Neuropathic pain is often chronic and occurs when the pain system – brain, nervous and immune system – is not working correctly. When the pain system function well, nerves fire “danger” signals to the brain when a threat is present – when your hand is touching a stove, for example. If the brain perceives the threat as dangerous – the last time you touched the stove, your finger got badly burned – it creates pain to protect the body. 

An injury, a viral infection, a disease or cancer treatment can damage the pain system leading the nerves to misfire such danger signals and the brain to misinterpret threats. The pain persists because the brain thinks the body needs constant protection.

Opioids are the most commonly prescribed painkillers, but while they might be very effective in acute pain episodes, they are ineffective for the long-term treatment of ongoing pain and carry many severe side effects.

In a new study published today in Nature, Monash University researchers reported a new class of molecules that might be a safer and effective alternative to opioids.

“The world is in the grip of a global opioid crisis, and there is an urgent need for non-opioid drugs that are both safe and effective,” said Professor Arthur Christopoulos, dean of the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University and author of the study.

The researchers discovered that these molecules, called positive allosteric modulators (PAM), bind the adenosine A1 receptor (A1R), which has long been recognised as a promising therapeutic target for non-opioid drugs to treat neuropathic pain, with high precision in rats.

By binding to A1R, the PAM regulates the increased adenosine levels in the spinal cord of rats with neuropathic pain.

Although non-opioid analgesic agents targeting A1R had been studied before, the development of therapeutics has failed because of a lack of drug-A1R binding selectivity, which led to low efficacy and adverse effects.

The Monash researchers used high-resolution cryo-electron microscopy to solve the structure of the A1 receptor bound to either its natural activator, adenosine, and an analgesic PAM to the atomic level. That allowed them to zoom in into the mechanism underpinning allosteric drug actions, said Associate Professor Wendy Imlach, head of the Pain Mechanisms lab at Monash Biomedicine Discovery Institute and an author of the study.

Understanding the drug-A1R binding mechanism to the atomic level could help researchers design an allosteric drug that best binds A1R.

“This multidisciplinary study now provides a valuable launchpad for the next stage in our drug discovery pipeline, which will leverage structure-based insights for the design of novel non-opioid allosteric drugs to treat chronic pain successfully,” said Professor Christopoulos.

While the current best scientific evidence on chronic pain treatment includes a combination of pharmaceutical and non-pharmaceutical therapies, the lack of therapeutics has led to a global opioid crisis. If proved safe and effective in humans, this new class of analgesics could offer some relief to the millions who suffer from chronic pain across the world.