Visualization of trigeminal ganglion sensory neuronal signaling regulated by Cdk5

The mechanisms underlying facial 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 facial pain signaling and the possibility of therapeutic intervention at the level of mouse trigeminal ganglion primary neurons remain elusive. In this study, we use optimized intravital imaging to directly compare trigeminal neuronal activities after mechanical, thermal, and chemical stimulation. We then test whether facial inflammatory pain in mice could be alleviated by the Cdk5 inhibitor peptide TFP5. We demonstrate regulation of total Ca2+ intensity by Cdk5 activity using transgenic and knockout mouse models. In mice with vibrissal pad inflammation, application of TFP5 specifically decreases total Ca2+ intensity in response to noxious stimuli. It also alleviates inflammation-induced allodynia by inhibiting activation of trigeminal peripheral sensory neurons. Cdk5 inhibitors may provide promising non-opioid candidates for pain treatment. [Display omitted] •Characterization of calcium signaling in trigeminal ganglion using in vivo live imaging•Cdk5 activity regulates trigeminal peripheral neuronal pain signaling•Elevated Cdk5 activity increases the proportion of polymodal nociceptors•A Cdk5 inhibitor alleviates inflammation-induced trigeminal hyperalgesia signaling By using intravital live imaging to record mouse trigeminal ganglion neuronal activities in response to facial pain, Hu et al. demonstrate that Cdk5 regulates primary sensory neuronal pain signaling. In addition, a Cdk5 peptide inhibitor can suppress inflammation-induced pain signaling at the peripheral nervous system level.