In Brief:
- Using an imaging technique to visualize pain signals in facial nerves, NIDCR researchers identified a protein that enhances neurons’ responses to painful stimuli.
- Blocking the protein in mice blunted pain signaling; the results could inform the development of safer, non-opioid pain therapies.
Certain stimuli—such as a paper cut, an oven burn, or a flaming-hot chili pepper—activate pain receptors on nerve endings in the skin, prompting an influx of calcium that acts as a pain signal that neurons then pass on to the brain. Using fluorescence to track calcium surges, the NIDCR researchers were able to watch mouse neurons flicker like twinkling lights under the microscope in response to several types of stimuli, allowing them to visualize orofacial pain down to individual neurons.
“Essentially, the intensity of the imaging signals correlates with pain signaling at the molecular level,” says Kulkarni, whose lab has been studying Cdk5 for over 20 years. “This research really takes our science to the next step—we’re imaging and quantifying pain signals in real-time.”
Hu and Andrew Doyle, PhD, a staff scientist in Yamada’s lab, worked together to develop the imaging technique and used it to find out whether Cdk5, a protein known to play a role in pain at other body sites, is involved in orofacial pain signaling. The researchers applied different types of stimuli—mechanical (brushing and poking), thermal (heat), and chemical (chili extract)—to mouse cheeks and measured neuronal responses. In mice engineered to produce high levels of Cdk5, each of these stimuli—even gentle brushing—evoked more intense calcium signaling and activated a higher number of neurons, compared to normal mice. A closer look revealed a shift in the neurons’ response patterns. A larger number of neurons responded to two or more types of stimuli instead of just one. Taken together, these findings indicate that increased Cdk5 activity appears to heighten pain-sensing neurons’ sensitivity to painful and nonpainful stimuli.
“These mixed-up neurons can be a problem,” says Yamada, whose lab specializes in advanced imaging techniques. “For example, we saw neurons that interpret light touch as pain, which corresponds with a major problem we see in a type of clinical pain called allodynia.”
For patients with allodynia, even the gentle brush of a soft sweater can be painful. So the researchers next examined mice with a similar condition. They found that blocking Cdk5 activity in these animals reduced calcium-based pain signals and decreased the number of neurons that responded to both gentle brushing and chili extract, a chemical irritant. These findings suggest that targeting Cdk5 in nerves outside the brain and spinal cord could be a safer treatment avenue than existing pain therapies.
Kulkarni and Yamada suggest that potential new treatments based on their findings could relieve severe pain without affecting brain functions involved in the development of opioid use disorder, which can be a serious side effect of taking opioids. “We hope that our study may eventually become relevant to human conditions by raising the possibility of a drug that can target the peripheral sensing of pain without affecting the central nervous system,” adds Yamada.
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