New research into the adenosine receptor has uncovered a way to block a pain pathway in animal models of chronic neuropathic pain, suggesting a promising new approach to pain relief.
A team from St Louis University, the National Institutes of Health (NIH) and other academic institutions demonstrated that turning on a receptor in the brain and spinal cord counteracts chronic nerve pain in male and female rodents. The researchers, led by Daniela Salvemini, showed that activating the A3 receptor – either by its native chemical stimulator, the small molecule adenosine, or by powerful synthetic small molecule drugs invented at NIH – prevents or reverses pain that develops slowly from nerve damage, without causing analgesic tolerance or intrinsic reward.
Pain is an enormous problem and, as an unmet medical need, causes suffering and comes with a huge societal cost. The majority of current treatments cause intolerable side effects, diminish quality of life and do not sufficiently quell pain.
The most successful pharmacological approaches for the treatment of chronic pain rely on pathways involving opioid, adrenergic and calcium channels. While adenosine has shown potential for painkilling in humans, until now this particular pain pathway has not been used because the targeted receptors engaged too many side effects.
Salvemini and colleagues have demonstrated that activation of the A3 adenosine receptor subtype is key in mediating the pain-relieving effects of adenosine.
“It has long been appreciated that harnessing the potent painkilling effects of adenosine could provide a breakthrough step towards an effective treatment for chronic pain,” said Salvemini. “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 advanced clinical trials as anti-inflammatory and anticancer agents and show good safety profiles.
“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 added.
Little, J.W., Ford, A., Symons-Liguori, A.M., et al. (2014) Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain PMID: 25414036.