Chronic neuropathic pain affects 7-10% of the population and is often refractory to conventional pharmacological and non-pharmacological treatments. Due to limited treatment options and largely poor outcomes, the condition imposes a significant burden on affected individuals, societies and economies worldwide, and remains a major unmet clinical need. A growing body of evidence suggests that stress and negative affect (anxiety or depression) are highly prevalent in patients with chronic neuropathic pain, with comorbidity in over 50%. However, most studies have focused on how chronic neuropathic pain induces stress, anxiety and depression, and far less attention has been paid to the inverse question: how do stress and negative affect modulate the course and severity of chronic neuropathic pain? These affective factors are known to modulate pain perception and processing, but their role in driving the chronicity and exacerbation of neuropathic pain has yet to be elucidated. The overarching aim of this project is to address this critical knowledge gap using an integrative, whole-systems, translational neuroscience approach. By employing preclinical and clinical research methodologies, as well as advanced machine learning techniques, we will unravel the complex interactions between stress, emotion, and central nervous system pain processing with a focus on the descending pain modulatory system – which is known to play a key role in nociception and is hypothesized to be dysregulated in the context of stress and affective disturbances – to identify novel therapeutic strategies for improved management of chronic neuropathic pain. For this, we have assembled a highly multidisciplinary network of experts in the basic and clinical neuroscience of pain, stress and negative affect, and in advanced data analytics, across 6 countries. Our work plan is structured around 4 key objectives, each of which straddle preclinical and clinical domains. These objectives are operationalized in a cohesive and synergistic manner across 9 work packages, which encompass multi-level, systems-based characterization using animal models, human cohort studies, neuroimaging, behavioural and psychometric assessments, molecular analyses, and computational modelling. The expected project outcomes are mechanistic and translational in nature, and will deliver novel insights into the neural circuits, molecular pathways, and neurochemical mediators that underpin the exacerbation of chronic neuropathic pain by stress and negative affect. Through these efforts, this project will make a significant contribution to the field of neuropsychiatric pain research, with the potential to inform and transform clinical practice.
