Lack of oxygen can sensitize nerve cells, leading to long-term pain
More than 100 million people worldwide are affected by obstructive sleep apnea. This health condition causes a person to stop breathing numerous times while they are sleeping. Reduced sleep time and sleep quality can lead to numerous health problems including obesity, high blood pressure, diabetes, high cholesterol, asthma and depression. While not as well-studied as other comorbidities, chronic pain is diagnosed at a much higher rate in people with obstructive sleep apnea than those with normal sleep patterns.
A study by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) scientists, published July 30 in Science Signaling, is the first of its kind to explain the mechanism behind persistent pain related to obstructive sleep apnea.
Primary investigator of this study is Nathaniel Jeske, PhD, director of research for the Department of Oral and Maxillofacial Surgery in the School of Dentistry, associate professor with cross-appointments in pharmacology, physiology and neuroscience. Jeske’s lab focuses primarily on the biochemistry and molecular physiology of pain signaling mechanisms and understanding how acute injury transitions into persistent or chronic pain.
The peripheral nervous system controls messages from nerves that run throughout arms, legs and skin and sends these messages to the central nervous system. Nociceptors in this system are nerve cells specialized in detecting stimuli that produce pain.
“We are looking at maladaptive neuroplasticity in these primary nociceptors that are representing persistent pain, which serves as a bridge between the acute and the chronic,” Jeske said.
Jeske and his team discovered that a sleep apnea model studying hyperalgesic priming, or increased sensitivity to, or longer duration of, pain, had not been created. Clinical reports find that people with obstructive sleep apnea are more likely than normal sleepers to have chronic pain such as rheumatoid arthritis and fibromyalgia. They also require higher doses of pain medication following surgery and have a longer duration of post-operative pain.
In the lab
To mimic the effects of obstructive sleep apnea in a mouse model, the researchers created a chronic intermittent hypoxia environment. During the mouse’s regular sleep cycle, oxygen was cycled between 21% and 8% every six minutes for a total of eight hours each day, for up to 14 days. Behavioral analysis determined that the mice developed persistent pain by the 14-day mark. This analysis was further confirmed by three biochemical markers of hyperalgesic priming. Sleep interruption did not lead to persistent pain, which places the focus on the lack of oxygen, rather than the interruption of sleep, as the catalyst for obstructive sleep apnea-related persistent pain.
How does it work?
In studying the mouse model, Jeske’s team observed an increase in cytokines, which are molecules released by the immune system that tell other cells to produce an inflammatory state. In this case, cytokines are released by neighboring specialized immune cells called macrophages. Macrophages communicate within the peripheral and central nervous systems to modify how the body responds to a stimulus. In a state of chronic reduced oxygen, these released cytokines cause sensitivity in nociceptors that produce prolonged sensitivity to pain.
Analysis in this study found an increase of cytokines in both the dorsal root ganglia and sciatic nerve tissue. The cytokines then prime nociceptors to go into the hyperalgesic state, causing a longer duration of pain through peripheral nervous system plasticity.
To further confirm the role of peripheral macrophages in persistent pain, the researchers studied a mouse model with reduced peripheral macrophages. When exposed to chronic intermittent hypoxia, this model produced fewer inflammatory cytokines in the peripheral nervous system and did not display hyperalgesic priming behavior. From this data, researchers conclude that chronic intermittent hypoxia exposure increases macrophage production of cytokines to prime nociceptors into a hyperalgesic state.
Far-ranging implications
Given the extensive prevalence of obstructive sleep apnea, this study has far-ranging implications for both its treatment and treatment of associated persistent pain. Jeske said most people who have obstructive sleep apnea remain untreated. Many people who are diagnosed and prescribed a continuous positive airway pressure (CPAP) machine do not adhere to its consistent use. He urges people who are prescribed a CPAP device to use it consistently or find alternative treatments. He also encourages anyone who thinks they may have obstructive sleep apnea to get tested. Symptoms can include drowsiness during the day, inability to concentrate, heavy snoring and waking multiple times during the night.
“The puzzle of pain remains unsolved and has led to many untoward events including accelerating the epidemic of opioid use disorder,” said Ken Hargreaves, DDS, PhD, director of the Center for Pain Therapeutics and Addiction Research and professor in the Department of Endodontics, School of Dentistry.
“The findings of Dr. Jeske and his research team offer a novel and potentially insightful approach to resolving this puzzle for patients with obstructive sleep apnea. The discovery that CPAP may contribute to pain reduction is not only unique, but critically important in that it is available today without years of delay in the federal approval process. This is another example of our university’s commitment to ‘make lives better.’”
Findings in this study suggest treatment that corrects the chronic lack of oxygen or targets the peripheral macrophages could correct persistent pain for some obstructive sleep apnea patients. By identifying the mechanisms behind pain related to the condition, future research can explore these and other targeted treatments.
“This study represents a significant advancement in our understanding of the relationship between sleep apnea and chronic pain,” said Peter M. Loomer, DDS, PhD, MBA, FACD, dean of the School of Dentistry. “Insight into the role of oxygen deprivation in pain sensitization will pave the way for innovative treatment approaches that could enhance patient outcomes. Creating a novel model of hyperalgesic priming is a fundamental step in understanding the underlying mechanisms behind chronic pain in relation to sleep apnea.”
The collaborative efforts of researchers in this study were strengthened, Jeske said, by the recently established School of Dentistry’s Center for Pain Therapeutics and Addiction Research. Within this center, researchers from all UT Health San Antonio departments are encouraged to work together to find solutions for pain. For this study, pain researchers from four different departments collaborated including the Department of Oral and Maxillofacial Surgery, Department of Physiology, Department of Medicine and Department of Pharmacology.
“As pain researchers, we’ve always had loose collaborations, but this center strengthens that connection and generates more interest and participation in larger, clinically relevant projects,” Jeske said.
Samuel B. Chivers, Mary Ann Andrade, Robert J. Hammach, John Shannonhouse, Ruben Gomez, Yan Zhang, Brian Nguyen, Pankil Shah, Yu Shin Kim, Glenn M. Toney, Nathaniel A. Jeske. Peripheral macrophages contribute to nociceptor priming in mice with chronic intermittent hypoxia. Science Signaling, published July 30, 2024. DOI:10.1126/scisignal.adn8936