A collaborative research team led by Kim Sun-kwang, a professor of Dept. of Physiology, College of Korean Medicine at Kyung Hee University (KHU), and Kim Sang-jeong, a professor of Dept. of Biomedical Sciences at Seoul National University, has identified a new mechanism for processing pain through cerebellar neuronal-glial circuits. The research, supported by the National Research Foundation of Korea and others, was published in the online edition of Nature Neuroscience on January 2, 2025, under the title, Cerebellar Bergmann glia integrate noxious information and modulate nocifensive behaviours.

Photo: The Scientist(the-scientist.com)

Background of Research

Prof. Kim has been specializing in the field of pain research since graduate school, where he conducted research on the analgesic effects of electroacupuncture on chronic pain and its central nervous system mechanisms. Then He then spent about four years studying abroad at the National Institute for Physiological Science, Japan, with the desire to do pain research that no one else in the world had ever done before. While studying at the institute, he was the first in the world to apply in vivo two-photon microscopy imaging, which laid the foundation for his recent research on the brain mechanisms of pain. “As the saying goes, ‘New methods lead to new discoveries,’ we have achieved several firsts in the field of brain mechanisms of pain. It has indeed been an exciting journey," he said.

The cerebellum is well known for its role in sensory-motor integration and motor control, but its involvement in the field of pain has remained largely unexplored. Despite this, human brain imaging studies have repeatedly reported activation of cerebellar regions in groups with pain. Prof. Kim explained that this observation inspired him to initiate the study to identify the mechanisms of cerebellar pain information processing at the molecular, cellular, and circuit levels for the first time.

While he was at the Japanese institute, a Ph.D. student from the laboratory of Prof. Kim Sang-jeong came to the institute for a year's training. At that time, Prof. Kim's lab was struggling to apply in vivo two-photon microscopy imaging to their research, which led to an exchange of experimental methods through the student. When he returned to Korea as an assistant professor at KHU, Prof. Kim proposed a joint research proposal, and they have been conducting research together for more than 10 years.

Key Points of Research: Cerebellum and Bergmann Glia

The research team utilized advanced experimental techniques, including opto/chemogenetics and in vivo two-photon microscopy imaging, to conduct an in-depth analysis of the cerebellar mechanisms underlying pain processing. This research investigated how Bergmann glia (BG) in the cerebellum integrate noxious stimuli and modulate pain-related behaviors. BG, a specialized type of cerebellar glial cell, plays a crucial role in ensuring proper synaptic plasticity in the cerebellum. They also regulate synaptic function by clearing neurotransmitters from the synaptic cleft and releasing gliotransmitters such as Adenosine Triphosphate.

At the initial stages of the research, the researchers observed the responses of cerebellar cortical cells in mice subjected to pain stimuli—calcium activity in BG significantly increased. Notably, they found that this activation was mediated by noradrenaline released from neurons in the Locus Coeruleus (LC), which binds to α1-adrenergic receptors on BG. This was an unexpected finding, as previous pain research had established that LC neurons primarily release noradrenaline in the spinal cord, leading to neuronal inhibition and analgesic effects. In contrast, the cerebellum exhibited the opposite phenomenon, with glial cells like BG playing a key mediating role. According to Prof. Kim, the novelty and significance of these findings have laid the foundation for a long-term research journey into the cerebellar mechanisms of pain processing.

Based on their findings, the research team identified a novel pain suppression mechanism. When BG was inactivated using chemogenetics, pain responses were significantly reduced. Furthermore, selective blockade of α1-adrenergic receptors or their inhibition through genetic manipulation also demonstrated analgesic effects. The research team later applied these findings to a chronic neuropathic pain model, where modulation of BG led to pain relief. This suggests that the cerebellar neuron-glia circuitry could serve as a new therapeutic target for chronic pain treatment.

