Over decades of research, adenosine, a compound found throughout the body with a role in many biological processes, has been shown to soothe pain. But scattered reports have also shown that adenosine can produce pain. Now, new research carried out in mice helps make sense of this apparent contradiction.
Yang Xia and colleagues at the University of Texas Medical School at Houston, US, show that when adenosine is elevated chronically, it causes hypersensitivity to touch and heat by binding to a protein, known as the A2B receptor, which lies on the surface of myeloid cells, a type of immune cell. Binding of adenosine to the receptor prompts the myeloid cells to signal to and activate pain-sensing neurons in the dorsal root ganglion; these are nerve cells that transmit pain signals coming from the body into the spinal cord.
Together, the results show how communication between the immune system and nervous system contributes to pain.
“There’s a nice scientific detective story here. These findings provide a mechanistic understanding for a neuro-immune interaction in chronic pain,’” says Jana Sawynok from Dalhousie University in Halifax, Nova Scotia, Canada, referring to the communication between the myeloid cells and the dorsal root ganglion neurons. Sawynok is an expert on the pain-related effects of adenosine, but was not involved in the study.
The research was published online July 16 in the journal Cell Reports.
Chronic adenosine, chronic pain
Before the current study, most investigations of the role of adenosine in pain had examined only what happens when adenosine levels are briefly elevated. Xia and her colleagues knew, however, that when its levels remain high, adenosine can cause inflammation, sickling of red blood cells, and tissue damage. As a result, they wondered whether a sustained rise in adenosine could also contribute to chronic pain.
To answer that question, they studied mice genetically engineered to lack a gene that makes a protein called adenosine deaminase (ADA). ADA is essential for the breakdown of adenosine, and prevents levels of adenosine from getting too high. Thus, mice (and people too) with low ADA levels show dangerously high blood levels of adenosine.
Like these mice, people with low levels of ADA will die of severe metabolic disturbances, unless given a replacement for the missing protein. There is a US Food and Drug Administration (FDA)-approved drug called polyethylene glycol-ADA, or PEG-ADA, that reverses the deficiency of ADA, allowing patients to survive, and mice to remain alive for experiments.
In the new study, after the researchers gave PEG-ADA to the genetically engineered mice missing ADA, to normalize adenosine levels, the drug was then withheld for two weeks. That gradually drove up levels of adenosine in the blood, compared to animals still treated with PEG-ADA or animals with a working copy of the gene that makes ADA.
In parallel, the genetically engineered animals became hypersensitive to touch and heat, suggesting that in chronic excess, adenosine causes chronic pain. The same was true in two other mouse models of chronic pain, including a model of sickle cell disease characterized by high adenosine levels, and a model of chronic inflammation where adenosine is also elevated.
The painful effects of these sustained adenosine levels were only reversed by blocking adenosine’s A2B receptor, but not by interfering with other adenosine receptors (there are four receptors in total). This showed that adenosine causes pain by acting specifically at the A2B receptor. Thus, the investigators provided one reason why adenosine could both cause and relieve pain, because in each case different adenosine receptors are involved.
From immune cells to neurons
The study went on to find that the A2B receptors were not on dorsal root ganglion neurons—the ones that relay pain signals from the body into the spinal cord. Instead, the receptors were identified on myeloid cells. Adenosine circulating in the blood attached to the receptors on the myeloid cells, resulting in a surge in blood levels of a molecular complex of two immune system proteins. This complex then activated neurons in the dorsal root ganglion to promote pain.
Sawynok agrees that the findings could help researchers reconcile the opposing effects of adenosine on pain. Because adenosine binds to the A2B receptor to a lesser degree than to its other receptors, a temporary jump in adenosine levels may leave the A2B receptor unoccupied. “But, under conditions like chronic inflammation, adenosine would reach high enough levels to recruit the A2B receptor, producing chronic pain,” she says.
Since PEG-ADA is already FDA approved and has been used to treat ADA deficiency in people for decades, Xia suggests that the drug may be a safe and effective option for reducing adenosine levels in those with chronic pain. Additionally, the study underscores the potential for developing drugs that block the binding of adenosine to its A2B receptor, which presumably would prevent the neuro-immune signaling identified in the new research. –Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman