An interesting article titled “Visualization of trigeminal ganglion sensory neuronal signaling regulated by Cdk5,” written by M. Hu and et al. appears in the 2022 editon of Cell Reports (Mar 8, vol. 38, no. 10, pp. 110458). The article seeks to explore some of the mechanisms underlying facial pain and used intravital imaging to compare trigeminal neuronal activities after mechanical, thermal, and chemical stimulation. The work was carried out by researchers for the NIH’s National Institute of Dental and Craniofacial Research.
Orofacial pain that occurs in the oral and facial region affects 5% to 12% of the U.S. population. This pain can affect daily activities and causes many to seek medications like opioids for releif, but opioids can be addicting. Thus researchers are interested in learning more about how facial nerves process pain signals to help lead to more efficeitn pain interventions.
In the article the researchers used an intravital imaging technique to visualize pain signals in facial nerves and were able to identify a protein that enhances neurons’ responses to pain sensations. The protein is called called cyclin-dependent kinase 5 (Cdk5). In the lab the researchers were able to see that blocking Cdk5 stopped the activity of neurons that signal pain. From this work the researchers used fluorescence to track calcium surges and were able to watch mouse neurons flicker like twinkling lights under the microscope. This allowed them to see the response to different types of stimuli and visualize orofacial pain on a neuronal scale.
The researchers applied different types of stimuli to mouse cheeks and measured neuronal responses. Mice that were engineered to produce high levels of Cdk5 had more intense calcium signaling and activated a higher number of neurons when the stimuli was applied when compared to normal mice. The researchers were able to determine a shift in the neurons’ response patterns and that a larger number of neurons responded to two or more types of stimuli. This suggest that increased Cdk5 activity appears to heighten pain-sensing neurons’ sensitivity to stimuli. The researchers note that both painful and nonpainful stimuli caused the heightened activity. They note that this mixing up of neurons corresponds to a pain problem known as allodynia.
The researchers also examined mice with a condition similar to allodynia. They blocked Cdk5 activity in these mice and this was found to reduce calcium-based pain signals and decreased the number of neurons that responded to gentle brushing as stimuli and a chemical irritant. This suggest that targeting Cdk5 in nerves outside the brain and spinal cord may be a better treatment than current pain medications and treatments.
The authors state
“Our study directly demonstrates the roles of Cdk5 activity in facial pain signaling in primary sensory neurons, suggesting an alternative approach to pain therapeutics. … This finding might ultimately have substantial translational impact, since most current pain medications are not selective for primary neurons and target multiple tissues…Targeting Cdk5 activity at [trigeminal ganglion] TG primary sensory neurons could offer better and safer treatments for facial pain.”
Thus these new treatments could help without the harmful side effects with medications like opioids. The researchers hope that their findings may help lead to development of a drug that can target the peripheral sensing of pain without also affecting the central nervous system.