Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS).
Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS).
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DOI：
10.1007/s12031-020-01649-x
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Vizzard MA
中科院分区：
文献类型：
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作者：
Girard BM;Campbell SE;Beca KI;Perkins M;Hsiang H;May V;Vizzard MA
压力导致膀胱功能障碍的症状恶化。然而，应激对排尿反射功能影响的潜在介质和潜在机制尚不清楚。我们的特点是PACAP（Adcyap 1）和PAC 1受体（Adcyap 1 r1）信号在应激诱导的小鼠膀胱功能障碍。我们测定了重复变量应激（RVS）或对照小鼠（仅处理）组膀胱和腰骶DRG和脊髓中PACAP和PAC 1的转录和蛋白表达。RVS组小鼠血清皮质酮和膀胱神经生长因子含量显著升高（p ≤ 0.01），体重增长显著下降（p <0.01）。PACAP和PAC 1 mRNA和蛋白在下尿路组织中的表达存在差异，在腰骶DRG和脊髓中观察到变化，但在膀胱中未观察到变化。使用清醒膀胱测压法测定，小鼠中的RVS暴露量显著（p ≤ 0.01）增加（2.5倍）排尿频率。膀胱内给予PAC 1受体拮抗剂PACAP（6-38）（300 nM）显著（p ≤ 0.01）增加了输注量（1.5-2.7倍），以引发排尿事件，并增加了收缩间期（即，排尿频率降低），但对照组小鼠的变化幅度较小。我们还使用von Frey细丝测试评估了在膀胱水平阻断PAC 1对RVS或对照小鼠组中骨盆敏感性的影响。膀胱内给予PACAP（6-38）（300 nM）可显著（p ≤ 0.01）降低RVS后的骨盆敏感性。CNS和PNS中的PACAP/受体信号传导有助于RVS后排尿频率和骨盆敏感性增加，并可能代表治疗干预的潜在靶点。
Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP (Adcyap1) and PAC1 receptor (Adcyap1r1) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcript and protein expression in the urinary bladder and lumbosacral DRG and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly (p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly (p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6–38) (300 nM), significantly (p ≤ 0.01) increased infused volume (1.5–2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6–38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention.