Inflammatory signalling in the pain pathway: age-dependent differences in the response of neuronal ensembles to pain promoting molecules

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The dorsal horn (DH) of the spinal cord, as part of the central nervous system, is a complex network of neurons whose purpose is to respond and process afferent sensory information conveyed to it from the peripheral nervous system. The DH is a layered (laminated) structure, much like the cerebral cortex, with each lamina receiving different sensory inputs. Neurons in each lamina are also highly heterogenous, some are interneurons conveying information to the brain, others are interneurons relaying information from site to site within the DH. Recently we have shown that the systemic immune system responds differently to inflammatory stimuli in early life compared to adulthood. It has been shown, by us and others, that pain in early life is detected and processed differently by children and neonates. This is due to normal maturational changes which take place throughout the body including the brain and spinal cord. More recently other groups have shown that inflammation is able to leave a lasting "memory" in parts of the brain which can be reactivated later in life to drive further inflammation even when the initial challenge has resolved. We have also shown that the immune cells of the CNS, microglia, also respond to damage and infection differently in early life and that the molecules they secrete, the so called "inflammatory soup", in response to these challenges is different. This project will use our world-leading expertise in pain neurobiology and our unique technological tools to assess how pain processing is effected by specific inflammatory signalling at different points in the life-course. We will use a combination of in vivo and ex-vivo approaches to see how spinal networks respond to specific components of the inflammatory soup when they are applied to the spinal cord or parts of the brain which process and respond to pain. We will see how early life events can impact on the response of these brain centres to inflammation and by identifying differences in these processes in different ages identify targets for age appropriate therapies to treat and manage pain.Pain is a neurological phenomenon that affects the lives of people of all ages and regardless of sex or ethnicity. It blights the lives of people leading to social withdrawal, anxiety and depression. Central to the experience of pain is the DH and this project will break new ground in understanding how these complex networks function and ultimately lead to behavioural responses and the experienced of pain, with the long-term aim of identifying populations of neurons or signalling pathways that can be manipulated to relieve pain in people and animals.