Nociceptive pain is a vital physiologic sensation as an early warning system that alarms the presence of potentially damaging stimuli. However, the increased sensitivity of pain after injury or tissue damage can lead to pain in the absence of any noxious stimulus. It is a major challenge to identify the mechanisms for these hypersensitivity and find a way of normalizing sensitivity without removing the warning system of pain. Here, we formulated and analyzed a mechanistic mathematical model of peripheral sensitization induced by inflammatory mediators (ATP, PGE2, etc) in hypothetical primary sensory neurons. Our model highlights the mechanisms and regulations of TRPV1 (transient receptor potential receptor vanilloid 1, which is a non-selective cationic channel responsible for a variety of stimuli, including heat, capsaicin, and low pH) by kinase activities in a calcium signaling dependent way. The signaling network was based on the experimental and computational literature and mass action kinetics were employed to formulate the rate of interaction. The complete model was composed of 771 reactions and 280 states and an evolutionary ensemble approach was used to account for parametric uncertainty. Given the complexity of the signaling networks that regulate TRPV1 activity and cytosolic calcium levels, mathematical modeling and analysis could be an important step toward the development of the next generation of molecular treatments for clinical pain.

Extended Abstract Status: Not Uploaded