P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors

摘要: Activation of visceral nociceptors by inflammatory mediators contributes to hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine pyrimidine nucleotides (e.g., ATP UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation the gut, immune inflammation. Actions mediated through both ionotropic P2X receptors metabotropic P2Y receptors. receptor activation causes excitation afferents; however, impact on afferents innervating gut is unclear. Here we investigate effects stimulating isolated mouse colonic sensory neurons, nociceptor fibers human nerve-gut preparations. Additionally, role Nav1.9 mediating murine responses. The application UTP (P2Y2 P2Y4 agonist) sensitized neurons increasing action potential firing current injection depolarizing membrane potential. ADP (P2Y1, P2Y12, P2Y13 also increased firing, an effect blocked selective P2Y1 antagonist MRS2500. or stimulated afferents, including nociceptors, P2Y2 transcripts were detected 80% 56% retrogradely labeled respectively. colocalized 86% P2Y1-positive 100% P2Y2-positive consistent reduced afferent fiber responses Nav1.9−/− mice. These data demonstrate that stimulates highlighting P2Y-dependent mechanisms generation disease. SIGNIFICANCE STATEMENT Chronic a debilitating symptom pain-sensing nerves located bowel wall sensitization physiological stimuli, movements, underpins development such pain, released disease. This work addresses unstudied purine modulating via using combination electrophysiological recordings ex vivo samples detailed functional study mouse. first report identify purinergic signaling as function activation, addition established activity, results contribute our understanding