Validation of peripheral CGRP signaling as a target for the treatment of pain in chronic pancreatitis

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Abstract Chronic pancreatitis remains a common and challenging clinical syndrome. Its cardinal feature, pain, has been difficult to treat effectively despite a multitude of empirical therapeutic approaches often leading to opioid addiction. Our laboratory has been actively pursuing the molecular pathogenesis of pain in pancreatitis for over a decade. In the process, we have established highly useful and relevant rodent models of CP and gained valuable insight into the contribution of specific molecules, such as nerve growth factor, NGF and transforming growth factor beta (TGF ). These molecules appear to be acting by a common effector and our preliminary data implicates calcitonin-gene related peptide (CGRP). CGRP has been classically thought to mediate pain by its role as a neurotransmitter relaying signals to second order neurons in the spinal cord (i.e. a central role) and in the case of migraine specifically, as a potent vasodilator. Recent developments in the treatment of migraine have increased interest in anti-CGRP strategies for pain. However, many questions about the mechanisms of action remain. Our overall hypothesis in this proposal is that peripheral CGRP is a major mediator of peripheral nociceptive sensitization in chronic pancreatitis and that peripherally restricted anti-CGRP treatment is an efficient and sufficient approach for pain in this condition. We will attempt to prove this hypothesis, using a comprehensive multidisciplinary approach encompassing molecular, electrophysiological and behavioral assays. The significance of this proposal is that if will validate CGRP as a therapeutic target, opening up the possibility for new non-addictive therapies in many other chronic painful disorders that may be inflammatory in origin.