Sidwell Amanda B, Girard Beatrice M, Campbell Susan E, Vizzard Margaret A
Department of Neurological SciencesThe Larner College of Medicine, University of VermontBurlingtonVermontUnited States.
Am J Physiol Renal Physiol. 2024 Sep 1;327(3):F476-F488. doi: 10.1152/ajprenal.00125.2024. Epub 2024 Jul 11.
The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown but likely multifactorial. IC/BPS symptoms can be exacerbated by psychological stress, but underlying mechanisms remain to be defined. Transient receptor potential vanilloid 1 (TRPV1) channels, expressed on nerve fibers, have been implicated in bladder dysfunction and colonic hypersensitivity with stress in rodents. Histamine/H1R activation of TRPV1 nerves increases bladder afferent fiber sensitivity to distension. TRPV1 channels are also expressed on mast cells, previously implicated in contributing to IC/BPS etiology and symptoms. We have examined the contribution of TRPV1 and mast cells to bladder dysfunction after repeated variate stress (RVS). RVS increased ( ≤ 0.05) serum and fecal corticosterone expression and induced anxiety-like behavior in wild-type (WT) mice. Intravesical instillation of the selective TRPV1 antagonist capsazepine (CPZ) rescued RVS-induced bladder dysfunction in WT mice. knockout (KO) mice did not increase voiding frequency with RVS and did not exhibit increased serum corticosterone expression despite exhibiting anxiety-like behavior. Mast cell-deficient mice (B6.Cg-) failed to demonstrate RVS-induced increased voiding frequency or serum corticosterone expression, whereas control (no stress) mast cell-deficient mice had similar functional bladder capacity to WT mice. TRPV1 protein expression was significantly increased in the rostral lumbar (L1-L2) spinal cord and dorsal root ganglia (DRG) in WT mice exposed to RVS, but no changes were observed in lumbosacral (L6-S1) spinal segments or DRG. These studies demonstrated TRPV1 and mast cell involvement in RVS-induced increased voiding frequency and suggest that TRPV1 and mast cells may be useful targets to mitigate stress-induced urinary bladder dysfunction. Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.
间质性膀胱炎/膀胱疼痛综合征（IC/BPS）的病因尚不清楚，但可能是多因素的。IC/BPS症状可因心理压力而加重，但其潜在机制仍有待明确。在啮齿动物中，表达于神经纤维上的瞬时受体电位香草酸受体1（TRPV1）通道与应激引起的膀胱功能障碍和结肠超敏反应有关。组胺/H1R激活TRPV1神经会增加膀胱传入纤维对扩张的敏感性。TRPV1通道也表达于肥大细胞上，肥大细胞先前被认为与IC/BPS的病因和症状有关。我们研究了TRPV1和肥大细胞在反复可变应激（RVS）后对膀胱功能障碍的作用。RVS增加了（≤0.05）野生型（WT）小鼠的血清和粪便皮质酮表达，并诱导了焦虑样行为。膀胱内灌注选择性TRPV1拮抗剂辣椒素（CPZ）可挽救RVS诱导的WT小鼠膀胱功能障碍。TRPV1基因敲除（KO）小鼠在RVS后排尿频率没有增加，尽管表现出焦虑样行为，但血清皮质酮表达也没有增加。肥大细胞缺陷小鼠（B6.Cg-）未能表现出RVS诱导的排尿频率增加或血清皮质酮表达增加，而对照（无应激）肥大细胞缺陷小鼠的膀胱功能容量与WT小鼠相似。暴露于RVS的WT小鼠，其腰髓头段（L1-L2）和背根神经节（DRG）中的TRPV1蛋白表达显著增加，但在腰骶段（L6-S1）脊髓节段或DRG中未观察到变化。这些研究证明了TRPV1和肥大细胞参与了RVS诱导的排尿频率增加，并表明TRPV1和肥大细胞可能是减轻应激诱导的膀胱功能障碍的有用靶点。在雌性小鼠的反复可变应激（RVS）模型中，使用药理学工具和转基因小鼠，我们证明了瞬时受体电位香草酸受体1（TRPV1）和肥大细胞导致了RVS后观察到的排尿频率增加。在应激诱导的膀胱功能障碍中，TRPV1和肥大细胞应继续被视为改善膀胱功能的靶点。
