Effects of IP-751, ajulemic acid, on bladder overactivity induced by bladder irritation in rats
Effects of IP-751, ajulemic acid, on bladder overactivity induced by bladder irritation in rats
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DOI：
10.1016/j.urology.2007.02.069
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发表时间：
2007-07-01
期刊：
影响因子：
2.1
通讯作者：
Yoshimura, Naoki
中科院分区：
文献类型：
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作者：
Hiragata, Shiro;Ogawa, Teruyuki;Yoshimura, Naoki
目的：阿菊酸（IP-751）是四氢大麻酚的合成类似物，四氢大麻酚是植物大麻的主要成分。据报道，IP-751具有强效抗炎活性，是一种强效镇痛剂。因此，我们研究了IP-751是否可以抑制膀胱内伤害性刺激引起的尿频。方法采用尿氨麻醉下连续膀胱术（输注速度0.04 mL/min），评价静脉注射IP-751联合或不联合大麻素-1受体拮抗剂（AM251）或大麻素-2受体拮抗剂（AM630）对正常大鼠和0.25%醋酸或环磷酰胺（CYP）腹腔内输注（150 mg/kg，膀胱造影前48 h）所致尿频大鼠膀胱功能的影响。结果正常大鼠注射10 mg/kg IP-751后，心肌收缩间期（ICI）和压力阈值升高。0.25%乙酸可诱导尿频，lcl降低，而IP-751 （10 mg/kg）可抑制lcl。在cyp治疗的大鼠中也观察到尿频，表明ICI显著减少。给药IP-751 （10 mg/kg）可显著抑制cypp诱导的尿频，如ICI的增加所证实。在IP-751之前给药AM251，而不给药AM630，三组均可阻止IP-751诱导的ICI和压力阈值升高。此外，单独给药AM251降低了cypp处理大鼠的ICIs。结论IP-751可能通过抑制膀胱传入活动，抑制膀胱痛觉刺激引起的正常膀胱活动和尿频。IP-751的这些抑制作用至少部分是由大麻素-1受体介导的。
OBJECTIVES Ajulemic acid (IP-751) is a synthetic analog of tetrahydrocannabinol, which is a major ingredient of the plant Cannabis. IP-751 reportedly shows potent anti-inflammatory activity and is a powerful analgesic agent. Thus, we examined whether IP-751 can suppress urinary frequency induced by nociceptive stimuli in the bladder. METHODS Continuous cystometry (infusion rate 0.04 mL/min) under urethane anesthesia was performed to evaluate the effect of intravenous injection of IP-751 with or without a cannabinoid-1 receptor antagonist (AM251) or a cannabinoid-2 receptor antagonist (AM630) on bladder function in normal rats and rats with urinary frequency induced by intravesical infusion with 0.25% acetic acid or cyclophosphamide (CYP) (150 mg/kg intraperitoneally, 48 hours before cystometrography). RESULTS When 10 mg/kg of IP-751 was injected in normal rats, the intercontraction interval (ICI) and pressure threshold increased. A 0.25% acetic acid infusion induced urinary frequency, as evidenced by a reduction in lCls, which were suppressed by injection of IP-751 (10 mg/kg). Urinary frequency, indicated by significant ICI reductions, was also observed in the CYP-treated rats. Administration of IP-751 (10 mg/kg) significantly suppressed CYP-induced urinary frequency, as evidenced by the increase in the ICI. When AM251, but not AM630, was administered before IP-751, the IP-751-induced increases in the ICI and pressure threshold were prevented in all three groups. In addition, administration of AM251 alone decreased the ICIs in CYP-treated rats. CONCLUSIONS IP-751 can suppress normal bladder activity and urinary frequency induced by bladder nociceptive stimuli, probably by suppression of bladder afferent activity. These inhibitory effects of IP-751 are at least in part mediated by the cannabinoid-1 receptor.