Contributions of prefrontal-midbrain-spinal cord network dynamics to the development and maintenance of chronic neuropathic pain.

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Long term pain (chronic pain) is widely prevalent, severely impacts upon a patient's health and poses an enormous cost to our economy. Pain relieving drugs developed for acute (normal) pain are ineffective in the majority of chronic pain patients. As a result, chronic pain remains one of the greatest unmet clinical needs. Tissue damage is detected by peripheral nerves that convey pain information to the spinal cord (SC) where initial pain processing occurs. Pain information then travels to the brain for further processing in a distributed network of brain regions that produce sensory and emotional aspects of the pain experience. Recent advances in our understanding of pain indicate that alterations to pain processing in the brain, rather than in the peripheral nervous system, may form a critical locus for chronic pain disorders and, as such, a better understanding of these processes is required if we are to develop more effective treatments for patients. The pain experience is not fixed, and can be altered by a descending pain modulatory system (DPMS) that affects spinal pain processing, which in turn modulates the flow of pain information to the brain. Thus the pain experience is determined by the interplay between descending control of spinal pain processing, the resultant ascending pain information, and pain processing in the brain. In chronic pain the relationship between the magnitude of peripheral pain input and the pain experience is lost, such that pain is maintained beyond the period of tissue damage. We postulate that, in these circumstances, changes in central nervous system networks that process pain information alter the DPMS control of spinal pain processing and, in so doing, contribute to enhanced pain perception and negative emotion. Specifically, recent findings have placed particular importance on the medial prefrontal cortex (mPFC), an area of the brain involved in higher processing such as the generation and regulation of emotion, and the integration of emotional with sensory information that then feeds into conscious awareness. However, understanding of the mechanisms that underlie the role of the mPFC in pain are not fully understood and there is little information about its interactions with other brain regions that mediate effects on pain sensation and/or emotion. It is these questions our proposed investigations will address. Direct connections exist between the mPFC and the midbrain periaqueductal grey (PAG); the latter being a key orchestrator of the DPMS. We propose that mPFC-PAG connections are important pathways that mediate effects of high order PFC function on lower order pain processing in the spinal cord, and thus contribute to altered pain sensation and emotion in chronic pain. In an established animal model of chronic pain we will manipulate, and characterise, the communication within the mPFC-PAG-SC network in anaesthetised and behaving animals during the development of chronic pain. This will enable us to relate underlying mechanisms to disease symptomology. Critically, selective inactivation of mPFC-PAG connections at a number of time points will enable identification of their dynamic contributions to sensory and emotional aspects of the pain state as it progresses. The study will generate novel data about the causal relationship between alterations to high-order pain processing in the brain, its interplay with the DPMS and the enhanced experience of pain sensation and negative emotion. The findings will further our understanding of brain mechanisms that contribute to chronic pain and will support and inform studies in human patients. The long-term benefits include the identification of potential targets for effective therapeutic strategies.