Visualization of trigeminal ganglion sensory neuronal signaling regulated by Cdk5

Abstract

The mechanisms underlying facial and oral pain are still incompletely understood, posing major therapeutic challenges. Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase involved in pain signaling. However, the regulatory roles of Cdk5 in orofacial pain signaling and the possibility of therapeutic intervention at the level of mouse trigeminal ganglion primary neurons remain elusive. In this study, we used optimized intravital imaging to directly compare trigeminal neuronal activities after mechanical, thermal, and chemical stimulation. We then tested whether facial inflammatory pain in mice could be alleviated by the Cdk5 inhibitor peptide TFP5. We demonstrated regulation of total Ca2+ intensities by Cdk5 activity using transgenic and knockout mouse models. In mice with orofacial inflammation, application of TFP5 specifically decreased total Ca2+ intensities in response to noxious stimuli. It also alleviated inflammation-induced allodynia by inhibiting activation of trigeminal peripheral sensory neurons. Cdk5 inhibitors may provide promising non-opioid candidates for pain treatment.