Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan Pharmacological Research Laboratories, Ono Pharmaceutical Co, Ltd, Osaka 618-8585, Japan.
Pain. 2011 Jun;152(6):1373-1381. doi: 10.1016/j.pain.2011.02.019. Epub 2011 Mar 10.
Given the previous evidence for involvement of prostanoid EP1 receptors in facilitation of the bladder afferent nerve activity and micturition reflex, the present study investigated the effect of ONO-8130, a selective EP1 receptor antagonist, on cystitis-related bladder pain in mice. Cystitis in mice was produced by intraperitoneal administration of cyclophosphamide at 300mg/kg. Bladder pain-like nociceptive behavior and referred hyperalgesia were assessed in conscious mice. Phosphorylation of extracellular signal-regulated kinase (ERK) in the L6 spinal cord was determined by immunohistochemistry in anesthetized mice. Cyclophosphamide treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms, including increased bladder weight and vascular permeability and upregulation of cyclooxygenase-2 in the bladder tissue. Oral preadministration of ONO-8130 at 0.3-30 mg/kg strongly prevented both the bladder pain-like behavior and referred hyperalgesia in a dose-dependent manner, but had slight effect on the increased bladder weight and vascular permeability. Oral ONO-8130 at 30 mg/kg also reversed the established cystitis-related bladder pain. Intravesical administration of prostaglandin E2 caused prompt phosphorylation of ERK in the L6 spinal cord, an effect blocked by ONO-8130. Our findings strongly suggest that the prostaglandin E2/EP1 system participates in processing of cystitis-related bladder pain, and that EP1 antagonists including ONO-8130 are useful for treatment of bladder pain, particularly in interstitial cystitis. Prostaglandin E2 contributes to cystitis-related bladder pain via EP1 receptors in mice, indicating possible therapeutic usefulness of selective EP1 antagonists.
鉴于前列腺素 EP1 受体参与促进膀胱传入神经活动和排尿反射的先前证据，本研究调查了 ONO-8130（一种选择性 EP1 受体拮抗剂）对小鼠膀胱炎相关膀胱疼痛的影响。通过腹腔内给予 300mg/kg 的环磷酰胺在小鼠中产生膀胱炎。在清醒小鼠中评估膀胱疼痛样伤害感受行为和牵涉性痛觉过敏。在麻醉小鼠中通过免疫组织化学测定 L6 脊髓中细胞外信号调节激酶（ERK）的磷酸化。环磷酰胺处理导致膀胱疼痛样伤害感受行为和牵涉性痛觉过敏伴随着膀胱炎症状，包括膀胱重量和血管通透性增加以及膀胱组织中环氧化酶-2 的上调。口服给予 ONO-8130 0.3-30mg/kg 可强烈地以剂量依赖性方式预防膀胱疼痛样行为和牵涉性痛觉过敏，但对增加的膀胱重量和血管通透性仅有轻微作用。口服 ONO-8130 30mg/kg 还可逆转已建立的膀胱炎相关膀胱疼痛。前列腺素 E2 经膀胱内给药导致 L6 脊髓中 ERK 的迅速磷酸化，该作用被 ONO-8130 阻断。我们的发现强烈表明，前列腺素 E2/EP1 系统参与处理膀胱炎相关的膀胱疼痛，并且包括 ONO-8130 在内的 EP1 拮抗剂对于治疗膀胱疼痛是有用的，特别是在间质性膀胱炎中。前列腺素 E2 通过小鼠中的 EP1 受体参与膀胱炎相关的膀胱疼痛，表明选择性 EP1 拮抗剂可能具有治疗用途。
