Translational Pain Discovery: BridGing MicE, Rat, aNd HUman Studies (GENUS)

Chronic pain affects one in five individuals and is estimated to cost over €500 billion annually. Chronic pain following nervous system damage, i.e. neuropathic pain, is extremely difficult to treat and only 40-50% of individuals achieve significant (>50%) pain relief from current therapies. The major impediment to developing novel and effective treatments is our lack of understanding of the underlying pathophysiology. While numerous preclinical and clinical studies have begun to explore chronic pain mechanisms, these studies are almost exclusively cross-sectional and explore only one or two biological measures. There needs to be a longitudinal, integrated and translatable approach to define the timing and interactions between biological measures during pain chronification, so that appropriate biological targets can be identified for effective treatment development. We propose a multidisciplinary, translational approach that integrates brain, nerve, sensory, behavioural, sleep, and electrophysiological measures in a novel longitudinal, clinically relevant preclinical experimental pipeline, and in individuals with chronic orofacial neuropathic pain. A suite of directly translatable techniques will establish consistency and the critical commonality of changes between species, providing a platform for translatable treatment development. The use of an orofacial neuropathic pain model will allow us to explore the entire neural pathway from peripheral nerve to brainstem to cerebral cortex.
Our diverse team of world leaders in relevant disciplines and research methods from preclinical to clinical research will address four primary aims. Aim 1 (University of Sydney): Characterize changes in the anatomy of trigeminal nerve and ganglion; brain anatomy, function and glial activity; sensory, behavioural, and sleep changes; during the development of chronic orofacial neuropathic pain in rodents. Aim 2 (University of Glasgow): Determine the response of spinal trigeminal nucleus circuits to astrocyte activation and aberrant afferent input arising from injured sensory neurons in a mouse model of orofacial neuropathic pain. Aim 3 (University of Galway): Characterise endocannabinoid system changes and functionality during the development of chronic orofacial neuropathic pain in rodents. Aim 4 (University of Sydney): Characterise nerve anatomy, brain anatomy, function, glial reactivity, sensory, behavioural and sleep  characteristics in humans with chronic orofacial neuropathic pain. This multidisciplinary research program  will define biological changes underpinning chronic orofacial pain, providing a robust platform for the identification of modifiable biological targets for drug development which will ultimately result in translation into clinical trials and practice.