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We previously demonstrated a differential expression of hyperpolarization-activated cyclic nucleotidegated cation channels, HCN2 and HCN3, in spinal and vagal afferents of the mutine jejunum.Here we explore the role of HCNs in TNBS-induced visceral hypersensitivity.Ramp distension (to 60 mmHg) of ex vivo jejunum segments from naive or TNBS-treated (50 mg/kg, 1 to 8 weeks prior to experiment) mice both evoked biphasic increases in mesenteric afferent nerve activity, reflecting the activation of low and high threshold fibers.High threshold mechanosensory responses (HTRs) were greater in TNBS-treated than in native preparations.HCN blocker ZD7288 (10 μM) inhibited the low threshold mechanosensory responses (LTRs) in naive preparations but in contrast attenuated HTRs in TNBS-treated preparations.HCN modulator cAMP (1 mM) augmented HTRs in TNBS-treated preparations and was without effect on the mechanosensory activity of nafve preparations.PKA activator Sp-cAMPS (30 μM) didnt alter the mechanosensory activity of naive or TNBS-treated preparations.With the presence of PKA inhibitor, Rp-cAMPS (12 μM), cAMP still potentiated HTRs of TNBS-treated preparations.These results together with histological data suggest that upregulation of HCN2-mediated signaling might contribute to TNBS-induced post-inflammatory small intestinal hypersensitivity.