Extracellular vesicle communication for nociceptive processing in acute and chronic pain

Chronic pain is a distressing condition that, unlike acute pain, remains poorly treated by currently available medicines. Chronic pain affects over a third of the world population and costs billions to the economy. Moreover, since prevalence of chronic pain increases with age, economic burden of pain will raise due to the ageing population of our society. We will study the mechanisms for chronic pain and provide novel targets for treatment of nerve pain which results from damage to the nervous system. We have made remarkable progress in our understanding of the biology of pain and can control acute pain. However, here we wish to understand what is responsible for pain to stay; we now have evidence pointing towards pain cells outside the brain in a structure that is called 'dorsal root ganglion' (DRG). Using rodent models of chronic pain, we made breakthrough discoveries, uncovering sharing of 'packaged information' between pain nerves and other cells within the DRG. This information exchange at the DRG can control pain signals before they reach spinal cord, on their way to the brain, where pain is felt. We discovered that there are miniature capsules called 'extracellular vesicles' (EVs) that shuttle from one cell to the other within the DRG and are also able to escape into the blood. We propose that there are hubs for such EVs communication in the DRG which regulate chronic pain and can be targeted to decrease pain sensitivity. We believe that EV-mediated mechanisms can be exploited to regulate pain cell activity; this, in turn, may give raise to novel approaches to both treating chronic pain and finding diagnostic markers for such pains. The fact that DRGs are outside the brain, offers additional benefits for the development of targeted therapies which are devoid of many unwanted side effects, which are notoriously associated with current analgesics (for instance, the opioids). The high-gain objective of our research programme is to elucidate this new biological phenomenon. We will characterise vesicles released by nerve cells and other cells residing in the DRG and identify those which may have escaped into the blood; we will establish their ingredients and properties to define their role in pain mechanisms and diagnostics. This objective will be achieved through four focused aims. Aim#1) To map the direction of vesicle signals between pain nerves and other cells in DRG. Aim#2) To discover properties and composition of vesicles from specific cells. Aim#3) To investigate short-, mid- and long-term effects of cell-specific vesicles and their components on pain cell activity. Aim#4) To unveil how vesicle communication changes in chronic pain conditions, identify vesicle-associated diagnostic markers of chronic pain and explore innovative vesicle-based therapeutic approaches. We will use a variety of methods to characterise DRG-derived vesicles in animal models and in blood samples obtained from people with chronic pain. We will determine the effect of such vesicles on the nerve cells that carry pain signals and measure readouts of pain when specific EV-mediated mechanisms have been blocked. In both animal and human blood samples we will assess whether vesicles are potential biomarkers of neuropathic pain. Our research will bring novel understanding of chronic pain mechanisms and will shape innovative approaches for analgesia and pain management, thus having far-reaching benefits not only for the fundamental science but, ultimately, for individuals suffering from chronic pain conditions.