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.

Nociceptive signaling through transient receptor potential vanilloid 1 is regulated by Cyclin Dependent Kinase 5-mediated phosphorylation of T407 in vivo

“… 29 With GCaMP6f imaging in mice, we also saw that Cdk5 hyperactivity both promotes higher fluorescent signaling intensities and increased numbers of activated neurons in the TG following facial application of heat and capsaicin. 30 Overall, this in vivo data suggest that TRPV1-mediated nociception can be regulated by Cdk5 activity.…”

“…Cdk5 activity can affect Ca 2+induced desensitization in TRPV1 while also shaping the extent of nociceptor firing in response to heat and capsaicin. 10,30 The development of the TRPV1 T407A mice further establishes a direct link between Cdk5 phosphorylation and pain signaling through TRPV1. Our study shows that loss of the Cdk5 T407 phosphorylation site in TRPV1 in mice causes alterations in oral aversion to capsaicin, reduced facial expressions after the injection of capsaicin, and increased paw withdrawal latency to heat on a hot plate.…”

“…The peptide TFP5 can reduce Cdk5 hyperactivity back to normal physiological levels and is able to decrease neuronal hyperexcitability in the TG caused by injection of complete Freund’s adjuvant. 30 , 47 Cdk5 has a phospho-regulatory role in influencing pain sensitivity by modulating nociceptive signaling through TRPV1. Cdk5 activity can affect Ca 2+ -induced desensitization in TRPV1 while also shaping the extent of nociceptor firing in response to heat and capsaicin.…”