Mgi Id | MGI:6830362 | Doi | 10.1097/j.pain.0000000000000527 |
| Citation | Rozas P, et al. (2016) Targeted overexpression of tumor necrosis factor-alpha increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons. Pain 157(6):1346-1362 |
| abstractText | We reported earlier that TNF-alpha, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF) that can conditionally overexpresses TNF-alpha upon genomic recombination by Cre recombinase. TNF mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-alpha:Nav1.8-Cre (TNF-alpha cTg) mice. Although TNF-alpha cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-alpha levels after activation of NFkappaB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-alpha cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-alpha overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-alpha cTg mice displayed more aversive behavior to noxious thermal stimulation (45 degrees C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-alpha overexpression in the sensory neurons of TNF-alpha cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-alpha involved in orofacial pain. |
