Pain, the cardinal feature of chronic pancreatitis, is a difficult, often intractable clinical problem with uncertain pathogenesis. Experimental data in somatic pain models and descriptive studies in human chronic pancreatitis implicate a role for nerve growth factor in the pathogenesis of pain in this condition. We have developed a novel validated rat model of chronic pancreatitis similar to human condition both pathologically and in the expression of NGF in the pancreas. It is associated with nociceptive sensitization, as demonstrated in vivo by hyperalgesic behavioral responses to pancreatic stimulation as well as referred (somatic) allodynia. It is also accompanied by significant changes in the excitability of pancreas-specific nociceptive neurons, as well as by increases in the expression and release of neuropeptide transmitters by them. Our model therefore is eminently suitable for a mechanistic approach to understanding the pathogenesis of pain in chronic pancreatitis. We hypothesize that this involves changes in voltage-gated sodium and potassium channels as well as TRPV1 receptors, along with increased neuropeptide expression/release and that such changes are mediated by excessive and ectopic nerve growth factor expression in the chronically inflamed pancreas. In this regard, we propose the following specific aims for this proposal: (1) to determine the ionic and molecular basis for increased excitability of pancreas-specific primary nociceptive neurons in chronic pancreatitis, (2) to determine the effects of chronic pancreatitis on expression and release of peptide neurotransmitters and their role in maintaining nociceptive sensitization, and (3) to determine the role of NGF in the pathogenesis of pain behavior and pancreas-specific sensory neuronal responses in chronic pancreatitis. We will accomplish these aims using a variety of behavioral, electrophysiological, cellular and molecular techniques. Pancreas-specific nociceptors will be identified by retrograde labeling and changes in Nav, Kv and TRPV1 channel currents will be examined by patch-clamping. Laser capture microdissection will be used to collect these neurons for analysis of mRNA expression of specific ion channel genes corresponding to observed changes in currents and protein expression will be confirmed by Western blotting and immunostaining. Similarly, the expression of NGF-dependent neuropeptides SP/NKA, CGRP and BDNF will be examined using protein and RNA analysis. Ex vivo techniques will be used to study stimulus evoked neurotransmitter release from dorsal root ganglia preparations. The contribution of these peptides to pain behavior will be examined by chronic intrathecal administration of antagonists including pharmacological and molecular (antisense) approaches. Finally, using a neutralizing antibody, we will examine the role of NGF in mediating overall pain behavior as well as specific elements identified in the first two aims. This study will provide important information on the neurobiology of chronic pancreatitis and identify potentially novel therapeutic targets.
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