Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
J Neurophysiol. 2013 Jul;110(2):408-17. doi: 10.1152/jn.00945.2012. Epub 2013 May 1.
Using patch-clamp techniques, we studied the plasticity of acid-sensing ion channels (ASIC) and transient receptor potential V1 (TRPV1) channel function in dorsal root ganglia (DRG) neurons retrogradely labeled from the bladder. Saline (control) or cyclophosphamide (CYP) was given intraperitoneally on days 1, 3, and 5. On day 6, lumbosacral (LS, L6-S2) or thoracolumbar (TL, T13-L2) DRG were removed and dissociated. Bladders and bladder DRG neurons from CYP-treated rats showed signs of inflammation (greater myeloperoxidase activity; lower intramuscular wall pH) and increased size (whole cell capacitance), respectively, compared with controls. Most bladder neurons (>90%) responded to protons and capsaicin. Protons produced multiphasic currents with distinct kinetics, whereas capsaicin always triggered a sustained response. The TRPV1 receptor antagonist A-425619 abolished capsaicin-triggered currents and raised the threshold of heat-activated currents. Prolonged exposure to an acidic environment (pH range: 7.2 to 6.6) inhibited proton-evoked currents, potentiated the capsaicin-evoked current, and reduced the threshold of heat-activated currents in LS and TL bladder neurons. CYP treatment reduced density but not kinetics of all current components triggered by pH 5. In contrast, CYP-treatment was associated with an increased current density in response to capsaicin in LS and TL bladder neurons. Correspondingly, heat triggered current at a significantly lower temperature in bladder neurons from CYP-treated rats compared with controls. These results reveal that cystitis differentially affects TRPV1- and ASIC-mediated currents in both bladder sensory pathways. Acidification of the bladder wall during inflammation may contribute to changes in nociceptive transmission mediated through the TRPV1 receptor, suggesting a role for TRPV1 in hypersensitivity associated with cystitis.
使用膜片钳技术，我们研究了背根神经节（DRG）神经元中酸感应离子通道（ASIC）和瞬时受体电位 V1（TRPV1）通道功能的可塑性，这些神经元是从膀胱逆行标记的。在第 1、3 和 5 天腹腔内给予生理盐水（对照）或环磷酰胺（CYP）。第 6 天，取出腰骶部（LS，L6-S2）或胸腰段（TL，T13-L2）DRG 并进行解离。与对照组相比，CYP 处理大鼠的膀胱和膀胱 DRG 神经元分别表现出炎症迹象（髓过氧化物酶活性增加；肌内壁 pH 值降低）和体积增大（全细胞电容增加）。大多数膀胱神经元（>90%）对质子和辣椒素有反应。质子产生具有不同动力学的多相电流，而辣椒素总是触发持续反应。TRPV1 受体拮抗剂 A-425619 可消除辣椒素触发的电流，并提高热激活电流的阈值。长时间暴露于酸性环境（pH 值范围：7.2 至 6.6）抑制质子诱发电流，增强辣椒素诱发电流，并降低 LS 和 TL 膀胱神经元中热激活电流的阈值。CYP 处理降低了 pH 5 触发的所有电流成分的密度，但不改变动力学。相比之下，CYP 处理与 LS 和 TL 膀胱神经元中对辣椒素的电流密度增加有关。相应地，与对照组相比，CYP 处理大鼠的膀胱神经元触发电流的温度显著降低。这些结果表明，膀胱炎以不同的方式影响两条膀胱感觉通路中的 TRPV1 和 ASIC 介导的电流。炎症期间膀胱壁酸化可能导致 TRPV1 受体介导的痛觉传递发生变化，表明 TRPV1 在与膀胱炎相关的过敏反应中起作用。
