Neuropathic vs. inflammatory pain in chronic pancreatitis: can unique biomarkers be identified to guide mechanistic approaches to pain treatment?

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Abstract Chronic pancreatitis (CP) is often accompanied by profoundly debilitating pain that is quite difficult to treat. There are no tools available in clinics to properly characterize the subtype of pain a patient is experiencing to choose a therapy most likely to benefit a patient’s pain symptoms. There are two peripheral mechanisms that could contribute, inflammatory pain (IP) and neuropathic pain (NP). A major driver of IP is neurogenic inflammation, inflammation resulting from increased neural activity that drives release of neuropeptides that recruit/activate immune cells. NP results from direct nerve injury (compression or lesion). Importantly, both types of pain are accompanied by unique changes in cytokine expression that can be used to identify mechanisms (IP and/or NP) contributing to a patient’s pain. The development of tools to differentiate IP and NP in the clinic could ultimately streamline CP pain management because there is evidence that certain therapies are far more efficacious for one type of pain versus the other. For example, opioids are more effective for IP while gabapentinoids are more useful for NP. This proposal is designed to compare a novel animal model in which pancreatitis pain is induced purely by IP (optogenetic) and a commonly used animal model of CP (chronic cerulein) in which pain is a result of both IP and NP. The goal is to identify cytokine profiles associated with the specific pain phenotypes and compare to legacy samples from a well-characterized clinical cohort of CP patients. We will also test whether patients show correlations between cytokine profiles and pain characteristics. The long-term plan is to use an iterative approach that uses patient data to refine animal models of CP that can then be used to develop pain-type specific therapies. In addition to incorporating new technologies (optogenetic) to the study of CP, this project will provide in depth training in handling and analyzing human data and will provide a foundation for future prospective human studies that will include survey tools specifically designed for diagnosis of inflammatory and neuropathic pain in humans with CP.