Abstract
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.
Highlights
The trigeminal ganglion (TG) of the peripheral nervous system contains nociceptor cell bodies that innervate and contribute to pain sensing in the face and the oral cavity (Kim et al, 2014; Rothermel et al, 2011), transmitting pain sensation through the TG to the central nervous system (CNS) (Bista and Imlach, 2019)
We discovered that enhanced Cyclin-dependent kinase 5 (Cdk5) activity in TG increased calcium influx in individual neurons, and expanded the numbers of nociceptive cells responding to vibrissal pad noxious stimuli
To monitor dynamic neuronal activities of the TG in real time as it responds to facial stimulation and pain, we adapted an intravital in vivo liveimaging technique (Ghitani et al, 2017) to expose the TG and optically record activity from large ensembles of genetically encoded primary sensory neurons (Figures 1A and 1B)
Summary
Facial and oral pain afflicts 5%–12% of the world’s population and can severely decrease quality of life (Crandall, 2018; Herrero Babiloni et al, 2018) and contributes to problems such as the opioid crisis (Sugawara et al, 2019). The trigeminal ganglion (TG) of the peripheral nervous system contains nociceptor cell bodies that innervate and contribute to pain sensing in the face and the oral cavity (Kim et al, 2014; Rothermel et al, 2011), transmitting pain sensation through the TG to the central nervous system (CNS) (Bista and Imlach, 2019). Both noxious and non-noxious stimuli can activate specific nociceptors in TG neurons. TRPV1 activity can be regulated by phosphorylation, which increases sensitivity to pain stimuli (Hall et al, 2018; Jendryke et al, 2016)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call