Chronic pain often leads to severe impairment of patient's normal psychological and physical functions. Models of hyperalgesic priming, which can be established with paradigms such as the mouse incision model, provide important insight about the nature of persistent neuronal plasticity that causes these impairments. This model is also an important tool for understanding the molecular mechanisms involved in the transition from acute to chronic pain, which have largely been unstudied in the brain. There is strong evidence for memory-like mechanisms controlling hyperalgesic priming at the level of the peripheral nociceptor, but preliminary work from the sponsor laboratory suggests that plasticity in central synapses is paramount for this chronic pain state. Specifically, the central nucleus of the amygdaloid complex (CeA) is an important area in the brain responsible for mediating integration of affective and sensory components of noxious stimuli and this area displays remarkable signs of plasticity as pain becomes chronic. The proposed study will use advanced cellular reporters to identify plasticity mechanisms in the CeA as pain becomes chronic, will use inhibitors of these pathways in the CeA to test the hypothesis that chronic pain can be reversed with CeA targeting and will culminate with the use of optogenetics to manipulate circuit changes in the CeA along the continuum of development of chronic pain in the hyperalgesic priming model. Considering the strong affective component involved in this kind of pain this work will evaluate the emotional response to pain by using the Mouse Grimace Scale in addition to the assessment of the hyperalgesia and allodynia sensory responses. Concomitantly, we will evaluate the conspecific cagemate of the mouse subjected to these procedures to observe possible behavioral changes induced by this cohabitation.
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