Researchers unlock the key that could lead to the development of non-opioid painkillers to treat chronic pain

Monash researchers unlock the key that could lead to the development of non-opioid painkillers to treat chronic pain. Monash researchers have made a breakthrough discovery that could pave the way for the development of novel non-opioid painkillers (analgesics) to safely and effectively treat neuropathic pain. Neuropathic pain is a type of chronic pain that can occur if your nervous system is damaged or not working correctly, and can be caused by injury, virus infection or cancer treatment, or be a symptom or complication of conditions such as multiple sclerosis and diabetes. The new study, led by world-renowned drug researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) and the Monash Biomedicine Discovery Institute (BDI), has demonstrated a new mode of targeting the adenosine A1 receptor protein, which has long been recognised as a promising therapeutic target for non-opioid painkillers to treat neuropathic pain but for which the development of painkillers had failed due to a lack of sufficient on-target selectivity, as well as undesirable adverse effects. In the study, Monash researchers used electrophysiology and preclinical pain models to demonstrate that a particular class of molecule, called a 'positive allosteric modulator' (PAM), can provide much more selective targeting of the A1 receptor by binding to a different region of the protein than traditional, previously investigated, activators. Another breakthrough in the study was facilitated by the application of cryo electron microscopy (cryoEM) to solve the high-resolution structure of the A1 receptor bound to both its natural activator, adenosine, and an analgesic PAM, thus providing the first atomic level snapshot of where these drugs bind.