Is There an "Off Switch" for Pain?

Researchers identified what they term an “off switch” for pain in animals, according to findings published in the journal Brain.

Led by Daniela Salvemini, PhD, from Saint Louis University in Missouri, researchers set out to identify new therapeutic treatments for chronic pain. The demonstrated that by activating the A3 adenosine receptor (A3AR), the pain relief effects of adenosine can be mediated.

“It has long been appreciated that harnessing the potent pain-killing effects of adenosine could provide a breakthrough step towards an effective treatment for chronic pain,” Salvemini said in a press release. “Our findings suggest that this goal may be achieved by focusing future work on the A3AR pathway, in particular, as its activation provides robust pain reduction across several types of pain.”

A3AR agonists are already in clinical trials being tested as anti inflammatory and anti cancer agents. So far, the trials have shown good safety profiles for the A3AR agonists.

“These studies suggest that A3AR activation by highly selective small molecular weight A3AR agonists such as MRS5698 activates a pain-reducing pathway supporting the idea that we could develop A3AR agonists as possible new therapeutics to treat chronic pain,” Salvemini said.

By turning on a receptor in the brain and spinal cord, they were able to counteract the effects in animal models of chronic nerve pain. The investigators activated the A3AR which prevented or reversed pain that developed slowly from nerve damage without causing analgesic tolerance or intrinsic rewards, unlike opioids. This can be achieved either by the native chemical stimulator of the A3 receptor, the small molecule adenosine, or by a powerful synthetic molecule drug invented at the National Institutes of Health (NIH).

“Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits,” the authors concluded in the study. “These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.”

Currently, treatment for pain comes in the form of opioids, adrenergic, and calcium channels. Before this study, investigators had not yet successfully found a way to forge this pathway because target receptors engaged many side effects.