Chronic pain remains a major health care issue and presents a therapeutic challenge. A complex disorder with different dimensions, pain involves and affects neural function at various levels. And so it is not surprising that chronic pain mechanisms are still not well understood. To address this important knowledge gap we will build on our NIH-funded work (since 1999) that impacted the field by identifying neuroplasticity in the amygdala, a brain center for emotions, as a key mechanism for emotional-affective aspects of pain and pain modulation (Neugebauer, 2015). Control of amygdala activity has emerged as a desirable therapeutic goal (see Simons et al., 2014;Baliki and Apkarian, 2015), but mechanisms of abnormal excitability and amygdala output in chronic pain remain poorly understood. The proposed project will test the novel hypothesis that loss of function of small conductance calcium-activated potassium (SK) channels is a critical mechanism of uncontrolled amygdala output in neuropathic pain, which allows the abnormal persistence of pain behaviors but can be mitigated with a gene transfer based rescue strategy (AAV-mediated SK2 expression). SK channels are important regulators of neuronal excitability and hold promise as targets for neuropsychiatric and neurodegenerative disorders. More recently, they have also been implicated in the regulation of peripheral and spinal nociceptive processing. Role, regulation and therapeutic potential of SK channels in pain-related brain functions and plasticity are unknown, and the concept of SK channel dysfunction as a pain mechanism is novel. A comprehensive multidisciplinary approach will be used that integrates state-of-the-art behavioral assays, brain slice physiology, pharmacology, optogenetics, viral vector strategies, and molecular biology for mechanistic loss and gain of function analyses of SK channels in the amygdala output region (central nucleus, CeA) in the well-established spinal nerve ligation (SNL) rat model of neuropathic pain. We will use posthoc analysis of biocytin-labelled CeA neurons and a novel transgenic Crh-Cre rat model to study SK dysfunction in corticotropin releasing factor (CRF) containing CeA neurons that are known to project to brain centers for behavioral regulation (Pomrenze et al., 2015). CRF plays an important role in amygdala plasticity (Neugebauer, 2015).
Aim 1 will determine the behavioral significance of loss and rescue of SK2 channel function in neuropathic pain. Sensory thresholds, emotional responses, and anxiety- and depression-like behaviors will be measured.
Aim 2 will determine electrophysiological mechanisms of SK2 channel dysfunction and rescue in neuropathic pain, using patch-clamp recordings of CeA neurons in brain slices from behaviorally tested rats.
Aim 3 will determine molecular mechanisms of SK2 channel dysfunction and regulation, and validate gene transfer rescue, using CeA tissue from behaviorally tested rats. Successful completion of these conceptually innovative studies will significantly advance our knowledge of brain plasticity in chronic pain, provide novel targets, and validate a gene transfer rescue strategy to mitigate chronic neuropathic pain.
) A complex disorder, chronic pain is a major health care issue, but mechanisms still remain to be determined despite tremendous progress in recent years. The proposed multidisciplinary research project addresses this important knowledge gap by identifying a novel brain mechanism of chronic neuropathic pain, which is the loss of function of a certain type of potassium channels (SK channels) in the amygdala, a brain center for emotions. Successful completion of the proposed studies will yield a novel neuropathic pain mechanism and gene transfer based rescue strategy, which is highly significant from a basic science and clinical perspective hence translational.
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