U.S. Department of Health and Human Services

New Insights into Chronic Pain

Researchers have shown that molecules that activate the A3 subtype of the cellular receptor for the molecule adenosine have a potent anti-pain effect ​in two different rodent models of chronic pain. These results identify a novel class of drugs that could be used to alleviate chronic pain arising from various causes, including some forms of chemotherapy for cancer. 

“Neuropathic pain” is caused by damage to the nervous system. It often manifests as abnormal sensations, such as numbness or tingling, or as pain produced by mild stimuli that are normally not painful, such as light touching. Using a mouse model of pain sensation, the scientists observed that treatment with any one of three different molecules that selectively activate the A3 subtype of the adenosine receptor—receptor “agonists”—could alleviate neuropathic pain. Similar pain relief following treatment with A3 adenosine receptor agonists was seen in rats that had been given drugs used in chemotherapy. While these agents were effective in alleviating neuropathic pain, they had no effect on so-called “nociceptive pain,” which is pain sensed in response to a potentially harmful stimulus such as heat Notably, the administration of any one of the three A3 receptor agonists at very low doses could significantly increase the effectiveness of opiate pain relievers, such as morphine, in the mouse model. Studies of cells in culture showed that the A3 receptor agonists did not limit the ability of chemotherapeutic drugs to inhibit the growth of cancer cells, an important consideration given that patients undergoing chemotherapy sometimes develop neuropathic pain that is so debilitating that it leads them to discontinue treatment. 

Currently, the most effective treatments for chronic neuropathic pain involve opiate-derived drugs. However, their usefulness is limited because patients often develop tolerance for the drugs, necessitating higher and higher doses to achieve pain relief, and because these high doses can result in serious side effects, including the possibility of addiction. The identification of the A3 adenosine receptor signaling pathway as a potential target for treatment of chronic neuropathic pain, and the existence of highly specific, potent activators of this pathway, represents a novel approach to treatment of chronic pain. 

Chen Z, Janes K, Chen C, et al. Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J 26: 1855-1865, 2012.