Defining pain circuitry in health and disease.

Despite intensive investigation into its underlying mechanisms, pain remains a major unmet clinical need. A key issue limiting rational treatment design is lack of knowledge of the neuronal circuitry subserving pain and the pathophysiological changes leading to chronicity. We will harness the multidisciplinary expertise of the London Pain Consortium using the latest advances in mouse genetics, neural circuit analysis and functional imaging to tackle this important problem. An essential feature will be the integration of animal and human studies. Important goals are to: Understand the role of distinct nociceptor populations in acute and pathological pain. Map their projections to the dorsal horn of the spinal cord and understand how connectivity changes in pathophysiological pain states. Define both convergence of primary afferent inputs onto spinal projection neurons and connectivity of interneuronal populations within the dorsal horn. Determine the circuitry underlying descending pai n modulation in human and rodent and reveal how basal activity in this system may predispose to subsequent pain behaviour. Finally to establish which brain regions are causally related to pain experience using a combination of multivariate analysis in human (defining pain-specific cortical/subcortical regions) complemented by functional inactivation of these regions in rodent.