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mising therapeutic target for visceral pain management in IBD. Objectives: We set out to determine signaling mechanisms deployed by PAR2 in the lumbar splanchnic nerve and whether inhibiting PAR2 with the mouse monoclonal antibody (mAb), PAR650097 (mPAR650097) provided therapeutic benefit in dextran sulfate sodium (DSS)-induced colitis. Methods: We first used ex vivo electrophysiological recordings of mouse lumbar splanchnic nerve to determine how stimulation of PAR2 alters afferent activity and the intracellular signaling mechanisms involved. Second, we used the DSS model of colitis in mice and determined how mPAR650097 altered disease activity, behavior, colon histology, and the activity of nociceptive circuitry. Results: Protease-activated receptor 2 stimulation in the colon activated visceral afferent fibers and sensitized them to mechanical and chemical stimuli. We found that endosomal internalization and protein kinase A/C signaling mediate both activating and sensitizing effects of PAR2 in visceral pain. We further show that inhibiting PAR2 with the mAb mPAR650097 reduces DSS-induced colitis severity and pain. mPAR650097 also reduced several colitis-induced pain correlates at key points along the pain-signaling axis, including peripheral nociceptive neuron signaling and sensitivity, expression of proinflammatory mediators, spinal cord signaling, and, fundamentally, behavior. Conclusion: These findings illustrate that mAb inhibition of PAR2 represents a promising approach to provide relief from abdominal pain in those living with IBD....