Spinal circuits underlying spreading pain

Chronic pain affects more than two fifths of the UK population, with one third of this experiencing pain that impedes their quality of life. This pain is often difficult to treat, making pain-related diseases the leading cause of disability and disease burden worldwide. One particularly challenging symptom of this pathology is spreading pain, whereby pain can spread unpredictably across multiple body regions, with no identifiable cause. Interestingly, spreading pain is a common feature of a large number of difficult to treat pain syndromes including neuropathic pain and fibromyalgia, which suggests common underlying mechanisms and there is evidence that this pain may be the result of changes in central nervous system pain circuitry and plasticity. This project aims to address this challenge of spreading pain by revealing the circuits and mechanisms that underlie its aetiology with the aim of identifying how to correct these circuits when they are maladapted. Plasticity in neural circuits occurs predominantly in two cases: in pathology, such as chronic pain states, and over the course of development, when circuits are being established. The central nervous system learns to restrict and refine its response to pain over the course of early life: infants show whole body responses to painful stimuli, or spreading nociceptive reflexes, much as is seen in spreading pain conditions. These pain responses subsequently become refined over adulthood, leading to restricted pain responses seen in the healthy adult. Studying the developmental plasticity of pain circuits from the unrefined responses seen in the infant to refined pain responses seen in the adult therefore provides a novel framework to understanding how circuit dysfunction leads to spreading pain symptoms. Combining state of the art approaches and molecular biology in transgenic mouse models, this programme aims to determine the mechanisms by which the nervous system transmits pain throughout the body and establish how spreading pain pathology can coopt these circuits, leading to widespread pain signals. To do this, we have three objectives: 1) characterise the functional development of a spinal circuit we have already identified as potential target for spreading pain; 2) identify how these cells change their connectivity following spreading pain states; and 3) test the hypothesis that dampening their activity pharmacologically and non-pharmacologically can treat spreading pain symptoms and aetiology. Understanding how pain spreads is the first step to begin to identify how to prevent this spreading. We have already identified a promising target circuit that could underlie this symptom and now seek to reveal the circuit mechanisms that underlie its pathology, which will benefit both pain sufferers and their doctors. By revealing mechanisms by which the body limits spreading pain, this work has the potential to identify molecular targets to treat this pain, either by targeting growth factors or by identifying future pharmacological and non-pharmacological therapies that may silence aberrant circuits leading to spreading pain.