Prof. Kim cited the lengthy process of publishing the research as one of the major challenges. After submission to an academic journal, a paper undergoes peer review for about two to three months. The research team’s paper received a revision request, and addressing all the reviewer’s comments required a significant amount of time. The main cause was the complexity of the research—relying heavily on genetically modified mice, advanced techniques such as optogenetics, chemogenetics, and in vivo two-photon imaging in awake mice. Prof. Kim remarked, “It took approximately two years from submission to publication, with the revision process lasting about a year and a half. However, this led to a significant improvement in the quality of our paper, and I am very satisfied with the outcome.”

Significance and Prospect of Research: Neuroscience-inspired Korean Medicine

The research team has made a groundbreaking discovery by identifying cerebellum’s crucial role in pain modulation, challenging the conventional studies’ focus on spinal cord and other brain regions. Prof. Kim also emphasized that the study offers new strategies and targets for chronic pain treatment at a critical time when understanding pain mechanisms is urgently needed for developing novel pain pathways and drugs. He added, “Despite numerous attempts to develop new analgesics, most have failed in clinical trials. Even the non-opioid analgesics recently approved by the U.S. Food and Drug Administration (FDA) mainly target peripheral nerves and are only effective for acute pain. The continued reliance on opioid-based painkillers remains a significant concern.” Furthermore, he noted that publishing in a top-tier journal like Nature Neuroscience is highly challenging, making this achievement a significant milestone in showcasing Dept. of Korean Medicine at KHU’s research capabilities. He expects that this will lead to increased opportunities for securing large-scale research grants for KHU.

Prof. Kim also highlighted the broader implications of glial cells in various diseases, stating, “Glial cells are increasingly recognized for their role in conditions such as Alzheimer’s disease, Parkinson’s disease, and obesity, and the cerebellum also recognized for its crucial role in memory, learning, and emotional processing.” Given this, he believes the findings of this research have high potential for application in other diseases from a glial cell and cerebellar perspective. As a follow-up study, his laboratory is currently exploring neuromodulation technologies rather than drug-based approaches. Specifically, they are investigating non-invasive neuromodulation techniques that can modulate cerebellar glial cells to alleviate pain. This approach aligns with the emerging field of electroceuticals, a technology like electroacupuncture in Korean medicine. Prof. Kim also expressed an interest in collaborating with pharmaceutical companies willing to develop glial cell-targeted analgesics. He remarked, “With the recent FDA approval of a non-opioid painkiller, global interest in this market is growing. Through technology transfer, I hope to contribute to the development of innovative pain therapeutics that align with these global trends.”

When asked about the differences between Korean medicine and Western medicine, Prof. Kim explained, “Korean medicine tends to view the entire forest, while Western medicine focuses on a single tree or branch where a problem has occurred. However, this distinction is gradually disappearing because in the end, the goal is to keep people healthy.”. For a long time, research on neurological disorders has primarily focused on neurons, the key players in the nervous system. Similarly, in the field of pain research, attention has been concentrated on the peripheral nerves and spinal cord, which are directly linked to the affected area. Prof. Kim stated, “In this study, we examined not only neurons but also glial cells, focusing on the cerebellum, which has extensive synaptic connections with the spinal cord, cerebrum, and brain stem. Glial cells surround neurons and play a crucial role in maintaining homeostasis.” He emphasized that this research was not just about looking at a single tree but about understanding the entire forest, aligning with the holistic perspective of Korean medicine. He said he believes that neuroscience-inspired Korean medicine is possible and is conducting research, and that there are many areas where Korean medicine and Western medicine can contribute to each other's development.

This research holds significant value as it opens the possibility of developing innovative pain treatments through cerebellar glial cells, especially when the importance of glial cells in various diseases is being increasingly recognized. Additionally, it is worth noting that this research was made possible through the collaborative efforts of Korean and Western medicine, demonstrating the potential for groundbreaking discoveries through interdisciplinary cooperation. These findings are expected to inspire follow-up studies across various fields, offering fascinating opportunities for further exploration.